Sample records for identifying genetic determinants

  1. Combining Quantitative Genetic Footprinting and Trait Enrichment Analysis to Identify Fitness Determinants of a Bacterial Pathogen

    PubMed Central

    Wiles, Travis J.; Norton, J. Paul; Russell, Colin W.; Dalley, Brian K.; Fischer, Kael F.; Mulvey, Matthew A.

    2013-01-01

    Strains of Extraintestinal Pathogenic Escherichia coli (ExPEC) exhibit an array of virulence strategies and are a major cause of urinary tract infections, sepsis and meningitis. Efforts to understand ExPEC pathogenesis are challenged by the high degree of genetic and phenotypic variation that exists among isolates. Determining which virulence traits are widespread and which are strain-specific will greatly benefit the design of more effective therapies. Towards this goal, we utilized a quantitative genetic footprinting technique known as transposon insertion sequencing (Tn-seq) in conjunction with comparative pathogenomics to functionally dissect the genetic repertoire of a reference ExPEC isolate. Using Tn-seq and high-throughput zebrafish infection models, we tracked changes in the abundance of ExPEC variants within saturated transposon mutant libraries following selection within distinct host niches. Nine hundred and seventy bacterial genes (18% of the genome) were found to promote pathogen fitness in either a niche-dependent or independent manner. To identify genes with the highest therapeutic and diagnostic potential, a novel Trait Enrichment Analysis (TEA) algorithm was developed to ascertain the phylogenetic distribution of candidate genes. TEA revealed that a significant portion of the 970 genes identified by Tn-seq have homologues more often contained within the genomes of ExPEC and other known pathogens, which, as suggested by the first axiom of molecular Koch's postulates, is considered to be a key feature of true virulence determinants. Three of these Tn-seq-derived pathogen-associated genes—a transcriptional repressor, a putative metalloendopeptidase toxin and a hypothetical DNA binding protein—were deleted and shown to independently affect ExPEC fitness in zebrafish and mouse models of infection. Together, the approaches and observations reported herein provide a resource for future pathogenomics-based research and highlight the diversity of factors required by a single ExPEC isolate to survive within varying host environments. PMID:23990803

  2. Sugarcane brown rust – determining genetic variation in the pathogen and identifying potential novel sources of resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A major reason for the withdrawal of sugarcane cultivars from production in is the breakdown of resistance to brown rust caused by Puccinia melanaocephala. Genetic characterization of diversity among races of P. melanocephala would help in breeding for resistance to the pathogen. Breeding for durabl...

  3. Yeast functional screen to identify genetic determinants capable of conferring abiotic stress tolerance in Jatropha curcas

    PubMed Central

    2010-01-01

    Background Environmentally inflicted stresses such as salinity and drought limit the plant productivity both in natural and agricultural system. Increasing emphasis has been directed to molecular breeding strategies to enhance the intrinsic ability of plant to survive stress conditions. Functional screens in microorganisms with heterologous genes are a rapid, effective and powerful tool to identify stress tolerant genes in plants. Jatropha curcas (Physic nut) has been identified as a potential source of biodiesel plant. In order to improve its productivity under stress conditions to benefit commercial plantations, we initiated prospecting of novel genes expressed during stress in J. curcas that can be utilized to enhance stress tolerance ability of plant. Results To identify genes expressed during salt tolerance, cDNA expression libraries were constructed from salt-stressed roots of J. curcas, regulated under the control of the yeast GAL1 system. Using a replica based screening, twenty thousand yeast transformants were screened to identify transformants expressing heterologous gene sequences from J. curcas with enhanced ability to tolerate stress. From the screen we obtained 32 full length genes from J. curcas [GenBank accession numbers FJ489601-FJ489611, FJ619041-FJ619057 and FJ623457-FJ623460] that can confer abiotic stress tolerance. As a part of this screen, we optimized conditions for salt stress in J. curcas, defined parameters for salt stress in yeast, as well as isolated three salt hypersensitive yeast strains shs-2, shs-6 and shs-8 generated through a process of random mutagenesis, and exhibited growth retardation beyond 750 mM NaCl. Further, we demonstrated complementation of the salt sensitive phenotypes in the shs mutants, and analyzed the expression patterns for selected J. curcas genes obtained from the screen in both leaf and root tissues after salt stress treatments. Conclusions The approach described in this report provides a rapid and universal assay system for large scale screening of genes for varied abiotic stress tolerance within a short span of time. Using this screening strategy we could isolate both genes with previously known function in stress tolerance as well as novel sequences with yet unknown function in salt stress tolerance from J. curcas. The isolated genes could be over-expressed using plant expression system to generate and evaluate transgenic plants for stress tolerance as well as be used as markers for breeding salt stress tolerance in plants. PMID:20302659

  4. Genetic determinants of cognitive responses to caffeine drinking identified from a double-blind, randomized, controlled trial.

    PubMed

    Renda, Giulia; Committeri, Giorgia; Zimarino, Marco; Di Nicola, Marta; Tatasciore, Alfonso; Ruggieri, Benedetta; Ambrosini, Ettore; Viola, Vanda; Antonucci, Ivana; Stuppia, Liborio; De Caterina, Raffaele

    2015-06-01

    The widely observed between-subject variability in cognitive responses to coffee may have a genetic basis. We evaluated cognitive responses to caffeine throughout three complex cognitive tasks assessing different subdomains of attention, namely Alerting and Orienting (Categorical Search Task) and Executive Control (Stroop Task and Eriksen Flanker Task). We explored whether they are influenced by gene variants affecting adenosine metabolism or catecholamine receptors. We recruited 106 healthy male subjects who were administered, in a double-blind design, 40mL of either a decaffeinated coffee preparation plus 3mg/kg caffeine (caf) or the corresponding vehicle (decaf). The protocol was repeated 24h later with the alternative preparation. Cognitive tasks were performed between 30min and 2h after caf or decaf administration. Each subject underwent ambulatory blood pressure monitoring for 2h. Blood samples were collected for genetic evaluations and for plasma caffeine and catecholamines measures. We found a significant reduction of reaction times in two of the cognitive tasks (Categorical Search Task and Stroop Task) after caf compared with decaf, indicating that caffeine, on average, improved the attention level in the domains under investigation. We also found, however, a great inter-individual variability in the cognitive performance responses to caffeine. In exploring genetic sources for such variability, we found a relation between polymorphisms of adenosine A2A and the caffeine effects on the attentional domains of Orienting and Executive control. In conclusion, variability in the attentional response to coffee may be partly explained by genetic polymorphisms of adenosine and adrenergic receptors. PMID:25819143

  5. Identifying genetic relatives without compromising privacy

    PubMed Central

    He, Dan; Furlotte, Nicholas A.; Hormozdiari, Farhad; Joo, Jong Wha J.; Wadia, Akshay; Ostrovsky, Rafail; Sahai, Amit; Eskin, Eleazar

    2014-01-01

    The development of high-throughput genomic technologies has impacted many areas of genetic research. While many applications of these technologies focus on the discovery of genes involved in disease from population samples, applications of genomic technologies to an individual’s genome or personal genomics have recently gained much interest. One such application is the identification of relatives from genetic data. In this application, genetic information from a set of individuals is collected in a database, and each pair of individuals is compared in order to identify genetic relatives. An inherent issue that arises in the identification of relatives is privacy. In this article, we propose a method for identifying genetic relatives without compromising privacy by taking advantage of novel cryptographic techniques customized for secure and private comparison of genetic information. We demonstrate the utility of these techniques by allowing a pair of individuals to discover whether or not they are related without compromising their genetic information or revealing it to a third party. The idea is that individuals only share enough special-purpose cryptographically protected information with each other to identify whether or not they are relatives, but not enough to expose any information about their genomes. We show in HapMap and 1000 Genomes data that our method can recover first- and second-order genetic relationships and, through simulations, show that our method can identify relationships as distant as third cousins while preserving privacy. PMID:24614977

  6. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.

    PubMed

    Bajrami, Ilirjana; Frankum, Jessica R; Konde, Asha; Miller, Rowan E; Rehman, Farah L; Brough, Rachel; Campbell, James; Sims, David; Rafiq, Rumana; Hooper, Sean; Chen, Lina; Kozarewa, Iwanka; Assiotis, Ioannis; Fenwick, Kerry; Natrajan, Rachael; Lord, Christopher J; Ashworth, Alan

    2014-01-01

    Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. PMID:24240700

  7. Genetic Determinants of Urolithiasis

    PubMed Central

    Monico, Carla G.; Milliner, Dawn S.

    2012-01-01

    Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made identifying the metabolic risk factors predisposing to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors have remained less clear, in part due to the candidate gene and linkage methods available until now, which are inherently low in their power of resolution and in assessing modest effects in complex traits. Even so, this approach, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors has afforded insights into biological pathways that appear to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in childhood and adolescence than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance due to associated renal injury and other potentially treatable disease manifestations, but is often delayed due to lack of familiarity with these rare disorders. Genetic advances in polygenic and monogenic forms of urolithiasis are reviewed. PMID:22183508

  8. Genetic Marker Identified for Aggressive Bladder Cancer

    Cancer.gov

    Researchers led by Ludmila Prokunina-Olsson, Ph.D., in DCEG's Laboratory of Translational Genomics, have identified the first genetic variant associated with risk of aggressive bladder cancer. The variant, rs7257330, is in the promoter region of the CCNE1 gene, which encodes for cyclin E protein, a cell cycle regulator. This result comes from a fine-mapping analysis of data from two bladder cancer genome-wide association studies and functional studies.

  9. Development and Use of an Efficient System for Random mariner Transposon Mutagenesis To Identify Novel Genetic Determinants of Biofilm Formation in the Core Enterococcus faecalis Genome

    Microsoft Academic Search

    Christopher J. Kristich; Vy T. Nguyen; Thinh Le; Aaron M. T. Barnes; Suzanne Grindle; Gary M. Dunny

    2008-01-01

    Enterococcus faecalis is a gram-positive commensal bacterium of the gastrointestinal tract and an important opportunistic pathogen. Despite the increasing clinical significance of the enterococci, most of the genetic analysis of these organisms has focused on mobile genetic elements, and existing tools for manipulation and analysis of the core E. faecalis chromosome are limited. We are interested in a comprehensive analysis

  10. Genetic determinants of urolithiasis

    Microsoft Academic Search

    Carla G. Monico; Dawn S. Milliner

    2011-01-01

    Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria

  11. Genetic of gonadal determination.

    PubMed

    Morel, Yves; Roucher, Florence; Mallet, Delphine; Plotton, Ingrid

    2014-05-01

    Fetal sexual differentiation results from complex subsequent intracellular signaling and hormonal events that interact together in a definite timing. This process contributes to the setting of gonad determination, internal and external genitalia resulting in a female or male phenotype. Here, we review our current knowledge of gonadal determination drawing on insights from knock-out and transgenic mouse models and analysis of patients with disorders of sex development (DSD). PMID:24793987

  12. Genetic determinants of cardiac hypertrophy

    PubMed Central

    Marian, Ali J.

    2009-01-01

    Purpose of review Cardiac hypertrophy is a common phenotypic response of the heart to stimulants. It is associated with increased morbidity and mortality in various cardiovascular disorders. Genetic factors are important determinants of phenotypic expression of cardiac hypertrophy, whether in single-gene disorders or in complex traits. We focus on the molecular genetics of cardiac hypertrophy in various conditions with an emphasis on hypertrophic cardiomyopathy, a genetic paradigm of cardiac hypertrophic response. Recent findings The molecular genetic basis of cardiac hypertrophy in single-gene disorders has been partially elucidated. Likewise, the impact of genetics on the expression of cardiac hypertrophy in the general population has been demonstrated. Identification of mutations in the Z disk proteins has expanded the spectrum of causal mutations beyond the thin and thick filaments of the sarcomeres. In addition, modifier loci have been mapped and shown to impart considerable effects on the expression of cardiac hypertrophy in hypertrophic cardiomyopathy. Elucidation of the molecular genetics of sarcomeric hypertrophic cardiomyopathy and many of the phenocopies has highlighted the limitations of clinical diagnosis as a determinant of management and prognostic advice. The findings have raised the importance of diagnosis and treatment algorithms, which are based on both genotype and phenotype information. Summary Cardiac hypertrophy, regardless of the cause, is the phenotypic consequence of complex interactions between genetic and nongenetic factors. PMID:18382207

  13. Genetic approaches for identifying kinetochore components in Saccharomyces cerevisiae

    SciTech Connect

    Doheny, K.F.; Puziss, J.; Spencer, F.; Hieter, P. [John Hopkins Univ. Medical School, Baltimore, MD (United States)

    1993-12-31

    A fundamental aspect of the cell division cycle is the chromosome cycle in which each of the chromosomal DNA molecules undergoes a series of morphological changes and complex movements to ensure faithful distribution at mitosis. The gene products responsible for execution of the chromosome cycle include structural components, such as those that assemble into the mitotic spindle apparatus, and regulatory components, such as those that coordinate the ordered series of events leading to chromosome segregation within the cell cycle. We have been taking several genetic approaches to identify genes encoding determinants critical to the chromosome cycle in the budding yeast, S. cerevisiae.

  14. Genetic markers cannot determine Jewish descent

    PubMed Central

    Falk, Raphael

    2015-01-01

    Humans differentiate, classify, and discriminate: social interaction is a basic property of human Darwinian evolution. Presumably inherent differential physical as well as behavioral properties have always been criteria for identifying friend or foe. Yet, biological determinism is a relatively modern term, and scientific racism is, oddly enough, largely a consequence or a product of the Age of Enlightenment and the establishment of the notion of human equality. In recent decades ever-increasing efforts and ingenuity were invested in identifying Biblical Israelite genotypic common denominators by analysing an assortment of phenotypes, like facial patterns, blood types, diseases, DNA-sequences, and more. It becomes overwhelmingly clear that although Jews maintained detectable vertical genetic continuity along generations of socio-religious-cultural relationship, also intensive horizontal genetic relations were maintained both between Jewish communities and with the gentile surrounding. Thus, in spite of considerable consanguinity, there is no Jewish genotype to identify. PMID:25653666

  15. Genetically determined encephalopathy: Rett syndrome.

    PubMed

    Bahi-Buisson, Nadia

    2013-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females that has an incidence of 1:10000 female births, one of the most common genetic causes of severe mental retardation in females. Development is apparently normal for the first 6-18 months until fine and gross motor skills and social interaction are lost, and stereotypic hand movements develop. Progression and severity of the classical form of RTT are most variable, and there are a number of atypical variants, including congenital, early onset seizure, preserved speech variant, and "forme fruste." Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) involve most of the classical RTT patients. Mutations in cyclin-dependent kinase like 5 (CDKL5) and FoxG1 genes have been identified in the early onset seizure and the congenital variants respectively. Management of RTT is mainly symptomatic and individualized. It focuses on optimizing each patient's abilities. A dynamic multidisciplinary approach is most effective, with specific attention given to epileptic and nonepileptic paroxysmal events, as well as scoliosis, osteoporosis, and the development of spasticity, which can have a major impact on mobility, and to the development of effective communication strategies for these severely disabled individuals. PMID:23622176

  16. Genetic essentialism: on the deceptive determinism of DNA.

    PubMed

    Dar-Nimrod, Ilan; Heine, Steven J

    2011-09-01

    This article introduces the notion of genetic essentialist biases: cognitive biases associated with essentialist thinking that are elicited when people encounter arguments that genes are relevant for a behavior, condition, or social group. Learning about genetic attributions for various human conditions leads to a particular set of thoughts regarding those conditions: they are more likely to be perceived as (a) immutable and determined, (b) having a specific etiology, (c) homogeneous and discrete, and (d) natural, which can lead to the naturalistic fallacy. There are rare cases of "strong genetic explanation" when such responses to genetic attributions may be appropriate; however, people tend to overweigh genetic attributions compared with competing attributions even in cases of "weak genetic explanation," which are far more common. The authors reviewed research on people's understanding of race, gender, sexual orientation, criminality, mental illness, and obesity through a genetic essentialism lens, highlighting attitudinal, cognitive, and behavioral changes that stem from consideration of genetic attributions as bases of these categories. Scientific and media portrayals of genetic discoveries are discussed with respect to genetic essentialism, as is the role that genetic essentialism has played (and continues to play) in various public policies, legislation, scientific endeavors, and ideological movements in recent history. Last, moderating factors and interventions to reduce the magnitude of genetic essentialism, which identify promising directions to explore in order to reduce these biases, are discussed. PMID:21142350

  17. Genetic Analysis of White-tailed Deer Population Structure in Iowa: Identifying Potential Patterns and Rates of Disease Spread

    E-print Network

    Koford, Rolf R.

    Genetic Analysis of White-tailed Deer Population Structure in Iowa: Identifying Potential Patterns and Objectives: o Conduct a statewide assessment of deer population genetic structure in Iowa to determine the degree of genetic connectivity between free-ranging deer populations in Iowa and free-ranging deer

  18. Genetic determinants of hypertension: An update

    Microsoft Academic Search

    Michael Harrison; Karen Maresso; Ulrich Broeckel

    2008-01-01

    Hypertension represents a global public health burden. In addition to the rarer Mendelian forms of hypertension, classic genetic\\u000a studies have documented a significant heritable component to the most common form, essential hypertension (EH). Extensive\\u000a efforts are under way to elucidate the genetic basis of this disease. Recently, a new form of Mendelian hypertension has been\\u000a identified, pharmacogenetic association studies in

  19. Genetical genomics identifies the genetic architecture for growth and weevil resistance in spruce.

    PubMed

    Porth, Ilga; White, Richard; Jaquish, Barry; Alfaro, René; Ritland, Carol; Ritland, Kermit

    2012-01-01

    In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. PMID:22973444

  20. Genetical Genomics Identifies the Genetic Architecture for Growth and Weevil Resistance in Spruce

    PubMed Central

    Porth, Ilga; White, Richard; Jaquish, Barry; Alfaro, René; Ritland, Carol; Ritland, Kermit

    2012-01-01

    In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil (Pissodes strobi Peck.) in a pedigree population of interior spruce (Picea glauca, P. engelmannii and their hybrids) that was growing at Vernon, B.C. and segregating for weevil resistance. Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci (QTLs) for gene expression and quantitative traits. Bark tissue of apical leaders from 188 trees was assayed for gene expression using a 21.8K spruce EST-spotted microarray; the same individuals were genotyped for 384 SNP markers for the genetic map. Many of the expression QTLs (eQTL) co-localized with resistance trait QTLs. For a composite resistance phenotype of six attack and oviposition traits, 149 positional candidate genes were identified. Resistance and growth QTLs also overlapped with eQTL hotspots along the genome suggesting that: 1) genetic pleiotropy of resistance and growth traits in interior spruce was substantial, and 2) master regulatory genes were important for weevil resistance in spruce. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. PMID:22973444

  1. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    PubMed Central

    Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

  2. Identifying Common Genetic Risk Factors of Diabetic Neuropathies.

    PubMed

    Witzel, Ini-Isabée; Jelinek, Herbert F; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60-70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual's quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient's risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

  3. Genetic Determinants of Phosphate Response in Drosophila

    PubMed Central

    Bergwitz, Clemens; Wee, Mark J.; Sinha, Sumi; Huang, Joanne; DeRobertis, Charles; Mensah, Lawrence B.; Cohen, Jonathan; Friedman, Adam; Kulkarni, Meghana; Hu, Yanhui; Vinayagam, Arunachalam; Schnall-Levin, Michael; Berger, Bonnie; Perkins, Lizabeth A.; Mohr, Stephanie E.; Perrimon, Norbert

    2013-01-01

    Phosphate is required for many important cellular processes and having too little phosphate or too much can cause disease and reduce life span in humans. However, the mechanisms underlying homeostatic control of extracellular phosphate levels and cellular effects of phosphate are poorly understood. Here, we establish Drosophila melanogaster as a model system for the study of phosphate effects. We found that Drosophila larval development depends on the availability of phosphate in the medium. Conversely, life span is reduced when adult flies are cultured on high phosphate medium or when hemolymph phosphate is increased in flies with impaired Malpighian tubules. In addition, RNAi-mediated inhibition of MAPK-signaling by knockdown of Ras85D, phl/D-Raf or Dsor1/MEK affects larval development, adult life span and hemolymph phosphate, suggesting that some in vivo effects involve activation of this signaling pathway by phosphate. To identify novel genetic determinants of phosphate responses, we used Drosophila hemocyte-like cultured cells (S2R+) to perform a genome-wide RNAi screen using MAPK activation as the readout. We identified a number of candidate genes potentially important for the cellular response to phosphate. Evaluation of 51 genes in live flies revealed some that affect larval development, adult life span and hemolymph phosphate levels. PMID:23520455

  4. Genetic and proteomic approaches to identify cancer drug targets

    PubMed Central

    Roti, G; Stegmaier, K

    2012-01-01

    While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification. PMID:22166799

  5. New genetic variants identified in donkey's milk whey proteins.

    PubMed

    Herrouin, M; Mollé, D; Fauquant, J; Ballestra, F; Maubois, J L; Léonil, J

    2000-02-01

    Novel genetic variants for donkey milk lysozyme and beta-lactoglobulins I and II have been identified by the combined use of peptide mass mapping and sequencing by tandem mass spectrometry in association with database searching. The novel donkey lysozyme variant designated as lysozyme B (Mr 14,631 Da) differed in three amino acid exchanges, N49 --> D, Y52 --> S, and S61 --> N, from the previously published sequence. Three novel genetic variants for donkey beta-lactoglobulins were identified. One of them is a type beta-lactoglobulin I with three amino acid exchanges at E36 --> S, S97 --> T, and V150 --> I (beta-lactoglobulin I B, Mr 18,510 Da). The two others are type beta-lactoglobulins II with two amino acid exchanges at C110 --> P and M118--> T (beta-lactoglobulin II B, Mr 18,227 Da) and with three amino acid exchanges at D96 --> E, C110 --> P, and M118 -->T (beta-lactoglobulin II C, Mr 18,241 Da). All these primary structures are closely related to those of homologous proteins in horse milk (percent identity >96%). PMID:10945434

  6. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules

    Cancer.gov

    Published on Office of Cancer Genomics (https://ocg.cancer.gov) Home > An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules An interactive resource to identify cancer genetic and lineage dependencies

  7. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules

    Cancer.gov

    Published on Office of Cancer Genomics (http://ocg.cancer.gov) Home > An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules An interactive resource to identify cancer genetic and lineage dependencies

  8. DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics

    PubMed Central

    2014-01-01

    Background De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. Results Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. Conclusions Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders. PMID:24602502

  9. SLDR: a computational technique to identify novel genetic regulatory relationships.

    PubMed

    Yue, Zongliang; Wan, Ping; Huang, Hui; Xie, Zhan; Chen, Jake Y

    2014-01-01

    We developed a new computational technique called Step-Level Differential Response (SLDR) to identify genetic regulatory relationships. Our technique takes advantages of functional genomics data for the same species under different perturbation conditions, therefore complementary to current popular computational techniques. It can particularly identify "rare" activation/inhibition relationship events that can be difficult to find in experimental results. In SLDR, we model each candidate target gene as being controlled by N binary-state regulators that lead to ?2N observable states ("step-levels") for the target. We applied SLDR to the study of the GEO microarray data set GSE25644, which consists of 158 different mutant S. cerevisiae gene expressional profiles. For each target gene t, we first clustered ordered samples into various clusters, each approximating an observable step-level of t to screen out the "de-centric" target. Then, we ordered each gene x as a candidate regulator and aligned t to x for the purpose of examining the step-level correlations between low expression set of x (Ro) and high expression set of x (Rh) from the regulator x to t, by finding max f(t, x): |Ro-Rh| over all candidate × in the genome for each t. We therefore obtained activation and inhibitions events from different combinations of Ro and Rh. Furthermore, we developed criteria for filtering out less-confident regulators, estimated the number of regulators for each target t, and evaluated identified top-ranking regulator-target relationship. Our results can be cross-validated with the Yeast Fitness database. SLDR is also computationally efficient with o(N²) complexity. In summary, we believe SLDR can be applied to the mining of functional genomics big data for future network biology and network medicine applications. PMID:25350940

  10. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways

    Microsoft Academic Search

    Ben Lehner; Catriona Crombie; Julia Tischler; Angelo Fortunato; Andrew G Fraser

    2006-01-01

    Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test ?65,000 pairs of genes for their ability to interact genetically. We identify ?350 genetic interactions between genes functioning

  11. Method of detecting genetic deletions identified with chromosomal abnormalities

    DOEpatents

    Gray, Joe W; Pinkel, Daniel; Tkachuk, Douglas

    2013-11-26

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acids probes are typically of a complexity greater tha 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particlularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar ut genetically different diseases, and for many prognostic and diagnostic applications.

  12. Optical Constants Determined by Genetic Algorithms

    NASA Astrophysics Data System (ADS)

    Smith, David Y.; Karstens, William; Malghani, Shaheen M.

    2005-03-01

    A recent determination^a of the complex refractive index, n(?) + i ?(?), of porous silicon employed a genetic^b algorithm to fit the Fresnel equations to reflectance spectra. The procedure appeared to involve more unknowns than explicit equations available for fitting, an indeterminate problem. However, the index values obtained were reasonable, and predicted the properties of porous-silicon multilayes. We have traced this success to the interpolation formulas used for n and ? in the fitting algorithm. They amount to an implicit optical-constant model with the de facto assumption of an analytic complex index that can be approximated by a cubic polynomial. Our analysis suggests the procedure can be improved by explicitly using a more appropriate model, e.g., one that uses wave number as the expansion variable and requires that n and ? be even and odd functions of ?, respectively. ^a V. Torres-Costa, R. J. Mart'in-Palma, and J. M. Mart'inez-Duart, J. Appl. Phys. 96, 4197 (2004). ^b D. E. Goldberg, Genetic Algorithms in Search, Optimization and Machine Learning (Addison-Wesley, Reading, 1989).

  13. Genetic determinants of Venezuelan equine encephalitis emergence.

    PubMed

    Weaver, S C; Anishchenko, M; Bowen, R; Brault, A C; Estrada-Franco, J G; Fernandez, Z; Greene, I; Ortiz, D; Paessler, S; Powers, A M

    2004-01-01

    Following a period of inactivity from 1973-1991, Venezuelan equine encephalitis (VEE) reemerged during the past decade in South America and Mexico. Experimental studies of VEE virus (VEEV) infection of horses with virus strains isolated during these outbreaks have revealed considerable variation in the ability of equine-virulent, epizootic strains to exploit horses as efficient amplification hosts. Subtype IC strains from recent outbreaks in Venezuela and Colombia amplify efficiently in equines, with a correlation between maximum viremia titers and the extent of the outbreak from which the virus strain was isolated. Studies of enzootic VEEV strains that are believed to represent progenitors of the epizootic subtypes support the hypothesis that adaptation to efficient replication in equines is a major determinant of emergence and the ability of VEEV to spread geographically. Correlations between the ability of enzootic and epizootic VEEV strains to infect abundant, equiphilic mosquitoes, and the location and extent of these outbreaks, also suggest that specific adaptation to Ochlerotatus taeniorhynchus mosquitoes is a determinant of some but not all emergence events. Genetic studies imply that mutations in the E2 envelope glycoprotein gene are major determinants of adaptation to both equines and mosquito vectors. PMID:15119762

  14. Using Random Sequence Primers in the Polymerase Chain Reaction to identify Gender-Specific Genetic Markers in House Wrens

    Microsoft Academic Search

    Jeremy J. Kirchman

    1994-01-01

    In order to fully understand the biology of asexually reproducing organism, it is essential that one is able to distinguish the males from the females. In determining the gender of monomorphic birds, standard techniques including visual identification, surgery, and karyotyping are impossible or impractical for large-scale studies. A reliable gender identification method that uses genetic markers identified within the DNA

  15. Automatic Relevance Determination for Identifying Thalamic Regions Implicated in Schizophrenia

    E-print Network

    Browne, Antony

    Automatic Relevance Determination for Identifying Thalamic Regions Implicated in Schizophrenia of schizophrenia. Several studies have found the thalamus to be altered in schizophrenia, and the thalamus has and mediodorsal nucleus, underscoring the importance of examining thalamic subregions in schizophrenia. A. Browne

  16. Identifying the genetic components underlying the pathophysiology of movement disorders

    PubMed Central

    Ezquerra, Mario; Compta, Yaroslau; Marti, Maria J

    2011-01-01

    Movement disorders are a heterogeneous group of neurological conditions, few of which have been classically described as bona fide hereditary illnesses (Huntington’s chorea, for instance). Most are considered to be either sporadic or to feature varying degrees of familial aggregation (parkinsonism and dystonia). In the late twentieth century, Mendelian monogenic mutations were found for movement disorders with a clear and consistent family history. Although important, these findings apply only to very rare forms of movement disorders. Already in the twenty-first century, and taking advantage of the modern developments in genetics and molecular biology, growing attention is being paid to the complex genetics of movement disorders. The search for risk genetic variants (polymorphisms) in large cohorts and the identification of different risk variants across different populations and ethnic groups are under way, with the most relevant findings to date corresponding to recent genome wide association studies in Parkinson’s disease. These new approaches focusing on risk variants may enable the design of screening tests for early or even preclinical disease, and the identification of likely therapeutic targets. PMID:23776369

  17. Riverscape genetics identifies replicated ecological divergence across an Amazonian ecotone.

    PubMed

    Cooke, Georgina M; Landguth, Erin L; Beheregaray, Luciano B

    2014-07-01

    Ecological speciation involves the evolution of reproductive isolation and niche divergence in the absence of a physical barrier to gene flow. The process is one of the most controversial topics of the speciation debate, particularly in tropical regions. Here, we investigate ecologically based divergence across an Amazonian ecotone in the electric fish, Steatogenys elegans. We combine phylogenetics, genome scans, and population genetics with a recently developed individual-based evolutionary landscape genetics approach that incorporates selection. This framework is used to assess the relative contributions of geography and divergent natural selection between environments as biodiversity drivers. We report on two closely related and sympatric lineages that exemplify how divergent selection across a major Amazonian aquatic ecotone (i.e., between rivers with markedly different hydrochemical properties) may result in replicated ecologically mediated speciation. The results link selection across an ecological gradient with reproductive isolation and we propose that assortative mating based on water color may be driving the divergence. Divergence resulting from ecologically driven selection highlights the importance of considering environmental heterogeneity in studies of speciation in tropical regions. Furthermore, we show that framing ecological speciation in a spatially explicit evolutionary landscape genetics framework provides an important first step in exploring a wide range of the potential effects of spatial dependence in natural selection. PMID:24641091

  18. Genetic?Genomic Replication to Identify Candidate Mouse Atherosclerosis Modifier Genes

    PubMed Central

    Hsu, Jeffrey; Smith, Jonathan D.

    2013-01-01

    Objective Genetics plays a large role in atherosclerosis susceptibility in humans and mice. We attempted to confirm previously determined mouse atherosclerosis?associated loci and use bioinformatics and transcriptomics to create a catalog of candidate atherosclerosis modifier genes at these loci. Methods and Results A strain intercross was performed between AKR and DBA/2 mice on the apoE?/? background generating 166 F2 progeny. Using the phenotype log10 of the aortic root lesion area, we identified 3 suggestive atherosclerosis quantitative trait loci (Ath QTLs). When combined with our prior strain intercross, we confirmed 3 significant Ath QTLs on chromosomes 2, 15, and 17, with combined logarithm of odds scores of 5.9, 5.3, and 5.6, respectively, which each met the genome?wide 5% false discovery rate threshold. We identified all of the protein coding differences between these 2 mouse strains within the Ath QTL intervals. Microarray gene expression profiling was performed on macrophages and endothelial cells from this intercross to identify expression QTLs (eQTLs), the loci that are associated with variation in the expression levels of specific transcripts. Cross tissue eQTLs and macrophage eQTLs that replicated from a prior strain intercross were identified. These bioinformatic and eQTL analyses produced a comprehensive list of candidate genes that may be responsible for the Ath QTLs. Conclusions Replication studies for clinical traits as well as gene expression traits are worthwhile in identifying true versus false genetic associations. We have replicated 3 loci on mouse chromosomes 2, 15, and 17 that are associated with atherosclerosis. We have also identified protein coding differences and multiple replicated eQTLs, which may be useful in the identification of atherosclerosis modifier genes. PMID:23525445

  19. Integrative network-based approach identifies key genetic elements in breast invasive carcinoma

    PubMed Central

    2015-01-01

    Background Breast cancer is a genetically heterogeneous type of cancer that belongs to the most prevalent types with a high mortality rate. Treatment and prognosis of breast cancer would profit largely from a correct classification and identification of genetic key drivers and major determinants driving the tumorigenesis process. In the light of the availability of tumor genomic and epigenomic data from different sources and experiments, new integrative approaches are needed to boost the probability of identifying such genetic key drivers. We present here an integrative network-based approach that is able to associate regulatory network interactions with the development of breast carcinoma by integrating information from gene expression, DNA methylation, miRNA expression, and somatic mutation datasets. Results Our results showed strong association between regulatory elements from different data sources in terms of the mutual regulatory influence and genomic proximity. By analyzing different types of regulatory interactions, TF-gene, miRNA-mRNA, and proximity analysis of somatic variants, we identified 106 genes, 68 miRNAs, and 9 mutations that are candidate drivers of oncogenic processes in breast cancer. Moreover, we unraveled regulatory interactions among these key drivers and the other elements in the breast cancer network. Intriguingly, about one third of the identified driver genes are targeted by known anti-cancer drugs and the majority of the identified key miRNAs are implicated in cancerogenesis of multiple organs. Also, the identified driver mutations likely cause damaging effects on protein functions. The constructed gene network and the identified key drivers were compared to well-established network-based methods. Conclusion The integrated molecular analysis enabled by the presented network-based approach substantially expands our knowledge base of prospective genomic drivers of genes, miRNAs, and mutations. For a good part of the identified key drivers there exists solid evidence for involvement in the development of breast carcinomas. Our approach also unraveled the complex regulatory interactions comprising the identified key drivers. These genomic drivers could be further investigated in the wet lab as potential candidates for new drug targets. This integrative approach can be applied in a similar fashion to other cancer types, complex diseases, or for studying cellular differentiation processes. PMID:26040466

  20. Determining Relative Importance and Best Settings for Genetic Algorithm Control

    E-print Network

    Determining Relative Importance and Best Settings for Genetic Algorithm Control Parameters A. L parameters of a classic genetic algorithm (GA). We plan to use these control settings to parameterize a GA findings are robust over 60 numeric optimization problems. Keywords Genetic algorithms, optimization

  1. Identifying the status of genetic lesions in cancer clinical trial documents using machine learning

    PubMed Central

    2012-01-01

    Background Many cancer clinical trials now specify the particular status of a genetic lesion in a patient's tumor in the inclusion or exclusion criteria for trial enrollment. To facilitate search and identification of gene-associated clinical trials by potential participants and clinicians, it is important to develop automated methods to identify genetic information from narrative trial documents. Methods We developed a two-stage classification method to identify genes and genetic lesion statuses in clinical trial documents extracted from the National Cancer Institute's (NCI's) Physician Data Query (PDQ) cancer clinical trial database. The method consists of two steps: 1) to distinguish gene entities from non-gene entities such as English words; and 2) to determine whether and which genetic lesion status is associated with an identified gene entity. We developed and evaluated the performance of the method using a manually annotated data set containing 1,143 instances of the eight most frequently mentioned genes in cancer clinical trials. In addition, we applied the classifier to a real-world task of cancer trial annotation and evaluated its performance using a larger sample size (4,013 instances from 249 distinct human gene symbols detected from 250 trials). Results Our evaluation using a manually annotated data set showed that the two-stage classifier outperformed the single-stage classifier and achieved the best average accuracy of 83.7% for the eight most frequently mentioned genes when optimized feature sets were used. It also showed better generalizability when we applied the two-stage classifier trained on one set of genes to another independent gene. When a gene-neutral, two-stage classifier was applied to the real-world task of cancer trial annotation, it achieved a highest accuracy of 89.8%, demonstrating the feasibility of developing a gene-neutral classifier for this task. Conclusions We presented a machine learning-based approach to detect gene entities and the genetic lesion statuses from clinical trial documents and demonstrated its use in cancer trial annotation. Such methods would be valuable for building information retrieval tools targeting gene-associated clinical trials. PMID:23282337

  2. Large-Scale Pooled Next-Generation Sequencing of 1077 Genes to Identify Genetic Causes of Short Stature

    PubMed Central

    Wang, Sophie R.; Carmichael, Heather; Andrew, Shayne F.; Miller, Timothy C.; Moon, Jennifer E.; Derr, Michael A.; Hwa, Vivian; Hirschhorn, Joel N.

    2013-01-01

    Context: The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses. Objectives: The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology. Design: This was a prospective cohort study of subjects with short stature. Setting: The setting was a pediatric endocrinology and genetics clinics at an academic center. Patients: A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied. Intervention: Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed. Main Outcome Measures: The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined. Results: We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject. Conclusions: Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature. PMID:23771920

  3. Identifying the genetic relatedness of poa utilizing PAL-PCR

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant genomes maintain a vast array of chromosomal arrangements ranging from miniature inverted repeat tandem elements and short interspersed regions; to larger genome rearrangements containing inverted repeats. Such regions may be randomly identified by utilizing single primer PCR, also called pal...

  4. Genetic determinants of phenotypic diversity in humans

    PubMed Central

    Rahim, Nazli G; Harismendy, Olivier; Topol, Eric J; Frazer, Kelly A

    2008-01-01

    New technologies for rapidly assaying DNA sequences have revealed that the degree and nature of human genetic variation is far more complex then previously realized. These same technologies have also resulted in the identification of common genetic variants associated with more than 30 human diseases and traits. PMID:18439327

  5. Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

    ERIC Educational Resources Information Center

    Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

    2008-01-01

    The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

  6. High-Throughput Association Testing on DNA Pools to Identify Genetic Variants that Confer Susceptibility

    E-print Network

    California at Berkeley, University of

    High-Throughput Association Testing on DNA Pools to Identify Genetic Variants that Confer designed for nine candidate genetic variants in DNA repair and cell cycle/apoptotic regulatory genes, including Cyclin D1 [codon 870 splice site variant (A>G)]; BRCA1, P871L; ERCC2, K751Q; FAS À1377 (G>A); h

  7. Molecular evolutionary genetic analysis of emerging parvoviruses identified in pigs.

    PubMed

    Xiao, Chao-Ting; Halbur, Patrick G; Opriessnig, Tanja

    2013-06-01

    Parvoviruses infect a wide variety of vertebrates and arthropods and are associated with various clinical manifestations. Due to the advent of new sequence-independent PCR methods and high-throughput sequencing, several novel members of parvoviruses within the subfamily Parvovirinae were recently described. Several of these viruses do not fit in the current classification and others now have confusing or contradictory nomenclature because two or more names were used for similar or identical groups of parvoviruses or identical names were used for distinct virus groups. In this study, recently described vertebrate parvoviruses with emphasis on those identified in pigs were classified through phylogenetic analyses based on the sequences of their complete or near complete genomes, open reading frame (ORF) 1 (non-structural protein, NS1), ORF2 (capsid protein, VP1), and ORF3 (nuclear phosphoprotein, NP1) genes by using Bayesian Markov chain Monte Carlo (MCMC), Maximum Likelihood (ML) and Neighbor-Joining (NJ) methods. Among all available vertebrate parvovirus sequences, eight distinct clades were identified, corresponding to the five well established genera Parvovirus, Erythrovirus, Denpendovirus, Amdovirus and Bocavirus. Moreover, three novel clades were identified and tentatively designated as PARV4-like virus, novel clade 1 and novel clade 2. Parvoviruses in pigs were found to be distributed across four different clades including Parvovirus, Bocavirus, PARV4-like virus and the novel clade 2. All pig parvoviruses identified to date were organized based on the current analysis. The present analysis will assist to clarify the nomenclature of parvoviruses in pigs and facilitate future uniform assignment of names for new parvoviruses within the subfamily Parvovirinae. PMID:23523595

  8. Harnessing gene expression to identify the genetic basis of drug resistance Supplementary Information

    E-print Network

    Pe'er, Dana

    . There are two parts, development and testing of the predictive model and post-linkage analysis. The predictive1 Harnessing gene expression to identify the genetic basis of drug resistance Supplementary .......................................................................................................................... 2 Triangle test

  9. Researchers Identify Genetic Variations That May Increase Risk of Breast Cancer | Office of Cancer Genomics

    Cancer.gov

    Researchers have identified new genetic variations in two regions of DNA -- located on chromosomes 1 and 14 -- that may be associated with the risk of sporadic breast cancer. This study also confirms some of the previously identified associations between specific regions in the genome and breast cancer risk. The findings are reported by the Cancer Genetic Markers of Susceptibility (CGEMS) team, which includes researchers at the National Cancer Institute (NCI), part of the National Institutes of Health.

  10. NCI Launches New Initiative to Identify Genetic Risk Factors for Breast and Prostate Cancer

    Cancer.gov

    The National Cancer Institute (NCI), part of the National Institutes of Health, today launched an initiative to identify genetic alterations that make people susceptible to prostate and breast cancer, two of the most commonly diagnosed cancers in the United States. Cancer Genetic Markers of Susceptibility (CGEMS) is a three-year initiative, funded for $14 million, that will conduct scans of the entire human genome (genotyping) to identify common, inherited gene mutations that increase the risks for breast and prostate cancer.

  11. Molecular and genetic determinants of alcohol dependence.

    PubMed

    Awofala, Awoyemi A

    2013-01-01

    Alcohol dependence is a complex disorder affecting all social and ethnic groups. Although the scientific understanding of the mechanism governing this multifactorial disease is still in its infancy, understanding its biological bases, including the potential contribution of genetic factors, is key to characterizing individual's risk and developing efficacious therapeutic target to combat the disease. This review provides an overview of different approaches that are being increasingly integrated to extend our knowledge of the genetic underpinnings of alcohol dependence. PMID:24074195

  12. Population genetics identifies challenges in analyzing rare variants.

    PubMed

    Johnston, Henry Richard; Hu, Yijuan; Cutler, David J

    2015-03-01

    Geneticists have, for years, understood the nature of genome-wide association studies using common genomic variants. Recently, however, focus has shifted to the analysis of rare variants. This presents potential problems for researchers, as rare variants do not always behave in the same way common variants do, sometimes rendering decades of solid intuition moot. In this paper, we present examples of the differences between common and rare variants. We show why one must be significantly more careful about the origin of rare variants, and how failing to do so can lead to highly inflated type I error. We then explain how to best avoid such concerns with careful understanding and study design. Additionally, we demonstrate that a seemingly low error rate in next-generation sequencing can dramatically impact the false-positive rate for rare variants. This is due to the fact that rare variants are, by definition, seen infrequently, making it hard to distinguish between errors and real variants. Compounding this problem is the fact that the proportion of errors is likely to get worse, not better, with increasing sample size. One cannot simply scale their way up in order to solve this problem. Understanding these potential pitfalls is a key step in successfully identifying true associations between rare variants and diseases. PMID:25640419

  13. Identifying rarer genetic variants for common complex diseases: diseased versus neutral discovery panels

    PubMed Central

    CURTIN, K.; ILES, M. M.; CAMP, N. J.

    2009-01-01

    SUMMARY The power of genetic association studies to identify disease susceptibility alleles fundamentally relies on the variants studied. The standard approach is to determine a set of tagging-SNPs (tSNPs) that capture the majority of genomic variation in regions of interest by exploiting local correlation structures. Typically, tSNPs are selected from neutral discovery panels, collections of individuals comprehensively genotyped across a region. We investigated the implications of discovery panel design on tSNP performance in association studies using realistically-simulated sequence data. We found that discovery panels of 24 sequenced ‘neutral’ individuals (similar to NIEHS or HapMap ENCODE data) were sufficient to select well-powered tSNPs to identify common susceptibility alleles. For less common alleles (0.01–0.05 frequency) we found neutral panels of this size inadequate, particularly if low-frequency variants were removed prior to tSNP selection; superior tSNPs were found using panels of diseased individuals. Only large neutral panels (200 individuals) matched diseased panel performance in selecting well-powered tSNPs to detect both common and rarer alleles. The 1000 Genomes Project initiative may provide larger neutral panels necessary to identify rarer susceptibility alleles in association studies. In the interim, our results suggest investigators can boost power to detect such alleles by sequencing diseased individuals for tSNP selection. PMID:19132978

  14. Harnessing genomics to identify environmental determinants of heritable disease

    EPA Science Inventory

    De novo mutation is increasingly being recognized as the cause for a range of human genetic diseases and disorders. Important examples of this include inherited genetic disorders such as autism, schizophrenia, mental retardation, epilepsy, and a broad range of adverse reproductiv...

  15. A genome-wide association study to identify genetic markers associated with endometrial cancer grade

    E-print Network

    2012-04-12

    MEETING ABSTRACT Open Access A genome-wide association study to identify genetic markers associated with endometrial cancer grade T O’Mara1,2, D Duffy2, DJ Thompson3, S Ahmed4, K Ferguson2, CS Healey4, ANECS2, G Montgomery2, M Shah4, J Morrison3, PP... of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are lim- ited published studies using GWAS data to identify...

  16. Genetic determinants of cutaneous malignant melanoma in Sinclair swine.

    PubMed Central

    Blangero, J.; Tissot, R. G.; Beattie, C. W.; Amoss, M. S.

    1996-01-01

    The role of genetic factors involved in the determination of risk of cutaneous malignant melanoma (CMM) in humans remains unclear owing to genetic heterogeneity and reliance on simplistic models of inheritance. Here, we report a statistical genetic analysis of cutaneous malignant melanoma in Sinclair swine (SSCM), a unique animal model for human CMM. Using complex segregation analysis a two-locus model involving an unknown major locus and a second locus that lies within or close to the swine leukocyte antigen (SLA) complex jointly determine risk of SSCM in pedigreed animals. These loci also influence severity of affection, accounting for approximately 20% of the phenotypic variation in quantitative tumour burden. PMID:8605105

  17. Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women

    PubMed Central

    Delahanty, R.J.; Beeghly-Fadiel, A.; Long, J.R.; Gao, Y.T.; Lu, W.; Xiang, Y.B.; Zheng, Y.; Ji, B.T.; Wen, W.Q.; Cai, Q.Y.; Zheng, W.; Shu, X.O.

    2013-01-01

    STUDY QUESTION Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? SUMMARY ANSWER Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. PARTICIPANTS AND SETTING We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. MAIN RESULTS For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10?6, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ?5 months later than those in the lowest quintile. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. STUDY FUNDING/COMPETING INTERESTS This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare. PMID:23406970

  18. Unique genetic loci identified for emotional behavior in control and chronic stress conditions

    PubMed Central

    Carhuatanta, Kimberly A. K.; Shea, Chloe J. A.; Herman, James P.; Jankord, Ryan

    2014-01-01

    An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purpose of this study is to identify chromosomal regions that affect emotional behavior and are sensitive to stress exposure. We utilized the BXD behavioral genetics mouse model to identify chromosomal regions that predict fear learning and emotional behavior following exposure to a control or chronic stress environment. 62 BXD recombinant inbred strains and C57BL/6 and DBA/2 parental strains underwent behavioral testing including a classical fear conditioning paradigm and the elevated plus maze. Distinct quantitative trait loci (QTLs) were identified for emotional learning, anxiety and locomotion in control and chronic stress populations. Candidate genes, including those with already known functions in learning and stress were found to reside within the identified QTLs. Our data suggest that chronic stress history reveals novel genetic predictors of emotional behavior. PMID:25374516

  19. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    PubMed Central

    Ashbrook, David G.; Williams, Robert W.; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  20. Towards Identifying Populations that Increase the Likelihood of Success in Genetic Programming

    E-print Network

    Fernandez, Thomas

    are pertinent to studies of population dynamics. In particular, auditing is a fairly straightforward, bruteTowards Identifying Populations that Increase the Likelihood of Success in Genetic Programming Jason M. Daida The University of Michigan Center for the Study of Complex Systems and the Department

  1. Evolutionary Analyses of Staphylococcus aureus Identify Genetic Relationships between Nasal Carriage and

    E-print Network

    Parkinson, Christopher L.

    Evolutionary Analyses of Staphylococcus aureus Identify Genetic Relationships between Nasal of America Abstract Nasal carriage of Staphylococcus aureus has long been hypothesized to be a major vector, Stinnett JW, Muthukrishnan G, Parkinson CL, Cole AM (2011) Evolutionary Analyses of Staphylococcus aureus

  2. Genetic Determinants of Pubertal Timing in the General Population

    PubMed Central

    Gajdos, Zofia K.Z.; Henderson, Katherine D.; Hirschhorn, Joel N.

    2010-01-01

    Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population. PMID:20144687

  3. Genetic determinants of reutericyclin biosynthesis in Lactobacillus reuteri.

    PubMed

    Lin, Xiaoxi B; Lohans, Christopher T; Duar, Rebbeca; Zheng, Jinshui; Vederas, John C; Walter, Jens; Gänzle, Michael

    2015-03-01

    Reutericyclin is a unique antimicrobial tetramic acid produced by some strains of Lactobacillus reuteri. This study aimed to identify the genetic determinants of reutericyclin biosynthesis. Comparisons of the genomes of reutericyclin-producing L. reuteri strains with those of non-reutericyclin-producing strains identified a genomic island of 14 open reading frames (ORFs) including genes coding for a nonribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), homologues of PhlA, PhlB, and PhlC, and putative transport and regulatory proteins. The protein encoded by rtcN is composed of a condensation domain, an adenylation domain likely specific for d-leucine, and a thiolation domain. rtcK codes for a PKS that is composed of a ketosynthase domain, an acyl-carrier protein domain, and a thioesterase domain. The products of rtcA, rtcB, and rtcC are homologous to the diacetylphloroglucinol-biosynthetic proteins PhlABC and may acetylate the tetramic acid moiety produced by RtcN and RtcK, forming reutericyclin. Deletion of rtcN or rtcABC in L. reuteri TMW1.656 abrogated reutericyclin production but did not affect resistance to reutericyclin. Genes coding for transport and regulatory proteins could be deleted only in the reutericyclin-negative L. reuteri strain TMW1.656?rtcN, and these deletions eliminated reutericyclin resistance. The genomic analyses suggest that the reutericyclin genomic island was horizontally acquired from an unknown source during a unique event. The combination of PhlABC homologues with both an NRPS and a PKS has also been identified in the lactic acid bacteria Streptococcus mutans and Lactobacillus plantarum, suggesting that the genes in these organisms and those in L. reuteri share an evolutionary origin. PMID:25576609

  4. Genetic Determinants of Responses to Selenium Supplementation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In a cohort of healthy adults (106 M, 155 W) in eastern North Dakota, we determined the relationships of five biomarkers of selenium (Se) status (plasma Se, serum selenoprotein P [SePP], plasma glutathione peroxidase [GPX3] activity, buccal cell Se, urine Se) to genotype for four selenoproteins (cyt...

  5. Developmental and Genetic Determinants of Leadership Role Occupancy Among Women

    Microsoft Academic Search

    Richard D. Arvey; Zhen Zhang; Bruce J. Avolio; Robert F. Krueger

    2007-01-01

    The genetic and developmental influences on leadership role occupancy were investigated using a sample of 178 fraternal and 214 identical female twins. Two general developmental factors were identified, one involving formal work experiences and the other a family experiences factor hypothesized to influence whether women move into positions of leadership in organizations. Results indicated that 32% of the variance in

  6. Genetic determinants of the metabolic syndrome

    Microsoft Academic Search

    Michèle M. Sale; Jonathan Woods; Barry I. Freedman

    2006-01-01

    Complex interactions between inherited factors and the environment determine an individual’s susceptibility to type 2 diabetes\\u000a mellitus and related syndromes. Insulin resistance, obesity, hypertension, and hyperlipidemia frequently precede the development\\u000a of frank diabetes and aggregate in families. Several genome-wide scans have recently been performed in families with this\\u000a constellation of findings, called the “metabolic syndrome.” These analyses strongly support an

  7. MPGN II--genetically determined by defective complement regulation?

    PubMed

    Licht, Christoph; Schlötzer-Schrehardt, Ursula; Kirschfink, Michael; Zipfel, Peter F; Hoppe, Bernd

    2007-01-01

    MPGN II is a rare disease which is characterized by complement containing deposits within the GBM. The disease is characterized by functional impairment of the GBM causing progressive loss of renal function eventually resulting in end stage renal disease. It now becomes evident that in addition to C3NeF, which inhibits the inactivation of the alternative C3 convertase C3bBb, different genetically determined factors are also involved in the pathogenesis of MPGN II. These factors though different from C3NeF also result in defective complement regulation acting either through separate pathways or synergistically with C3NeF. Following the finding of MPGN II in Factor H deficient animals, patients with MPGN II were identified presenting with an activated complement system caused by Factor H deficiency. Factor H gene mutations result in a lack of plasma Factor H or in a functional defect of Factor H protein. Loss of Factor H function can also be caused by inactivating Factor H autoantibodies, C3 mutations preventing interaction between C3 and Factor H, or autoantibodies against C3. Identification of patients with MPGN II caused by defective complement control may allow treatment by replacement of the missing factor via plasma infusion, thus possibly preventing or at least delaying disease progress. PMID:17024390

  8. New de novo Genetic Mutations in Schizophrenia Identified http://scicasts.com/bio/2039-disease-processes/4882-new-de-novo-genetic-mutations-in-schizophrenia-identified[11/12/2012 12:43:09 PM

    E-print Network

    performed whole-exome sequencing on 231 patient "trios" from the United States and South Africa. Each trioNew de novo Genetic Mutations in Schizophrenia Identified http://scicasts.com/bio/2039-disease-processes/4882-new-de-novo-genetic-mutations-in-schizophrenia-identified[11/12/2012 12:43:09 PM] Image: Dr. Bin

  9. New de novo genetic mutations in schizophrenia identified -Mental Wellness Today http://www.mentalwellnesstoday.com/...hizophrenia/schizophrenia-articles/16-shizophrenia-research/194-new-de-novo-genetic-mutations-in-schizophrenia-identified[10/10/2012 4:3

    E-print Network

    New de novo genetic mutations in schizophrenia identified - Mental Wellness Today http://www.mentalwellnesstoday.com/...hizophrenia/schizophrenia-articles/16-shizophrenia-research/194-new-de-novo-genetic-mutations-in-schizophrenia-identified[10/10/2012 4 Articles Heart attack more likely in those with schizophrenia: Study Faith Can Help Mental Health Outcomes

  10. Spatial and temporal determinants of genetic structure in Gentianella bohemica

    PubMed Central

    Königer, Julia; Rebernig, Carolin A; Brabec, Ji?í; Kiehl, Kathrin; Greimler, Josef

    2012-01-01

    The biennial plant Gentianella bohemica is a subendemic of the Bohemian Massif, where it occurs in seminatural grasslands. It has become rare in recent decades as a result of profound changes in land use. Using amplified fragment length polymorphisms (AFLP) fingerprint data, we investigated the genetic structure within and among populations of G. bohemica in Bavaria, the Czech Republic, and the Austrian border region. The aim of our study was (1) to analyze the genetic structure among populations and to discuss these findings in the context of present and historical patterns of connectivity and isolation of populations, (2) to analyze genetic structure among consecutive generations (cohorts of two consecutive years), and (3) to investigate relationships between intrapopulational diversity and effective population size (Ne) as well as plant traits. (1) The German populations were strongly isolated from each other (pairwise FST= 0.29–0.60) and from all other populations (FST= 0.24–0.49). We found a pattern of near panmixis among the latter (FST= 0.15–0.35) with geographical distance explaining only 8% of the genetic variance. These results were congruent with a principal coordinate analysis (PCoA) and analysis using STRUCTURE to identify genetically coherent groups. These findings are in line with the strong physical barrier and historical constraints, resulting in separation of the German populations from the others. (2) We found pronounced genetic differences between consecutive cohorts of the German populations (pairwise FST= 0.23 and 0.31), which can be explained by local population history (land use, disturbance). (3) Genetic diversity within populations (Shannon index, HSh) was significantly correlated with Ne (RS= 0.733) and reflected a loss of diversity due to several demographic bottlenecks. Overall, we found that the genetic structure in G. bohemica is strongly influenced by historical periods of high connectivity and isolation as well as by marked demographic fluctuations in declining populations. PMID:22822440

  11. Methods to determine DNA structural alterations and genetic instability

    PubMed Central

    Wang, Guliang; Zhao, Junhua; Vasquez, Karen M.

    2009-01-01

    Chromosomal DNA is a dynamic structure that can adopt a variety of non-canonical (i.e. non-B) conformations. In this regard, at least ten different forms of non-B DNA conformations have been identified, and many of them have been found to be mutagenic, and associated with human disease development. Despite the importance of non-B DNA structures in genetic instability and DNA metabolic processes, mechanisms remain largely undefined. The purpose of this review is to summarize current methodologies that are used to address questions in the field of non-B DNA structure-induced genetic instability. Advantages and disadvantages of each method will be discussed. A focused effort to further elucidate the mechanisms of non-B DNA-induced genetic instability will lead to a better understanding of how these structure-forming sequences contribute to the development of human disease. PMID:19245837

  12. Genetic Screens to Identify Elements of the Decapentaplegic Signaling Pathway in Drosophila

    PubMed Central

    Raftery, L. A.; Twombly, V.; Wharton, K.; Gelbart, W. M.

    1995-01-01

    Pathways for regulation of signaling by transforming growth factor-? family members are poorly understood at present. The best genetically characterized member of this family is encoded by the Drosophila gene decapentaplegic (dpp), which is required for multiple events during fly development. We describe here the results of screens for genes required to maximize dpp signaling during embryonic dorsal-ventral patterning. Screens for genetic interactions in the zygote have identified an allele of tolloid, as well as two novel alleles of screw, a gene recently shown to encode another bone morphogenetic protein-like polypeptide. Both genes are required for patterning the dorsalmost tissues of the embryo. Screens for dpp interactions with maternally expressed genes have identified loss of function mutations in Mothers against dpp and Medea. These mutations are homozygous pupal lethal, engendering gut defects and severely reduced imaginal disks, reminiscent of dpp mutant phenotypes arising during other dpp-dependent developmental events. Genetic interaction phenotypes are consistent with reduction of dpp activity in the early embryo and in the imaginal disks. We propose that the novel screw mutations identified here titrate out some component(s) of the dpp signaling pathway. We propose that Mad and Medea encode rate-limiting components integral to dpp pathways throughout development. PMID:7705627

  13. A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key

    E-print Network

    Sabatini, David M.

    A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter) Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosyla- tion, protein palmitoylation, ganglioside enters cells. Here, we identify in an unbiased genetic screen a transporter of the major facilitator

  14. Results of the BRD CAP project: progress toward identifying genetic markers associated with BRD susceptibility.

    PubMed

    Van Eenennaam, Alison; Neibergs, Holly; Seabury, Christopher; Taylor, Jeremy; Wang, Zeping; Scraggs, Erik; Schnabel, Robert D; Decker, Jared; Wojtowicz, Andrzej; Aly, Sharif; Davis, Jessica; Blanchard, Patricia; Crossley, Beate; Rossitto, Paul; Lehenbauer, Terry; Hagevoort, Robert; Chavez, Erik; Neibergs, J Shannon; Womack, James E

    2014-12-01

    The Bovine Respiratory Disease Coordinated Agricultural Project (BRD CAP) is a 5-year project funded by the United States Department of Agriculture (USDA), with an overriding objective to use the tools of modern genomics to identify cattle that are less susceptible to BRD. To do this, two large genome wide association studies (GWAS) were conducted using a case:control design on preweaned Holstein dairy heifers and beef feedlot cattle. A health scoring system was used to identify BRD cases and controls. Heritability estimates for BRD susceptibility ranged from 19 to 21% in dairy calves to 29.2% in beef cattle when using numerical scores as a semi-quantitative definition of BRD. A GWAS analysis conducted on the dairy calf data showed that single nucleotide polymorphism (SNP) effects explained 20% of the variation in BRD incidence and 17-20% of the variation in clinical signs. These results represent a preliminary analysis of ongoing work to identify loci associated with BRD. Future work includes validation of the chromosomal regions and SNPs that have been identified as important for BRD susceptibility, fine mapping of chromosomes to identify causal SNPs, and integration of predictive markers for BRD susceptibility into genetic tests and national cattle genetic evaluations. PMID:25384903

  15. Determining the effective dimensionality of the genetic variance-covariance matrix.

    PubMed

    Hine, Emma; Blows, Mark W

    2006-06-01

    Determining the dimensionality of G provides an important perspective on the genetic basis of a multivariate suite of traits. Since the introduction of Fisher's geometric model, the number of genetically independent traits underlying a set of functionally related phenotypic traits has been recognized as an important factor influencing the response to selection. Here, we show how the effective dimensionality of G can be established, using a method for the determination of the dimensionality of the effect space from a multivariate general linear model introduced by Amemiya (1985). We compare this approach with two other available methods, factor-analytic modeling and bootstrapping, using a half-sib experiment that estimated G for eight cuticular hydrocarbons of Drosophila serrata. In our example, eight pheromone traits were shown to be adequately represented by only two underlying genetic dimensions by Amemiya's approach and factor-analytic modeling of the covariance structure at the sire level. In contrast, bootstrapping identified four dimensions with significant genetic variance. A simulation study indicated that while the performance of Amemiya's method was more sensitive to power constraints, it performed as well or better than factor-analytic modeling in correctly identifying the original genetic dimensions at moderate to high levels of heritability. The bootstrap approach consistently overestimated the number of dimensions in all cases and performed less well than Amemiya's method at subspace recovery. PMID:16547106

  16. Quantiles Regression Approach to Identifying the Determinant of Breastfeeding Duration

    NASA Astrophysics Data System (ADS)

    Mahdiyah; Norsiah Mohamed, Wan; Ibrahim, Kamarulzaman

    In this study, quantiles regression approach is applied to the data of Malaysian Family Life Survey (MFLS), to identify factors which are significantly related to the different conditional quantiles of the breastfeeding duration. It is known that the classical linear regression methods are based on minimizing residual sum of squared, but quantiles regression use a mechanism which are based on the conditional median function and the full range of other conditional quantile functions. Overall, it is found that the period of breastfeeding is significantly related to place of living, religion and total number of children in the family.

  17. Genetic background determines metabolic phenotypes in the mouse.

    PubMed

    Champy, Marie-France; Selloum, Mohammed; Zeitler, Valérie; Caradec, Claudia; Jung, Barbara; Rousseau, Stéphane; Pouilly, Laurent; Sorg, Tania; Auwerx, Johan

    2008-05-01

    To evaluate the contribution of genetic background to phenotypic variation, we compared a large range of biochemical and metabolic parameters at different ages of four inbred mice strains, C57BL/6J, 129SvPas, C3HeB/FeJ, and Balb/cByJ. Our results demonstrate that important metabolic, hematologic, and biochemical differences exist between these different inbred strains. Most of these differences are gender independent and are maintained or accentuated throughout life. It is therefore imperative that the genetic background is carefully defined in phenotypic studies. Our results also argue that certain backgrounds are more suited to study a given physiologic phenomenon, as distinct mouse strains have a different propensity to develop particular biochemical, hematologic, and metabolic abnormalities. These genetic differences can furthermore be exploited to identify new genes/proteins that contribute to phenotypic abnormalities. The choice of the genetic background in which to generate and analyze genetically engineered mutant mice is important as it is, together with environmental factors, one of the most important contributors to the variability of phenotypic results. PMID:18392653

  18. Positive genetic interactors of HMG2 identify a new set of genetic perturbations for improving sesquiterpene production in Saccharomyces cerevisiae

    PubMed Central

    2012-01-01

    Background Terpenoids and isoprenoids are an important class of natural products, which includes currently used drugs, high value bioactive and industrial compounds, and fuel candidates. Due to their industrial application, there is increasing interest in the development of S. cerevisiae strains capable of producing high levels of terpenoids. Results Aiming to identify new gene targets which can be manipulated to increase sesquiterpene production, a set of HMG2 positive genetic interactors were assessed as single and digenic heterozygous deletions in the presence or absence of stable HMG2(K6R) overexpression. Upon single allele deletion, most genes examined led to increased sesquiterpene production in yeast cells. Tandem heterozygous deletion of a set of three genes, the ubiquitin ligases ubc7 and ssm4/doa10, and the ER resident protein pho86, led to an 11-fold increase in caryophyllene yields (125 mg/L in shake flasks) compared to cells lacking these modifications. The effect of the heterozygous deletions appears to be due to Hmg1p and Hmg2p stabilization. Conclusion Heterozygous deletions cause significant reductions in protein levels but do not lead to growth impediments frequently seen in haploid strains. By exploiting desirable haploinsufficiencies in yeast, we identified a new set of genes that can be disrupted in tandem and cause significant stabilization of Hmgp and a substantial increase in sesquiterpene production. The approach presented here allows new genetic perturbations to be compiled on yeast cell factory strains without negatively impacting cell growth and viability. PMID:23259547

  19. Methods to determine DNA structural alterations and genetic instability

    Microsoft Academic Search

    Guliang Wang; Junhua Zhao; Karen M. Vasquez

    2009-01-01

    Chromosomal DNA is a dynamic structure that can adopt a variety of non-canonical (i.e., non-B) conformations. In this regard, at least 10 different forms of non-B DNA conformations have been identified; many of them have been found to be mutagenic, and associated with human disease development. Despite the importance of non-B DNA structures in genetic instability and DNA metabolic processes,

  20. Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility

    PubMed Central

    Das, Swapan Kumar; Sharma, Neeraj Kumar

    2014-01-01

    Type 2 diabetes (T2D) is a common metabolic disorder which is caused by multiple genetic perturbations affecting different biological pathways. Identifying genetic factors modulating the susceptibility of this complex heterogeneous metabolic phenotype in different ethnic and racial groups remains challenging. Despite recent success, the functional role of the T2D susceptibility variants implicated by genome-wide association studies (GWAS) remains largely unknown. Genetic dissection of transcript abundance or expression quantitative trait (eQTL) analysis unravels the genomic architecture of regulatory variants. Availability of eQTL information from tissues relevant for glucose homeostasis in humans opens a new avenue to prioritize GWAS-implicated variants that may be involved in triggering a causal chain of events leading to T2D. In this article, we review the progress made in the field of eQTL research and knowledge gained from those studies in understanding transcription regulatory mechanisms in human subjects. We highlight several novel approaches that can integrate eQTL analysis with multiple layers of biological information to identify ethnic-specific causal variants and gene-environment interactions relevant to T2D pathogenesis. Finally, we discuss how the eQTL analysis mediated search for “missing heritability” may lead us to novel biological and molecular mechanisms involved in susceptibility to T2D. PMID:24748924

  1. A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes.

    PubMed

    Suzuki, Oscar T; Frick, Amber; Parks, Bethany B; Trask, O Joseph; Butz, Natasha; Steffy, Brian; Chan, Emmanuel; Scoville, David K; Healy, Eric; Benton, Cristina; McQuaid, Patricia E; Thomas, Russell S; Wiltshire, Tim

    2014-01-01

    New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways. PMID:25221565

  2. Identifying the determinants of response to MDM2 inhibition.

    PubMed

    Saiki, Anne Y; Caenepeel, Sean; Cosgrove, Elissa; Su, Cheng; Boedigheimer, Michael; Oliner, Jonathan D

    2015-04-10

    Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published. PMID:25730903

  3. Mapping the Genetic Determinants of Pathogenicity and Plaque Phenotype in Swine Vesicular Disease Virus

    Microsoft Academic Search

    TORU KANNO; DAVID MACKAY; TORU INOUE; GINETTE WILSDEN; MAKOTO YAMAKAWA; REIKO YAMAZOE; SHIGEO YAMAGUCHI; JUNSUKE SHIRAI; PAUL KITCHING; YOSUKE MURAKAMI

    1999-01-01

    A series of recombinant viruses were constructed using infectious cDNA clones of the virulent J1'73 (large plaque phenotype) and the avirulent H\\/3'76 (small plaque phenotype) strains of swine vesicular disease virus to identify the genetic determinants of pathogenicity and plaque phenotype. Both traits could be mapped to the region between nucleotides (nt) 2233 and 3368 corresponding to the C terminus

  4. A new system identification approach to identify genetic variants in sequencing studies for a binary phenotype.

    PubMed

    Kang, Guolian; Bi, Wenjian; Zhao, Yanlong; Zhang, Ji-Feng; Yang, Jun J; Xu, Heng; Loh, Mignon L; Hunger, Stephen P; Relling, Mary V; Pounds, Stanley; Cheng, Cheng

    2014-01-01

    We propose in this paper a set-valued (SV) system model, which is a generalized form of logistic (LG) and Probit (Probit) regression, to be considered as a method for discovering genetic variants, especially rare genetic variants in next-generation sequencing studies, for a binary phenotype. We propose a new SV system identification method to estimate all underlying key system parameters for the Probit model and compare it with the LG model in the setting of genetic association studies. Across an extensive series of simulation studies, the Probit method maintained type I error control and had similar or greater power than the LG method, which is robust to different distributions of noise: logistic, normal, or t distributions. Additionally, the Probit association parameter estimate was 2.7-46.8-fold less variable than the LG log-odds ratio association parameter estimate. Less variability in the association parameter estimate translates to greater power and robustness across the spectrum of minor allele frequencies (MAFs), and these advantages are the most pronounced for rare variants. For instance, in a simulation that generated data from an additive logistic model with an odds ratio of 7.4 for a rare single nucleotide polymorphism with a MAF of 0.005 and a sample size of 2,300, the Probit method had 60% power whereas the LG method had 25% power at the ? = 10(-6) level. Consistent with these simulation results, the set of variants identified by the LG method was a subset of those identified by the Probit method in two example analyses. Thus, we suggest the Probit method may be a competitive alternative to the LG method in genetic association studies such as candidate gene, genome-wide, or next-generation sequencing studies for a binary phenotype. PMID:25096228

  5. A screening method to identify genetic variation in root growth response to a salinity gradient.

    PubMed

    Rahnama, Afrasyab; Munns, Rana; Poustini, Kazem; Watt, Michelle

    2011-01-01

    Salinity as well as drought are increasing problems in agriculture. Durum wheat (Triticum turgidum L. ssp. durum Desf.) is relatively salt sensitive compared with bread wheat (Triticum aestivum L.), and yields poorly on saline soil. Field studies indicate that roots of durum wheat do not proliferate as extensively as bread wheat in saline soil. In order to look for genetic diversity in root growth within durum wheat, a screening method was developed to identify genetic variation in rates of root growth in a saline solution gradient similar to that found in many saline fields. Seedlings were grown in rolls of germination paper in plastic tubes 37 cm tall, with a gradient of salt concentration increasing towards the bottom of the tubes which contained from 50-200 mM NaCl with complete nutrients. Seedlings were grown in the light to the two leaf stage, and transpiration and evaporation were minimized so that the salinity gradient was maintained. An NaCl concentration of 150 mM at the bottom was found suitable to identify genetic variation. This corresponds to a level of salinity in the field that reduces shoot growth by 50% or more. The screen inhibited seminal axile root length more than branch root length in three out of four genotypes, highlighting changes in root system architecture caused by a saline gradient that is genotype dependent. This method can be extended to other species to identify variation in root elongation in response to gradients in salt, nutrients, or toxic elements. PMID:21118825

  6. A simulation study of the genetic regulatory hierarchy for butterfly eyespot focus determination.

    PubMed

    Evans, Travis M; Marcus, Jeffrey M

    2006-01-01

    The color patterns on the wings of butterflies have been an important model system in evolutionary developmental biology. Two types of models have been used to study these patterns. The first type of model employs computational techniques and generalized mechanisms of pattern formation to make predictions about how color patterns will vary as parameters of the model are changed. These generalized mechanisms include diffusion gradient, reaction-diffusion, lateral inhibition, and threshold responses. The second type of model uses known genetic interactions from Drosophila melanogaster and patterns of candidate gene expression in one of several butterfly species (most often Junonia (Precis) coenia or Bicyclus anynana) to propose specific genetic regulatory hierarchies that appear to be involved in color pattern formation. This study combines these two approaches using computational techniques to test proposed genetic regulatory hierarchies for the determination of butterfly eyespot foci (also known as border ocelli foci). Two computer programs, STELLA 8.1 and Delphi 2.0, were used to simulate the determination of eyespot foci. Both programs revealed weaknesses in a genetic model previously proposed for eyespot focus determination. On the basis of these simulations, we propose two revised models for eyespot focus determination and identify components of the genetic regulatory hierarchy that are particularly sensitive to changes in model parameter values. These components may play a key role in the evolution of butterfly eyespots. Simulations like these may be useful tools for the study of other evolutionary developmental model systems and reveal similar sensitive components of the relevant genetic regulatory hierarchies. PMID:16686638

  7. Use of a twin dataset to identify AMD-related visual patterns controlled by genetic factors

    NASA Astrophysics Data System (ADS)

    Quellec, Gwénolé; Abràmoff, Michael D.; Russell, Stephen R.

    2010-03-01

    The mapping of genotype to the phenotype of age-related macular degeneration (AMD) is expected to improve the diagnosis and treatment of the disease in a near future. In this study, we focused on the first step to discover this mapping: we identified visual patterns related to AMD which seem to be controlled by genetic factors, without explicitly relating them to the genes. For this purpose, we used a dataset of eye fundus photographs from 74 twin pairs, either monozygotic twins, who have the same genotype, or dizygotic twins, whose genes responsible for AMD are less likely to be identical. If we are able to differentiate monozygotic twins from dizygotic twins, based on a given visual pattern, then this pattern is likely to be controlled by genetic factors. The main visible consequence of AMD is the apparition of drusen between the retinal pigment epithelium and Bruch's membrane. We developed two automated drusen detectors based on the wavelet transform: a shape-based detector for hard drusen, and a texture- and color- based detector for soft drusen. Forty visual features were evaluated at the location of the automatically detected drusen. These features characterize the texture, the shape, the color, the spatial distribution, or the amount of drusen. A distance measure between twin pairs was defined for each visual feature; a smaller distance should be measured between monozygotic twins for visual features controlled by genetic factors. The predictions of several visual features (75.7% accuracy) are comparable or better than the predictions of human experts.

  8. Genetic caste determination in Pogonomyrmex harvester ants imposes costs during colony founding

    E-print Network

    Alvarez, Nadir

    Genetic caste determination in Pogonomyrmex harvester ants imposes costs during colony founding T with marked morphological differences between the queen and worker castes. These differences usually result). However, genetically determined caste differentiation has been recently discovered in two populations

  9. Using multilevel models to identify drivers of landscape-genetic structure among management areas.

    PubMed

    Dudaniec, Rachael Y; Rhodes, Jonathan R; Worthington Wilmer, Jessica; Lyons, Mitchell; Lee, Kristen E; McAlpine, Clive A; Carrick, Frank N

    2013-07-01

    Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape-genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land-cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation-by-resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale-dependent management actions. PMID:23730800

  10. Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine

    PubMed Central

    Davis, N A; Crowe, J E; Pajewski, N M; McKinney, B A

    2010-01-01

    The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene–gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene–gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor ? (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response. PMID:20613780

  11. Identifying flavor preference subgroups. Genetic basis and related eating behavior traits.

    PubMed

    Törnwall, Outi; Silventoinen, Karri; Hiekkalinna, Tero; Perola, Markus; Tuorila, Hely; Kaprio, Jaakko

    2014-04-01

    Subgroups based on flavor preferences were identified and their genetic and behavior related characteristics investigated using extensive data from 331 Finnish twins (21-25years, 146 men) including 47 monozygotic (MZ) and 93 dizygotic (DZ) pairs, and 51 twin individuals. The subgroup identification (hierarchical and K-means clustering) was based on liking responses to food names representing sour, umami, and spicy flavor qualities. Furthermore, sensory tests were conducted, a questionnaire on food likes completed, and various eating behavior related traits measured with validated scales. Sensory data included intensity ratings of PROP (6-n-propylthiouracil-impregnated filter paper), hedonic and intensity responses to sourness (orange juice with and without added citric acid, 0.42%), pungency (strawberry jelly with and without added capsaicin 0.00013%) and umami ('mouthfeel flavor' taste solution). Ratings of liking of 41 general food names were categorized into salty-and-fatty, sweet-and-fatty, fruits and vegetables and fish foods. Subgroup differences (complex samples procedure) and the genetics underlying the subgroups (structural equation modeling) were investigated. Of the resulting two groups (basic, n=140, adventurous n=152; non-grouped n=39), the adventurous expressed higher liking for sour and spicy foods, and had more tolerance for capsaicin burn in the sensory-hedonic test. The adventurous were also less food neophobic (25.9±9.1 vs. 32.5±10.6, respectively) and expressed higher liking for fruits and vegetables compared to the basic group. Genetic effects were shown to underlie the subgroups (heritability 72%, CI: 36-92%). Linkage analysis for 27 candidate gene regions revealed suggestively that being adventurous is linked to TAS1R1 and PKD1L3 genes. These results indicate that food neophobia and genetic differences may form a barrier through which individual flavor preferences are generated. PMID:24361469

  12. Genetic and environmental determinants of malaria parasite virulence in mosquitoes.

    PubMed Central

    Ferguson, H M; Read, A F

    2002-01-01

    Models of malaria epidemiology and evolution are frequently based on the assumption that vector-parasitic associations are benign. Implicit in this assumption is the supposition that all Plasmodium parasites have an equal and neutral effect on vector survival, and thus that there is no parasite genetic variation for vector virulence. While some data support the assumption of avirulence, there has been no examination of the impact of parasite genetic diversity. We conducted a laboratory study with the rodent malaria parasite, Plasmodium chabaudi and the vector, Anopheles stephensi, to determine whether mosquito mortality varied with parasite genotype (CR and ER clones), infection diversity (single versus mixed genotype) and nutrient availability. Vector mortality varied significantly between parasite genotypes, but the rank order of virulence depended on environmental conditions. In standard conditions, mixed genotype infections were the most virulent but when glucose water was limited, mortality was highest in mosquitoes infected with CR. These genotype-by-environment interactions were repeatable across two experiments and could not be explained by variation in anaemia, gametocytaemia, blood meal size, mosquito body size, infection rate or oocyst burden. Variation in the genetic and environmental determinants of virulence may explain conflicting accounts of Plasmodium pathogenicity to mosquitoes in the malaria literature. PMID:12065037

  13. Application of Genetic Algorithms To Identify Optimal Groundwater Monitoring Well Locations in 3D

    NASA Astrophysics Data System (ADS)

    Abdeh-Kolahchi, A.; Satish, M.; Datta, B.

    2004-12-01

    Monitoring groundwater aquifers for possible sources of contamination is an important aspect of water resources management. The design of monitoring networks has been one of the key concerns of researchers who deal with the management of groundwater quality. Optimal monitoring network design can be beneficial to both groundwater simulation as well as optimization modeling. This paper discusses the applications of various optimization techniques from traditional to global methods for the solution of groundwater monitoring network and groundwater quality management problems. In order to solve optimization-based groundwater management models, various mathematical programming techniques such as linear/nonlinear programming, mixed-integer programming, differential dynamic programming, stochastic programming, as well as global optimization methods such as Genetic Algorithms are used by researchers to obtain optimal solutions for groundwater management. The resent study will also discuss a state of the art method, which combines simulation of groundwater flow and transport with genetic algorithm optimization. In order to ensure that the optimal management strategy is physically acceptable, a simulation model is necessary to simulate the system behavior. The simulation model basically provides solutions that satisfy the equations governing the relevant processes in the system. Thus the simulation models can be used for checking the feasibility of a management strategy. Once the optimization model is formulated, a suitable mathematical programming technique such as genetic algorithm is applied to obtain the optimal solution. This approach not only accounts for the complex and non-linear behavior of the groundwater system, but also identifies the best monitoring strategy under a specific objective function with several constraints. The solution identifies the best location of monitoring wells.

  14. NCI Launches New Initiative to Identify Genetic Risk Factors for Breast and Prostate Cancer | Office of Cancer Genomics

    Cancer.gov

    The National Cancer Institute (NCI), part of the National Institutes of Health, today launched an initiative to identify genetic alterations that make people susceptible to prostate and breast cancer, two of the most commonly diagnosed cancers in the United States. Cancer Genetic Markers of Susceptibility (CGEMS) is a three-year initiative, funded for $14 million, that will conduct scans of the entire human genome (genotyping) to identify common, inherited gene mutations that increase the risks for breast and prostate cancer.

  15. Promoter Hypermethylation Profiling Identifies Subtypes of Head and Neck Cancer with Distinct Viral, Environmental, Genetic and Survival Characteristics

    PubMed Central

    Choudhury, Javed Hussain; Ghosh, Sankar Kumar

    2015-01-01

    Background Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status. Methodology The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively. Principal Findings Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival. Conclusions Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC. PMID:26098903

  16. Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection

    E-print Network

    2013-01-01

    of Salmonella typhimurium virulence gene expression bySalmonella typhimurium invasion gene expression and virulencegene deletion mutants to identify novel colonization and virulence determinants of Salmonella

  17. Genetic determinants for methotrexate response in juvenile idiopathic arthritis

    PubMed Central

    Pastore, Serena; Stocco, Gabriele; Favretto, Diego; De Iudicibus, Sara; Taddio, Andrea; d’Adamo, Pio; Malusà, Noelia; Addobbati, Riccardo; Decorti, Giuliana; Lepore, Loredana; Ventura, Alessandro

    2015-01-01

    Juvenile idiopathic arthritis (JIAs) is the most common chronic rheumatic disease of childhood and is an important cause of disability. The folic acid analog methotrexate is the first choice disease-modifying anti-rheumatic drug in this disease, however, 35–45% of patients fail to respond. Molecular elements, such as variants in genes of pharmacological relevance, influencing response to methotrexate in JIA, would be important to individualize treatment strategies. Several studies have evaluated the effects of candidate genetic variants in the complex pathway of genes involved in methotrexate pharmacodynamics and pharmacokinetics, however, results are still contrasting and no definitive genetic marker of methotrexate response useful for the clinician to tailor therapy of children with JIA has been identified. Recently, genome-wide approaches have been applied, identifying new potential biological processes involved in methotrexate response in JIA such as TGF-beta signaling and calcium channels. If these genomic results are properly validated and integrated with innovative analyses comprising deep sequencing, epigenetics, and pharmacokinetics, they will greatly contribute to personalize therapy with methotrexate in children with JIA. PMID:25852556

  18. The quest for genetic determinants of human longevity: challenges and insights

    PubMed Central

    Christensen, Kaare; Johnson, Thomas E.; Vaupel, James W.

    2009-01-01

    Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress. PMID:16708071

  19. Genetic Determinism and the Innate-Acquired Distinction in Medicine

    PubMed Central

    2009-01-01

    This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate–acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate–acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate–acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature–nurture debates. PMID:20234831

  20. Hierarchical Genetic Algorithm Approach to Determine Pulse Sequences in NMR

    E-print Network

    Ashok Ajoy; Anil Kumar

    2009-12-04

    We develop a new class of genetic algorithm that computationally determines efficient pulse sequences to implement a quantum gate U in a three-qubit system. The method is shown to be quite general, and the same algorithm can be used to derive efficient sequences for a variety of target matrices. We demonstrate this by implementing the inversion-on-equality gate efficiently when the spin-spin coupling constants $J_{12}=J_{23}=J$ and $J_{13}=0$. We also propose new pulse sequences to implement the Parity gate and Fanout gate, which are about 50% more efficient than the previous best efforts. Moreover, these sequences are shown to require significantly less RF power for their implementation. The proposed algorithm introduces several new features in the conventional genetic algorithm framework. We use matrices instead of linear chains, and the columns of these matrices have a well defined hierarchy. The algorithm is a genetic algorithm coupled to a fast local optimizer, and is hence a hybrid GA. It shows fast convergence, and running on a MATLAB platform takes about 20 minutes on a standard personal computer to derive efficient pulse sequences for any target 8X8 matrix $U$.

  1. Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species ( Thamnophis elegans and Thamnophis sirtalis )

    Microsoft Academic Search

    MOLLIE K. M ANIER; STEVAN J. A RNOLD

    Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same envi- ronment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis , to determine if shared landscape and biology imposed similar

  2. Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia.

    PubMed

    Poulain, Stéphanie; Roumier, Christophe; Galiègue-Zouitina, Sylvie; Daudignon, Agnès; Herbaux, Charles; Aiijou, Rachid; Lainelle, Amélie; Broucqsault, Natacha; Bertrand, Elisabeth; Manier, Salomon; Renneville, Aline; Soenen, Valérie; Tricot, Sabine; Roche-Lestienne, Catherine; Duthilleul, Patrick; Preudhomme, Claude; Quesnel, Bruno; Morel, Pierre; Leleu, Xavier

    2013-11-01

    SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in 31 WM with paired samples. Methylation status and mutation were analyzed on target genes. A total of 61 genetic aberrations were observed, 58 CNA (33 gains, 25 losses) in 58% of patients and CN-LOH in 6% of patients. The CNA were widely distributed throughout the genome, including 12 recurrent regions and identified new cryptic clonal chromosomal lesions that were mapped. Gene set expression analysis demonstrated a relationship between either deletion 6q or gain of chromosome 4 and alteration of gene expression profiling. We then studied methylation status and sought for mutations in altered regions on target genes. We observed methylation of DLEU7 on chromosome 13 in all patients (n?=?12) with WM, and mutations of CD79B/CD79A genes (17q region), a key component of the BCR pathway, in 15% of cases. Most importantly, higher frequency of ?3 CNA was observed in symptomatic WM. In conclusion, this study expands the view of the genomic complexity of WM, especially in symptomatic WM, including a potentially new mechanism of gene dysfunction, acquired uniparental disomy/CN-LOH. Finally, we have identified new potential target genes in WM, such as DLEU7 and CD79A/B. PMID:23861223

  3. Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs.

    PubMed

    Graham, Neil S; Hammond, John P; Lysenko, Artem; Mayes, Sean; O Lochlainn, Seosamh; Blasco, Bego; Bowen, Helen C; Rawlings, Chris J; Rios, Juan J; Welham, Susan; Carion, Pierre W C; Dupuy, Lionel X; King, Graham J; White, Philip J; Broadley, Martin R

    2014-07-01

    Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca(2+) transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca(2+) transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization. PMID:25082855

  4. Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma.

    PubMed

    Mann, Michael B; Black, Michael A; Jones, Devin J; Ward, Jerrold M; Yew, Christopher Chin Kuan; Newberg, Justin Y; Dupuy, Adam J; Rust, Alistair G; Bosenberg, Marcus W; McMahon, Martin; Print, Cristin G; Copeland, Neal G; Jenkins, Nancy A

    2015-05-01

    Although nearly half of human melanomas harbor oncogenic BRAF(V600E) mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf(V600E) mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF(V600E) melanoma and discover new genes with potential clinical importance in human melanoma. PMID:25848750

  5. Identifying genetic diversity of avirulence genes in Leptosphaeria maculans using whole genome sequencing.

    PubMed

    Zander, Manuel; Patel, Dhwani A; Van de Wouw, Angela; Lai, Kaitao; Lorenc, Michal T; Campbell, Emma; Hayward, Alice; Edwards, David; Raman, Harsh; Batley, Jacqueline

    2013-08-01

    Next generation sequencing technology allows rapid re-sequencing of individuals, as well as the discovery of single nucleotide polymorphisms (SNPs), for genomic diversity and evolutionary analyses. By sequencing two isolates of the fungal plant pathogen Leptosphaeria maculans, the causal agent of blackleg disease in Brassica crops, we have generated a resource of over 76 million sequence reads aligned to the reference genome. We identified over 21,000 SNPs with an overall SNP frequency of one SNP every 2,065 bp. Sequence validation of a selection of these SNPs in additional isolates collected throughout Australia indicates a high degree of polymorphism in the Australian population. In preliminary phylogenetic analysis, isolates from Western Australia clustered together and those collected from Brassica juncea stubble were identical. These SNPs provide a novel marker resource to study the genetic diversity of this pathogen. We demonstrate that re-sequencing provides a method of validating previously characterised SNPs and analysing differences in important genes, such as the disease related avirulence genes of L. maculans. Understanding the genetic characteristics of this devastating pathogen is vital in developing long-term solutions to managing blackleg disease in Brassica crops. PMID:23793572

  6. Can novel genetic analyses help to identify low-dispersal marine invasive species?

    PubMed Central

    Teske, Peter R; Sandoval-Castillo, Jonathan; Waters, Jonathan M; Beheregaray, Luciano B

    2014-01-01

    Genetic methods can be a powerful tool to resolve the native versus introduced status of populations whose taxonomy and biogeography are poorly understood. The genetic study of introduced species is presently dominated by analyses that identify signatures of recent colonization by means of summary statistics. Unfortunately, such approaches cannot be used in low-dispersal species, in which recently established populations originating from elsewhere in the species' native range also experience periods of low population size because they are founded by few individuals. We tested whether coalescent-based molecular analyses that provide detailed information about demographic history supported the hypothesis that a sea squirt whose distribution is centered on Tasmania was recently introduced to mainland Australia and New Zealand through human activities. Methods comparing trends in population size (Bayesian Skyline Plots and Approximate Bayesian Computation) were no more informative than summary statistics, likely because of recent intra-Tasmanian dispersal. However, IMa2 estimates of divergence between putatively native and introduced populations provided information at a temporal scale suitable to differentiate between recent (potentially anthropogenic) introductions and ancient divergence, and indicated that all three non-Tasmanian populations were founded during the period of European settlement. While this approach can be affected by inaccurate molecular dating, it has considerable (albeit largely unexplored) potential to corroborate nongenetic information in species with limited dispersal capabilities. PMID:25165524

  7. Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand.

    PubMed

    Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

    2014-11-15

    Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients' lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

  8. Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

    SciTech Connect

    Kleiman, Norman Jay [Columbia University] [Columbia University

    2013-11-30

    The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.

  9. Genetic and environmental determinants of risk for cholangiocarcinoma in Thailand

    PubMed Central

    Miwa, Masanao; Honjo, Satoshi; You, Gyokukou; Tanaka, Masakazu; Uchida, Kazuhiko; Srivatanakul, Petcharin; Khuhaprema, Thiravud; Loilome, Watcharin; Techasen, Anchalee; Wongkham, Chaisiri; Limpaiboon, Temduang; Yongvanit, Puangrat; Wongkham, Sopit

    2014-01-01

    Cholangiocarcinoma (CCA) is a difficult cancer to diagnose in the early stage and to treat by curative resection. The incidence of CCA in the northeast of Thailand is the highest in the world. To make progress in detecting a high risk group and in the prevention and detection of CCA, we have been analyzing the risk factors for CCA. Although liver fluke infection is known to be a risk factor, there are patients who are not infected with the liver fluke and not all people infected with the liver fluke will suffer from the disease. Therefore, it is of the utmost importance to analyze the risk factors and the mechanism to prevent the disease and also to detect the disease in its early stage to save patients’ lives. Through collaboration among Thai and Japanese researchers, we analyzed the genetic and environmental determinants of risks for CCA. Also, we have been trying to develop methods to detect the disease in a non-invasive way. Without repeating findings reported in various reviews on CCA, we will first discuss the environmental and genetic determinants of the risks for CCA. Second, we will discuss the properties of CCA, including the etiological agents and the mechanism of cholangiocarcinogenesis, and finally, we will discuss future approaches to prevent and cure CCA from the standpoint of evidence-based medicine. We will discuss these points by including the data from our laboratories. We would like to emphasize the importance of the genetic data, especially whole genome approaches, to understand the properties of CCA, to find a high risk population for CCA and to develop effective preventative methods to stop the carcinogenic steps toward CCA in the near future. In addition, it is of the upmost importance to develop a non-invasive, specific and sensitive method to detect CCA in its early stage for the application of modern medical approaches to help patients with CCA. PMID:25401000

  10. A proton current drives action potentials in genetically identified sour taste cells

    PubMed Central

    Chang, Rui B.; Waters, Hang; Liman, Emily R.

    2010-01-01

    Five tastes have been identified, each of which is transduced by a separate set of taste cells. Of these sour, which is associated with acid stimuli, is the least understood. Genetic ablation experiments have established that sour is detected by a subset of taste cells that express the TRP channel PKD2L1 and its partner PKD1L3, however the mechanisms by which this subset of cells detects acids remain unclear. Previous efforts to understand sour taste transduction have been hindered because sour responsive cells represent only a small fraction of cells in a taste bud, and numerous ion channels with no role in sour sensing are sensitive to acidic pH. To identify acid-sensitive conductances unique to sour cells, we created genetically modified mice in which sour cells were marked by expression of YFP under the control of the PKD2L1 promoter. To measure responses to sour stimuli we developed a method in which suction electrode recording is combined with UV photolysis of NPE-caged proton. Using these methods, we report that responses to sour stimuli are not mediated by Na+ permeable channels as previously thought, but instead are mediated by a proton conductance specific to PKD2L1-expressing taste cells. This conductance is sufficient to drive action potential firing in response to acid stimuli, is enriched in the apical membrane of PKD2L1-expressing taste cells and is not affected by targeted deletion of the PKD1L3 gene. We conclude that, during sour transduction, protons enter through an apical proton conductance to directly depolarize the taste cell membrane. PMID:21098668

  11. Integrated Analysis of Genetic and Proteomic Data Identifies Biomarkers Associated with Adverse Events Following Smallpox Vaccination

    PubMed Central

    Reif, David M.; Motsinger-Reif, Alison A.; McKinney, Brett A.; Rock, Michael T.; Crowe, James E.; Moore, Jason H.

    2009-01-01

    Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying development of adverse events (AEs) in patients following smallpox vaccination. Since vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In the current study, we examined 1442 genetic variables (SNPs) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests™ (RF) method to filter out the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well-suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein, and protein-protein interactions we hypothesize to be involved in development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines ICAM-1 (CD54), IL-10, and CSF-3 (G-CSF), and a genetic polymorphism in the cyokine gene IL4. The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study demonstrates the utility of RF for such analytical tasks, and both enhances and reinforces our working model of AE development following smallpox vaccination. PMID:18923431

  12. A New Restriction Fragment Length Polymorphism from Cryptosporidium parvum Identifies Genetically Heterogeneous Parasite Populations and Genotypic Changes Following Transmission from Bovine to Human Hosts

    Microsoft Academic Search

    MARGARETHA CARRAWAY; SAUL TZIPORI; GIOVANNI WIDMER

    1997-01-01

    Length and restriction site polymorphism within a 2.8-kb threonine-rich open reading frame from Crypto- sporidium parvum was identified and used to determine the genotypes of isolates from calves and humans. In agreement with observations of other genetic loci, all calf isolates were identical at this locus. In contrast, human isolates showed two profiles, one found exclusively in humans and one

  13. Genetic Differences in Transcript Responses to Low-Dose Ionizing Radiation Identify Tissue Functions Associated with Breast Cancer Susceptibility

    PubMed Central

    Snijders, Antoine M.; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W.; Wyrobek, Andrew J.

    2012-01-01

    High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGF?-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p?=?0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer. PMID:23077491

  14. What Determines Blood Vessel Structure? Genetic Prespecification vs. Hemodynamics

    NSDL National Science Digital Library

    Elizabeth A. V. Jones (College de France)

    2006-10-01

    Vascular network remodeling, angiogenesis, and arteriogenesis play an important role in the pathophysiology of ischemic cardiovascular diseases and cancer. Based on recent studies of vascular network development in the embryo, several novel aspects to angiogenesis have been identified as crucial to generate a functional vascular network. These aspects include specification of arterial and venous identity in vessels and network patterning. In early embryogenesis, vessel identity and positioning are genetically hardwired and involve neural guidance genes expressed in the vascular system. We demonstrated that, during later stages of embryogenesis, blood flow plays a crucial role in regulating vessel identity and network remodeling. The flow-evoked remodeling process is dynamic and involves a high degree of vessel plasticity. The open question in the field is how genetically predetermined processes in vessel identity and patterning balance with the contribution of blood flow in shaping a functional vascular architecture. Although blood flow is essential, it remains unclear to what extent flow is able to act on the developing cardiovascular system. There is significant evidence that mechanical forces created by flowing blood are biologically active within the embryo and that the level of mechanical forces and the type of flow patterns present in the embryo are able to affect gene expression. Here, we highlight the pivotal role for blood flow and physical forces in shaping the cardiovascular system.

  15. Identifying genetic traces of historical expansions: Phoenician footprints in the Mediterranean.

    PubMed

    Zalloua, Pierre A; Platt, Daniel E; El Sibai, Mirvat; Khalife, Jade; Makhoul, Nadine; Haber, Marc; Xue, Yali; Izaabel, Hassan; Bosch, Elena; Adams, Susan M; Arroyo, Eduardo; López-Parra, Ana María; Aler, Mercedes; Picornell, Antònia; Ramon, Misericordia; Jobling, Mark A; Comas, David; Bertranpetit, Jaume; Wells, R Spencer; Tyler-Smith, Chris

    2008-11-01

    The Phoenicians were the dominant traders in the Mediterranean Sea two thousand to three thousand years ago and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then they disappeared from history. We wished to identify their male genetic traces in modern populations. Therefore, we chose Phoenician-influenced sites on the basis of well-documented historical records and collected new Y-chromosomal data from 1330 men from six such sites, as well as comparative data from the literature. We then developed an analytical strategy to distinguish between lineages specifically associated with the Phoenicians and those spread by geographically similar but historically distinct events, such as the Neolithic, Greek, and Jewish expansions. This involved comparing historically documented Phoenician sites with neighboring non-Phoenician sites for the identification of weak but systematic signatures shared by the Phoenician sites that could not readily be explained by chance or by other expansions. From these comparisons, we found that haplogroup J2, in general, and six Y-STR haplotypes, in particular, exhibited a Phoenician signature that contributed > 6% to the modern Phoenician-influenced populations examined. Our methodology can be applied to any historically documented expansion in which contact and noncontact sites can be identified. PMID:18976729

  16. Identifying Genetic Traces of Historical Expansions: Phoenician Footprints in the Mediterranean

    PubMed Central

    Zalloua, Pierre A.; Platt, Daniel E.; El Sibai, Mirvat; Khalife, Jade; Makhoul, Nadine; Haber, Marc; Xue, Yali; Izaabel, Hassan; Bosch, Elena; Adams, Susan M.; Arroyo, Eduardo; López-Parra, Ana María; Aler, Mercedes; Picornell, Antònia; Ramon, Misericordia; Jobling, Mark A.; Comas, David; Bertranpetit, Jaume; Wells, R. Spencer; Tyler-Smith, Chris

    2008-01-01

    The Phoenicians were the dominant traders in the Mediterranean Sea two thousand to three thousand years ago and expanded from their homeland in the Levant to establish colonies and trading posts throughout the Mediterranean, but then they disappeared from history. We wished to identify their male genetic traces in modern populations. Therefore, we chose Phoenician-influenced sites on the basis of well-documented historical records and collected new Y-chromosomal data from 1330 men from six such sites, as well as comparative data from the literature. We then developed an analytical strategy to distinguish between lineages specifically associated with the Phoenicians and those spread by geographically similar but historically distinct events, such as the Neolithic, Greek, and Jewish expansions. This involved comparing historically documented Phoenician sites with neighboring non-Phoenician sites for the identification of weak but systematic signatures shared by the Phoenician sites that could not readily be explained by chance or by other expansions. From these comparisons, we found that haplogroup J2, in general, and six Y-STR haplotypes, in particular, exhibited a Phoenician signature that contributed > 6% to the modern Phoenician-influenced populations examined. Our methodology can be applied to any historically documented expansion in which contact and noncontact sites can be identified. PMID:18976729

  17. Genetic Determinants of Serum Testosterone Concentrations in Men

    PubMed Central

    Maggio, Marcello; Coviello, Andrea D.; Ferrucci, Luigi; Heier, Margit; Hofman, Albert; Holliday, Kate L.; Jansson, John-Olov; Kähönen, Mika; Karasik, David; Karlsson, Magnus K.; Kiel, Douglas P.; Liu, Yongmei; Ljunggren, Östen; Lorentzon, Mattias; Lyytikäinen, Leo-Pekka; Meitinger, Thomas; Mellström, Dan; Melzer, David; Miljkovic, Iva; Nauck, Matthias; Nilsson, Maria; Penninx, Brenda; Pye, Stephen R.; Vasan, Ramachandran S.; Reincke, Martin; Rivadeneira, Fernando; Tajar, Abdelouahid; Teumer, Alexander; Uitterlinden, André G.; Ulloor, Jagadish; Viikari, Jorma; Völker, Uwe; Völzke, Henry; Wichmann, H. Erich; Wu, Tsung-Sheng; Zhuang, Wei Vivian; Ziv, Elad; Wu, Frederick C. W.; Raitakari, Olli; Eriksson, Anna; Bidlingmaier, Martin; Harris, Tamara B.; Murray, Anna; de Jong, Frank H.; Murabito, Joanne M.; Bhasin, Shalender; Vandenput, Liesbeth; Haring, Robin

    2011-01-01

    Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n?=?871) and two de novo replication cohorts (n?=?4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p?=?1.2×10?41 and rs6258, p?=?2.3×10?22). Subjects with ?3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p?=?5.6×10?16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation. PMID:21998597

  18. The Real maccoyii: Identifying Tuna Sushi with DNA Barcodes – Contrasting Characteristic Attributes and Genetic Distances

    PubMed Central

    Lowenstein, Jacob H.; Amato, George; Kolokotronis, Sergios-Orestis

    2009-01-01

    Background The use of DNA barcodes for the identification of described species is one of the least controversial and most promising applications of barcoding. There is no consensus, however, as to what constitutes an appropriate identification standard and most barcoding efforts simply attempt to pair a query sequence with reference sequences and deem identification successful if it falls within the bounds of some pre-established cutoffs using genetic distance. Since the Renaissance, however, most biological classification schemes have relied on the use of diagnostic characters to identify and place species. Methodology/Principal Findings Here we developed a cytochrome c oxidase subunit I character-based key for the identification of all tuna species of the genus Thunnus, and compared its performance with distance-based measures for identification of 68 samples of tuna sushi purchased from 31 restaurants in Manhattan (New York City) and Denver, Colorado. Both the character-based key and GenBank BLAST successfully identified 100% of the tuna samples, while the Barcode of Life Database (BOLD) as well as genetic distance thresholds, and neighbor-joining phylogenetic tree building performed poorly in terms of species identification. A piece of tuna sushi has the potential to be an endangered species, a fraud, or a health hazard. All three of these cases were uncovered in this study. Nineteen restaurant establishments were unable to clarify or misrepresented what species they sold. Five out of nine samples sold as a variant of “white tuna” were not albacore (T. alalunga), but escolar (Lepidocybium flavorunneum), a gempylid species banned for sale in Italy and Japan due to health concerns. Nineteen samples were northern bluefin tuna (T. thynnus) or the critically endangered southern bluefin tuna (T. maccoyii), though nine restaurants that sold these species did not state these species on their menus. Conclusions/Significance The Convention on International Trade Endangered Species (CITES) requires that listed species must be identifiable in trade. This research fulfills this requirement for tuna, and supports the nomination of northern bluefin tuna for CITES listing in 2010. PMID:19924239

  19. Cellular and network mechanisms of genetically-determined absence seizures

    PubMed Central

    Pinault, Didier; O'Brien, Terence J.

    2005-01-01

    The absence epilepsies are characterized by recurrent episodes of loss of consciousness associated with generalized spike-and-wave discharges, with an abrupt onset and offset, in the thalamocortical system. In the absence of detailed neurophysiological studies in humans, many of the concepts regarding the pathophysiological basis of absence seizures are based on studies in animal models. Each of these models has its particular strengths and limitations, and the validity of findings from these models for the human condition cannot be assumed. Consequently, studies in different models have produced some conflicting findings and conclusions. A long-standing concept, based primarily from studies in vivo in cats and in vitro brain slices, is that these paroxysmal electrical events develop suddenly from sleep-related spindle oscillations. More specifically, it is proposed that the initial mechanisms that underlie absence-related spike-and-wave discharges are located in the thalamus, involving especially the thalamic reticular nucleus. By contrast, more recent studies in well-established, genetic models of absence epilepsy in rats demonstrate that spike-and-wave discharges originate in a cortical focus and develop from a wake-related natural corticothalamic sensorimotor rhythm. In this review we integrate recent findings showing that, in both the thalamus and the neocortex, genetically-determined, absence-related spike-and-wave discharges are the manifestation of hypersynchronized, cellular, rhythmic excitations and inhibitions that result from a combination of complex, intrinsic, synaptic mechanisms. Arguments are put forward supporting the hypothesis that layer VI corticothalamic neurons act as ‘drivers’ in the generation of spike-and-wave discharges in the somatosensory thalamocortical system that result in corticothalamic resonances particularly initially involving the thalamic reticular nucleus. However an important unresolved question is: what are the cellular and network mechanisms responsible for the switch from physiological, wake-related, natural oscillations into pathological spike-and-wave discharges? We speculate on possible answers to this, building particularly on recent findings from genetic models in rats. PMID:21909233

  20. Genetic determinants of mate recognition in Brachionus manjavacas (Rotifera)

    PubMed Central

    Snell, Terry W; Shearer, Tonya L; Smith, Hilary A; Kubanek, Julia; Gribble, Kristin E; Welch, David B Mark

    2009-01-01

    Background Mate choice is of central importance to most animals, influencing population structure, speciation, and ultimately the survival of a species. Mating behavior of male brachionid rotifers is triggered by the product of a chemosensory gene, a glycoprotein on the body surface of females called the mate recognition pheromone. The mate recognition pheromone has been biochemically characterized, but little was known about the gene(s). We describe the isolation and characterization of the mate recognition pheromone gene through protein purification, N-terminal amino acid sequence determination, identification of the mate recognition pheromone gene from a cDNA library, sequencing, and RNAi knockdown to confirm the functional role of the mate recognition pheromone gene in rotifer mating. Results A 29 kD protein capable of eliciting rotifer male circling was isolated by high-performance liquid chromatography. Two transcript types containing the N-terminal sequence were identified in a cDNA library; further characterization by screening a genomic library and by polymerase chain reaction revealed two genes belonging to each type. Each gene begins with a signal peptide region followed by nearly perfect repeats of an 87 to 92 codon motif with no codons between repeats and the final motif prematurely terminated by the stop codon. The two Type A genes contain four and seven repeats and the two Type B genes contain three and five repeats, respectively. Only the Type B gene with three repeats encodes a peptide with a molecular weight of 29 kD. Each repeat of the Type B gene products contains three asparagines as potential sites for N-glycosylation; there are no asparagines in the Type A genes. RNAi with Type A double-stranded RNA did not result in less circling than in the phosphate-buffered saline control, but transfection with Type B double-stranded RNA significantly reduced male circling by 17%. The very low divergence between repeat units, even at synonymous positions, suggests that the repeats are kept nearly identical through a process of concerted evolution. Information-rich molecules like surface glycoproteins are well adapted for chemical communication and aquatic animals may have evolved signaling systems based on these compounds, whereas insects use cuticular hydrocarbons. Conclusion Owing to its critical role in mating, the mate recognition pheromone gene will be a useful molecular marker for exploring the mechanisms and rates of selection and the evolution of reproductive isolation and speciation using rotifers as a model system. The phylogenetic variation in the mate recognition pheromone gene can now be studied in conjunction with the large amount of ecological and population genetic data being gathered for the Brachionus plicatilis species complex to understand better the evolutionary drivers of cryptic speciation. PMID:19740420

  1. Retrograde Intraflagellar Transport Mutants Identify Complex A Proteins With Multiple Genetic Interactions in Chlamydomonas reinhardtii

    PubMed Central

    Iomini, Carlo; Li, Linya; Esparza, Jessica M.; Dutcher, Susan K.

    2009-01-01

    The intraflagellar transport machinery is required for the assembly of cilia. It has been investigated by biochemical, genetic, and computational methods that have identified at least 21 proteins that assemble into two subcomplexes. It has been hypothesized that complex A is required for retrograde transport. Temperature-sensitive mutations in FLA15 and FLA17 show defects in retrograde intraflagellar transport (IFT) in Chlamydomonas. We show that IFT144 and IFT139, two complex A proteins, are encoded by FLA15 and FLA17, respectively. The fla15 allele is a missense mutation in a conserved cysteine and the fla17 allele is an in-frame deletion of three exons. The flagellar assembly defect of each mutant is rescued by the respective transgenes. In fla15 and fla17 mutants, bulges form in the distal one-third of the flagella at the permissive temperature and this phenotype is also rescued by the transgenes. These bulges contain the complex B component IFT74/72, but not ?-tubulin or p28, a component of an inner dynein arm, which suggests specificity with respect to the proteins that accumulate in these bulges. IFT144 and IFT139 are likely to interact with each other and other proteins on the basis of three distinct genetic tests: (1) Double mutants display synthetic flagellar assembly defects at the permissive temperature, (2) heterozygous diploid strains exhibit second-site noncomplemention, and (3) transgenes confer two-copy suppression. Since these tests show different levels of phenotypic sensitivity, we propose they illustrate different gradations of gene interaction between complex A proteins themselves and with a complex B protein (IFT172). PMID:19720863

  2. An exploration of the communication preferences regarding genetic testing in individuals from families with identified breast\\/ovarian cancer mutations

    Microsoft Academic Search

    Paboda Ratnayake; Claire E. Wakefield; Bettina Meiser; Graeme Suthers; Melanie A. Price; Jessica Duffy; Kathy Tucker

    2011-01-01

    The responsibility for informing at-risk relatives of the availability of genetic testing for breast\\/ovarian cancer gene (BRCA1\\u000a or BRCA2) mutations currently falls on the probands. This study explored the support needs of individuals from families with\\u000a identified BRCA1 or BRCA2 mutations when communicating about genetic risk and genetic testing with at-risk family members.\\u000a Thirty-nine semi-structured telephone interviews were conducted with

  3. Sarcolemmal phospholipid N-methylation in genetically determined hamster cardiomyopathy

    SciTech Connect

    Okumura, K.; Panagia, V.; Jasmin, G.; Dhalla, N.S.

    1987-02-27

    The heart sarcolemmal phosphatidylethanolamine N-methylation in UM-X7.1 strain of cardiomyopathic hamsters was examined by using 0.055, 10 and 150 microM S-adenosyl-L-(methyl-/sup 3/H) methionine as methyl donor for sites I, II and III, respectively. In comparison with control values, methylation activities at site I was increased in 40, 120 and 250 days old cardiomyopathic hamsters. On the other hand, methylation activities at sites II and III in 120 and 250 days old cardiomyopathic animals were depressed without any change in the 40 days old group. The alterations in N-methylation activities were associated with kinetic changes in apparent Vmax values without any changes in the apparent Km. These results indicate a defect in the phospholipid N-methylation process in heart sarcolemma during the development of genetically determined cardiomyopathy.

  4. Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.

    PubMed

    Frankum, Jessica; Moudry, Pavel; Brough, Rachel; Hodny, Zdenek; Ashworth, Alan; Bartek, Jiri; Lord, Christopher J

    2015-05-10

    Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors. PMID:25883215

  5. Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity

    PubMed Central

    Brough, Rachel; Hodny, Zdenek; Ashworth, Alan; Bartek, Jiri; Lord, Christopher J.

    2015-01-01

    Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors. PMID:25883215

  6. Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

    PubMed

    Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

    2010-10-01

    To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. PMID:20706997

  7. Genome-wide association study identifies possible genetic risk factors for colorectal adenomas

    PubMed Central

    Edwards, Todd L.; Shrubsole, Martha J.; Cai, Qiuyin; Li, Guoliang; Dai, Qi; Rex, Douglas K.; Ulbright, Thomas M.; Fu, Zhenming; Delahanty, Ryan H.; Murff, Harvey J.; Smalley, Walter; Ness, Reid M.; Zheng, Wei

    2013-01-01

    Background Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown. Methods In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. Results No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81–0.94, p-value = 4.4×10?4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 OR = 1.32, 95% CI 1.18–1.47, p-value = 1.1×10?6). Conclusions This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies. Impact These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis. PMID:23677573

  8. Evolution of a Pathogen: A Comparative Genomics Analysis Identifies a Genetic Pathway to Pathogenesis in Acinetobacter

    PubMed Central

    Sahl, Jason W.; Gillece, John D.; Schupp, James M.; Waddell, Victor G.; Driebe, Elizabeth M.; Engelthaler, David M.; Keim, Paul

    2013-01-01

    Acinetobacter baumannii is an emergent and global nosocomial pathogen. In addition to A. baumannii, other Acinetobacter species, especially those in the Acinetobacter calcoaceticus-baumannii (Acb) complex, have also been associated with serious human infection. Although mechanisms of attachment, persistence on abiotic surfaces, and pathogenesis in A. baumannii have been identified, the genetic mechanisms that explain the emergence of A. baumannii as the most widespread and virulent Acinetobacter species are not fully understood. Recent whole genome sequencing has provided insight into the phylogenetic structure of the genus Acinetobacter. However, a global comparison of genomic features between Acinetobacter spp. has not been described in the literature. In this study, 136 Acinetobacter genomes, including 67 sequenced in this study, were compared to identify the acquisition and loss of genes in the expansion of the Acinetobacter genus. A whole genome phylogeny confirmed that A. baumannii is a monophyletic clade and that the larger Acb complex is also a well-supported monophyletic group. The whole genome phylogeny provided the framework for a global genomic comparison based on a blast score ratio (BSR) analysis. The BSR analysis demonstrated that specific genes have been both lost and acquired in the evolution of A. baumannii. In addition, several genes associated with A. baumannii pathogenesis were found to be more conserved in the Acb complex, and especially in A. baumannii, than in other Acinetobacter genomes; until recently, a global analysis of the distribution and conservation of virulence factors across the genus was not possible. The results demonstrate that the acquisition of specific virulence factors has likely contributed to the widespread persistence and virulence of A. baumannii. The identification of novel features associated with transcriptional regulation and acquired by clades in the Acb complex presents targets for better understanding the evolution of pathogenesis and virulence in the expansion of the genus. PMID:23365658

  9. Cumulative effect of genome-wide association study-identified genetic variants for bladder cancer.

    PubMed

    Wang, Meilin; Chu, Haiyan; Lv, Qiang; Wang, Li; Yuan, Lin; Fu, Guangbo; Tong, Na; Qin, Chao; Yin, Changjun; Zhang, Zhengdong; Xu, Jianfeng

    2014-12-01

    Recent genome-wide association studies have identified 14 genetic variants associated with bladder cancer in Caucasians. The effects of these risk variants and their cumulative effects in Asian populations are unknown. We genotyped these newly identified variants in a case-control study of 1,050 patients diagnosed with bladder cancer and 1,404 controls in the Chinese population. Odds rations (ORs) and 95% confidence intervals (CIs) were computed by logistic regression, and cumulative effect of risk alleles were evaluated. Overall, seven of the 14 variants were significantly associated with bladder cancer risk (p?=?9.763?×?10(-3) for rs9642880 at 8q24.21, p?=?3.004?×?10(-3) for rs2294008 at 8q24.3, p?=?0.012 for rs798766 at 4p16.3, p?=?0.034 for rs1495741 at 8p22, p?=?2.306?×?10(-4) for GSTM1, p?=?8.507?×?10(-8) for rs17674580 at 18q12.3, p?=?7.179?×?10(-4) for rs10936599 at 3q26.2) and the odds ratios (ORs) ranged from 1.13 to 1.65. Moreover, there were a significant increased risk for bladder cancer positively correlated numbers of risk alleles and smoking status (Ptrend ?=?7.060?×?10(-16) ). However, no allelic interaction effects on bladder cancer risk were observed between cumulative effects of variants and clinical characteristics. These findings suggest that seven bladder cancer risk-associated variants (rs9642880, rs2294008, rs798766, rs1495741, GSTM1 null, rs17674580 and rs10936599) may be used, collectively, to effectively measure inherited risk for bladder cancer. PMID:24740636

  10. Polynesian genetic affinities with southeast Asian populations as identified by mtDNA analysis

    SciTech Connect

    Melton, T.; Redd, A.J.; Stoneking. M. [Pennsylvania State Univ., University Park, PA (United States)] [and others

    1995-08-01

    Polynesian genetic affinities to populations of Asia were studied using mtDNA markers. A total of 1,037 individuals from 12 populations were screened for a 9-bp deletion in the intergenic region between the COII and tRNA{sup Lys}genes that approaches fixation in Polynesians. Sequence-specific oligonucleotide probes that identify specific mtDNA control region nucleotide substitutions were used to describe variation in individuals with the 9-bp deletion. The 9-bp deletion was not observed in northern Indians, Bangladeshis, or Pakistanis but was seen at low to moderate frequencies in the nine other Southeast Asian populations. Three substitutions in the control region at positions 16217, 16247 and 16261 have previously been observed at high frequency in Polynesian mtDNAs; this {open_quotes}Polynesian motif{close_quotes} was observed in 20% of east Indonesians with the 9-bp deletion but was observed in only one additional individual. mtDNA types related to the Polynesian motif are highest in frequency in the corridor from Taiwan south through the Philippines and east Indonesia, and the highest diversity for these types is in Taiwan. These results are consistent with linguistic evidence of a Taiwanese origin for the proto-Polynesian expansion, which spread throughout Oceania by way of Indonesia. 37 refs., 3 figs., 4 tabs.

  11. Harnessing gene expression to identify the genetic basis of drug resistance

    PubMed Central

    Chen, Bo-Juen; Causton, Helen C; Mancenido, Denesy; Goddard, Noel L; Perlstein, Ethan O; Pe'er, Dana

    2009-01-01

    The advent of cost-effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants interact with the environment. We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both predict complex quantitative phenotypes and identify genes that actively influence these traits. Camelot integrates genotype and gene expression data, both generated under a reference condition, to predict the response to entirely different conditions. We systematically applied our algorithm to data generated from a collection of yeast segregants, using genotype and gene expression data generated under drug-free conditions to predict the response to 94 drugs and experimentally confirmed 14 novel gene–drug interactions. Our approach is robust, applicable to other phenotypes and species, and has potential for applications in personalized medicine, for example, in predicting how an individual will respond to a previously unseen drug. PMID:19888205

  12. A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence.

    PubMed

    Kim, Jee-Hyun; O'Brien, Kathryn M; Sharma, Ritu; Boshoff, Helena I M; Rehren, German; Chakraborty, Sumit; Wallach, Joshua B; Monteleone, Mercedes; Wilson, Daniel J; Aldrich, Courtney C; Barry, Clifton E; Rhee, Kyu Y; Ehrt, Sabine; Schnappinger, Dirk

    2013-11-19

    Antibacterial drug development suffers from a paucity of targets whose inhibition kills replicating and nonreplicating bacteria. The latter include phenotypically dormant cells, known as persisters, which are tolerant to many antibiotics and often contribute to failure in the treatment of chronic infections. This is nowhere more apparent than in tuberculosis caused by Mycobacterium tuberculosis, a pathogen that tolerates many antibiotics once it ceases to replicate. We developed a strategy to identify proteins that Mycobacterium tuberculosis requires to both grow and persist and whose inhibition has the potential to prevent drug tolerance and persister formation. This strategy is based on a tunable dual-control genetic switch that provides a regulatory range spanning three orders of magnitude, quickly depletes proteins in both replicating and nonreplicating mycobacteria, and exhibits increased robustness to phenotypic reversion. Using this switch, we demonstrated that depletion of the nicotinamide adenine dinucleotide synthetase (NadE) rapidly killed Mycobacterium tuberculosis under conditions of standard growth and nonreplicative persistence induced by oxygen and nutrient limitation as well as during the acute and chronic phases of infection in mice. These findings establish the dual-control switch as a robust tool with which to probe the essentiality of Mycobacterium tuberculosis proteins under different conditions, including those that induce antibiotic tolerance, and NadE as a target with the potential to shorten current tuberculosis chemotherapies. PMID:24191058

  13. Identifying Support Functions in Developmental Relationships: A Self-Determination Perspective

    ERIC Educational Resources Information Center

    Janssen, Suzanne; van Vuuren, Mark; de Jong, Menno D. T.

    2013-01-01

    This study examines the content of developmental networks from the perspective of self-determination theory. We qualitatively examine 18 proteges' constellations of developmental relationships to identify specific types of developmental support functions. Our study shows that the adoption of self-determination theory leads to a theory-based…

  14. Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen Identifies Two

    E-print Network

    Abney, Mark

    Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen, Massachusetts 02115 Context: Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels. Objective: The objective of this study was to identify quantitative trait

  15. Genetic Analysis of Fin Development in Zebrafish Identifies Furin and Hemicentin1 as Potential Novel Fraser Syndrome Disease Genes

    Microsoft Academic Search

    Thomas J. Carney; Natália Martins Feitosa; Carmen Sonntag; Krasimir Slanchev; Johannes Kluger; Daiji Kiyozumi; Jan M. Gebauer; Jared Coffin Talbot; Charles B. Kimmel; Kiyotoshi Sekiguchi; Raimund Wagener; Heinz Schwarz; Phillip W. Ingham; Matthias Hammerschmidt

    2010-01-01

    Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the

  16. Development of a genetic linkage map for Louisiana sugarcane: New microsatellite (SSR) DNA markers identified for LCP 85-384

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Application of the recently developed genetic linkage map of sugarcane (Saccharum spp.) cultivar LCP 85-384 has been limited due to the small number of DNA markers, in particular microsatellite (SSR) DNA markers, on the map. Adding DNA markers to the map improves its usefulness in identifying assoc...

  17. Candidate gene approach to identifying rare genetic variants associated with lone atrial fibrillation

    PubMed Central

    Weeke, Peter; Parvez, Babar; Blair, Marcia; Short, Laura; Ingram, Christie; Kucera, Gayle; Stubblefield, Tanya; Roden, Dan M.

    2013-01-01

    BACKGROUND Rare variants in candidate atrial fibrillation (AF) genes have been associated with AF in small kindreds. The extent to which such polymorphisms contribute to AF is unknown. OBJECTIVE The purpose of this study was to determine the spectrum and prevalence of rare amino acid coding (AAC) variants in candidate AF genes in a large cohort of unrelated lone AF probands. METHODS We resequenced 45 candidate genes in 303 European American (EA) lone AF probands (186 lone AF probands screened for each gene on average [range 89–303], 63 screened for all) identified in the Vanderbilt AF Registry (2002–2012). Variants detected were screened against 4300 EAs from the Exome Sequencing Project (ESP) to identify very rare (minor allele frequency ? 0.04%) AAC variants and these were tested for AF co-segregation in affected family members where possible. RESULTS Median age at AF onset was 46.0 years [interquartile range 33.0–54.0], and 35.6% had a family history of AF. Overall, 63 very rare AAC variants were identified in 60 of 303 lone AF probands, and 10 of 19 (52.6%) had evidence of co-segregation with AF. Among the 63 lone AF probands who had 45 genes screened, the very rare variant burden was 22%. Compared with the 4300 EA ESP, the proportion of lone AF probands with a very rare AAC variant in CASQ2 and NKX2-5 was increased 3–5-fold (P < .05). CONCLUSION No very rare AAC variants were identified in ~80% of lone AF probands. Potential reasons for the lack of very rare AAC variants include a complex pattern of inheritance, variants in as yet unidentified AF genes or in noncoding regions, and environmental factors. PMID:24120998

  18. New de novo Genetic Mutations in Schizophrenia Identified | Columbia University Medical Center http://www.cumc.columbia.edu/news-room/2012/10/03/new-de-novo-genetic-mutations-in-schizophrenia-identified/#.UKJgImdNKuJ[11/13/2012 9:59:28 AM

    E-print Network

    New de novo Genetic Mutations in Schizophrenia Identified | Columbia University Medical Center http://www.cumc.columbia.edu/news-room/2012/10/03/new-de-novo-genetic-mutations-in-schizophrenia-identified/#.UKJgImdNKuJ[11/13/2012 9 Profiles | Map | RSS | Giving New de novo Genetic Mutations in Schizophrenia Identified October 3, 2012 New

  19. Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species (Thamnophis elegans and Thamnophis sirtalis).

    PubMed

    Manier, Mollie K; Arnold, Stevan J

    2005-11-01

    Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same environment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis, to determine if shared landscape and biology imposed similar population genetic structures. These snakes inhabit a series of ponds, lakes and flooded meadows in northern California and tend to converge on prey type wherever they coexist. Both garter snakes had comparable effective population sizes and bidirectional migration rates (estimated using a maximum-likelihood method based on the coalescent) with low but significant levels of genetic differentiation (F(ST) = 0.024 for T. elegans and 0.035 for T. sirtalis). Asymmetrical gene flow revealed large source populations for both species as well as potential sinks, suggesting frequent extinction-recolonization and metapopulation dynamics. In addition, we found a significant correlation between their genetic structures based on both pairwise F(ST)s for shared populations (P = 0.009) and for bidirectional migration rates (P = 0.024). Possible ecological and evolutionary factors influencing similarities and differences in genetic structure for the two species are discussed. Genetic measures of effective population size and migration rates obtained in this study are also compared with estimates obtained from mark-recapture data. PMID:16262852

  20. Corneal Antifibrotic Switch Identified in Genetic and Pharmacological Deficiency of Vimentin*

    PubMed Central

    Bargagna-Mohan, Paola; Paranthan, Riya R.; Hamza, Adel; Zhan, Chang-Guo; Lee, Do-Min; Kim, Kyung Bo; Lau, Daniel L.; Srinivasan, Cidambi; Nakayama, Keiko; Nakayama, Keiichi I.; Herrmann, Harald; Mohan, Royce

    2012-01-01

    The type III intermediate filaments (IFs) are essential cytoskeletal elements of mechanosignal transduction and serve critical roles in tissue repair. Mice genetically deficient for the IF protein vimentin (Vim?/?) have impaired wound healing from deficits in myofibroblast development. We report a surprising finding made in Vim?/? mice that corneas are protected from fibrosis and instead promote regenerative healing after traumatic alkali injury. This reparative phenotype in Vim?/? corneas is strikingly recapitulated by the pharmacological agent withaferin A (WFA), a small molecule that binds to vimentin and down-regulates its injury-induced expression. Attenuation of corneal fibrosis by WFA is mediated by down-regulation of ubiquitin-conjugating E3 ligase Skp2 and up-regulation of cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1. In cell culture models, WFA exerts G2/M cell cycle arrest in a p27Kip1- and Skp2-dependent manner. Finally, by developing a highly sensitive imaging method to measure corneal opacity, we identify a novel role for desmin overexpression in corneal haze. We demonstrate that desmin down-regulation by WFA via targeting the conserved WFA-ligand binding site shared among type III IFs promotes further improvement of corneal transparency without affecting cyclin-dependent kinase inhibitor levels in Vim?/? mice. This dissociates a direct role for desmin in corneal cell proliferation. Taken together, our findings illuminate a previously unappreciated pathogenic role for type III IF overexpression in corneal fibrotic conditions and also validate WFA as a powerful drug lead toward anti-fibrosis therapeutic development. PMID:22117063

  1. Functional Genetic Screen Identifies Increased Sensitivity to WEE1 Inhibition in Cells with Defects in Fanconi Anemia and HR Pathways.

    PubMed

    Aarts, Marieke; Bajrami, Ilirjana; Herrera-Abreu, Maria T; Elliott, Richard; Brough, Rachel; Ashworth, Alan; Lord, Christopher J; Turner, Nicholas C

    2015-04-01

    WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition. Inhibition of kinases that regulate CDK activity, CHK1 and MYT1, synergized with WEE1 inhibition through both increased replication stress and forced mitotic entry of S-phase cells. Loss of multiple components of the Fanconi anemia (FA) and homologous recombination (HR) pathways, in particular DNA helicases, sensitized to WEE1 inhibition. Silencing of FA/HR genes resulted in excessive replication stress and nucleotide depletion following WEE1 inhibition, which ultimately led to increased unscheduled mitotic entry. Our results suggest that cancers with defects in FA and HR pathways may be targeted by WEE1 inhibition, providing a basis for a novel synthetic lethal strategy for cancers harboring FA/HR defects. Mol Cancer Ther; 14(4); 865-76. ©2015 AACR. PMID:25673822

  2. Genetic determinants of the stress response in cardiovascular disease.

    PubMed

    Hamet, Pavel; Tremblay, Johanne

    2002-06-01

    Originating from Hans Selye's general concept, the biological notion of the stress response implicates neuroendocrine and endocrine pathways as well as their cellular mediators as components of the general adaptation syndrome and its consequences. A highly variable degree of response to psychological and physical stresses has been noted in experimental animals and in human populations. Some stressors, such as the "cold pressor test," have been developed as tools for disease prediction. They apply to variable conditions, from hypertension to insulin resistance, but mostly in relation to cardiovascular outcomes. Other environmental factors, including the degree of salt intake, potentiate the stress response in animals and humans. Our group has undertaken to explore the genetic determinants of the stress response in inbred strains, recombinant congenic and congenic strains, as well as founder human populations. We have succeeded, initially, in linking increased body temperature, a major phenotypic response to stress, to the quantitative trait loci (QTL), one at myh3 on chromosome (Chr) 10, one at hsp27 on Chr 12, and one on Chr Y in the rat. The expression of several stress proteins is under the dominant influence of hstf1 at the rat Chr 7 locus (Mit3). The high prevalence of cardiovascular diseases with traits of enhanced stress responsiveness is discussed here in the context of a paradigm, such as hypertension, in the general population. PMID:12040536

  3. Cinematic Genetics: GATTACA, Essentially Yours, and the Rhetoric of Genetic Determinism

    Microsoft Academic Search

    Ron Von Burg

    2010-01-01

    This essay investigates the Australian Law Reform Commission's (ALRC) use of the fictional film GATTACA in the policy brief, “Essentially Yours,” as a rhetorical commonplace to frame various ethical, legal, and scientific issues related to genetic technologies. Because emerging genetic therapy technologies invite both fear and fascination, the ALRC faces the rhetorical challenge of maintaining a distinction between genetic science

  4. Determining Relative Importance and Effective Settings for Genetic Algorithm Control Parameters.

    PubMed

    Mills, K L; Filliben, J J; Haines, A L

    2015-01-01

    Setting the control parameters of a genetic algorithm to obtain good results is a long-standing problem. We define an experiment design and analysis method to determine relative importance and effective settings for control parameters of any evolutionary algorithm, and we apply this method to a classic binary-encoded genetic algorithm (GA). Subsequently, as reported elsewhere, we applied the GA, with the control parameter settings determined here, to steer a population of cloud-computing simulators toward behaviors that reveal degraded performance and system collapse. GA-steered simulators could serve as a design tool, empowering system engineers to identify and mitigate low-probability, costly failure scenarios. In the existing GA literature, we uncovered conflicting opinions and evidence regarding key GA control parameters and effective settings to adopt. Consequently, we designed and executed an experiment to determine relative importance and effective settings for seven GA control parameters, when applied across a set of numerical optimization problems drawn from the literature. This paper describes our experiment design, analysis, and results. We found that crossover most significantly influenced GA success, followed by mutation rate and population size and then by rerandomization point and elite selection. Selection method and the precision used within the chromosome to represent numerical values had least influence. Our findings are robust over 60 numerical optimization problems. PMID:25254350

  5. The role of nutrition and genetics as key determinants of the positive height trend.

    PubMed

    Grasgruber, P; Cacek, J; Kalina, T; Sebera, M

    2014-12-01

    The aim of this study was to identify the most important variables determining current differences in physical stature in Europe and some of its overseas offshoots such as Australia, New Zealand and USA. We collected data on the height of young men from 45 countries and compared them with long-term averages of food consumption from the FAOSTAT database, various development indicators compiled by the World Bank and the CIA World Factbook, and frequencies of several genetic markers. Our analysis demonstrates that the most important factor explaining current differences in stature among nations of European origin is the level of nutrition, especially the ratio between the intake of high-quality proteins from milk products, pork meat and fish, and low-quality proteins from wheat. Possible genetic factors such as the distribution of Y haplogroup I-M170, combined frequencies of Y haplogroups I-M170 and R1b-U106, or the phenotypic distribution of lactose tolerance emerge as comparably important, but the available data are more limited. Moderately significant positive correlations were also found with GDP per capita, health expenditure and partly with the level of urbanization that influences male stature in Western Europe. In contrast, male height correlated inversely with children's mortality and social inequality (Gini index). These results could inspire social and nutritional guidelines that would lead to the optimization of physical growth in children and maximization of the genetic potential, both at the individual and national level. PMID:25190282

  6. [Improvement of methods for determining genetic correlations for selection indices].

    PubMed

    Riabko, V M; Gorlov, A I

    1999-06-01

    The possibility of using partial correlation as a measure of genetic correlation in estimating selection indices was studied. The methods of estimation were analyzed, and the use of one of them was substantiated. The applicability of partial correlations in estimating genetic correlations was demonstrated theoretically and with an example from actual practice. The proposed algorithm was illustrated by an example. PMID:10505274

  7. Copyright 1998 by the Genetics Society of America Evidence for a Genomic Imprinting Sex Determination Mechanism

    E-print Network

    Dobson, Stephen L.

    Copyright © 1998 by the Genetics Society of America Evidence for a Genomic Imprinting Sex different models have been proposed for the sex determination mechanism of Chalcidoidea (Hymenoptera). Except for the most recently proposed model (genomic imprinting sex determination; GISD), each

  8. Seascape continuity plays an important role in determining patterns of spatial genetic structure in a coral reef fish.

    PubMed

    D'Aloia, C C; Bogdanowicz, S M; Harrison, R G; Buston, P M

    2014-06-01

    Detecting patterns of spatial genetic structure (SGS) can help identify intrinsic and extrinsic barriers to gene flow within metapopulations. For marine organisms such as coral reef fishes, identifying these barriers is critical to predicting evolutionary dynamics and demarcating evolutionarily significant units for conservation. In this study, we adopted an alternative hypothesis-testing framework to identify the patterns and predictors of SGS in the Caribbean reef fish Elacatinus lori. First, genetic structure was estimated using nuclear microsatellites and mitochondrial cytochrome b sequences. Next, clustering and network analyses were applied to visualize patterns of SGS. Finally, logistic regressions and linear mixed models were used to identify the predictors of SGS. Both sets of markers revealed low global structure: mitochondrial ?ST=0.12, microsatellite FST=0.0056. However, there was high variability among pairwise estimates, ranging from no differentiation between sites on contiguous reef (?ST=0) to strong differentiation between sites separated by ocean expanses?20 km (maximum ?ST=0.65). Genetic clustering and statistical analyses provided additional support for the hypothesis that seascape discontinuity, represented by oceanic breaks between patches of reef habitat, is a key predictor of SGS in E. lori. Notably, the estimated patterns and predictors of SGS were consistent between both sets of markers. Combined with previous studies of dispersal in E. lori, these results suggest that the interaction between seascape continuity and the dispersal kernel plays an important role in determining genetic connectivity within metapopulations. PMID:24803419

  9. Application of complementation tests in identifying pathogenicity determinants of the chickpea pathogen Ascochyta rabiei

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The necrotrophic pathogen Ascochyta rabiei causes chickpea Ascochyta blight. Very little is known about its pathogenicity mechanisms. The objective of this research was to identify pathogenicity determinants of A. rabiei using complementation tests. The hygromycin-resistant mutant ArW519 was non-pa...

  10. Prevalence and Potential Genetic Determinants of Sensorineural Deafness in KCNQ1 Homozygosity and Compound Heterozygosity

    PubMed Central

    Giudicessi, John R.; Ackerman, Michael J.

    2013-01-01

    Background Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome (JLNS), a rare, autosomal recessive form of long QT syndrome (LQTS) characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. Here, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of LQTS patients. Methods and Results Retrospective analysis of all LQTS patients evaluated from July 1998 to April 2012 was used to identify those with ?1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 patients (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 (73%) of these patients presented without the sensorineural deafness associated with JLNS. The degree of QT interval prolongation and number of breakthrough cardiac events were similar between cases with and without deafness. Interestingly, truncating mutations were more prevalent in JLNS (79%) than non-deaf cases (36%, p<0.001) derived from this study and those in the literature. Conclusions Here, we provide evidence that the “recessive” inheritance of a severe LQT1 phenotype in the absence of an auditory phenotype may represent a more common pattern of LQTS inheritance than previously anticipated and that these cases should be treated as a higher-risk LQTS subset similar to their JLNS counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ?1 KCNQ1 mutation on each allele. PMID:23392653

  11. Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study

    PubMed Central

    Jorgensen, Andrea L.; Al-Zubiedi, Sameh; Zhang, Jieying Eunice; Keniry, Andrew; Hanson, Anita; Hughes, Dyfrig A.; van Eker, Diane; Stevens, Lisa; Hawkins, Karen; Toh, Cheng H.; Kamali, Farhad; Daly, Ann K.; Fitzmaurice, David; Coffey, Alison; Williamson, Paula R.; Park, Brian Kevin; Deloukas, Panos; Pirmohamed, Munir

    2012-01-01

    Background In this prospective cohort study, we have undertaken a comprehensive evaluation of clinical parameters along with variation in 29 genes (including CYP2C9 and VKORC1) to identify factors determining interindividual variability in warfarin response. Methods Consecutive patients (n = 311) were followed up prospectively for 26 weeks. Several outcomes chosen to capture both warfarin efficacy and toxicity were assessed. Univariate and multiple regression analyses were undertaken to assess the combined effect of clinical and genetic factors. Results CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small. On the basis of the results of microcosting, adverse events were shown to be a significant predictor of total cost. Conclusion Accurate prediction of warfarin dose requirement needs to take into account multiple genetic and environmental factors, the contributions of which vary in the induction and maintenance phases of treatment. PMID:19752777

  12. Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma.

    PubMed

    Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

    2014-01-01

    Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12,000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to result in asthma. Our top associated genes included those related to neurodevelopment or neural signaling (brain-derived neurotrophic factor (BDNF), neutral sphingomyelinase 2 (SMPD2), homeobox b2 (HOXB2), neural cell adhesion molecule (NCAM2), heterogeneous nuclear ribonucleoprotein A0 (HNRNPA0)), inflammation (free fatty acid receptor 2 (FFAR2)) and inflammation with additional evidence of neuronal involvement (oxidized low density lipoprotein receptor 1 (OLR1), toll-like receptor 3 (TLR3)). Of particular interest, BDNF has been previously implicated in both psychiatric disorders and asthma. Our results demonstrate the utility of combining pedigree and co-occurring phenotypes to identify rare variants associated with suicide risk in conjunction with specific co-occurring conditions. PMID:25335167

  13. Genetic determinants in the development of sensitization to environmental allergens in early childhood

    PubMed Central

    Tripathi, Priya; Hong, Xiumei; Caruso, Deanna; Gao, Peisong; Wang, Xiaobin

    2014-01-01

    Sensitization to environmental allergens remains one of the strongest risk factors for asthma, and there is likely a genetic basis. We sought to identify genetic determinants for the development of allergic sensitization to environmental allergens, particularly cockroach allergen, in early childhood. A total of 631 children with the information about genotypic data on 895 single nucleotide polymorphisms (SNPs) in 179 candidate genes were selected from an existing dataset (Boston Birth Cohort). Genetic analysis was performed for allergic sensitizations among all subjects and sub-population, Black/African, respectively. Eight SNPs in seven genes showed significant association with allergic sensitization with P?identified several loci that may confer the susceptibility to allergic sensitization, and suggested that sensitization to allergens may depend on their unique loci. PMID:25505553

  14. Identifying genetic interactions in genome-wide data using Bayesian networks.

    PubMed

    Jiang, Xia; Barmada, M Michael; Visweswaran, Shyam

    2010-09-01

    It is believed that interactions among genes (epistasis) may play an important role in susceptibility to common diseases (Moore and Williams [2002]. Ann Med 34:88-95; Ritchie et al. [2001]. Am J Hum Genet 69:138-147). To study the underlying genetic variants of diseases, genome-wide association studies (GWAS) that simultaneously assay several hundreds of thousands of SNPs are being increasingly used. Often, the data from these studies are analyzed with single-locus methods (Lambert et al. [2009]. Nat Genet 41:1094-1099; Reiman et al. [2007]. Neuron 54:713-720). However, epistatic interactions may not be easily detected with single-locus methods (Marchini et al. [2005]. Nat Genet 37:413-417). As a result, both parametric and nonparametric multi-locus methods have been developed to detect such interactions (Heidema et al. [2006]. BMC Genet 7:23). However, efficiently analyzing epistasis using high-dimensional genome-wide data remains a crucial challenge. We develop a method based on Bayesian networks and the minimum description length principle for detecting epistatic interactions. We compare its ability to detect gene-gene interactions and its efficiency to that of the combinatorial method multifactor dimensionality reduction (MDR) using 28,000 simulated data sets generated from 70 different genetic models We further apply the method to over 300,000 SNPs obtained from a GWAS involving late onset Alzheimer's disease (LOAD). Our method outperforms MDR and we substantiate previous results indicating that the GAB2 gene is associated with LOAD. To our knowledge, this is the first successful model-based epistatic analysis using a high-dimensional genome-wide data set. PMID:20568290

  15. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

    PubMed

    Goris, An; Pauwels, Ine; Gustavsen, Marte W; van Son, Brechtje; Hilven, Kelly; Bos, Steffan D; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål; Aarseth, Jan; Myhr, Kjell-Morten; D'Alfonso, Sandra; Barizzone, Nadia; Leone, Maurizio A; Martinelli Boneschi, Filippo; Sorosina, Melissa; Liberatore, Giuseppe; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan; Alfredsson, Lars; Bedri, Sahl Khalid; Hemmer, Bernhard; Buck, Dorothea; Berthele, Achim; Knier, Benjamin; Biberacher, Viola; van Pesch, Vincent; Sindic, Christian; Bang Oturai, Annette; Søndergaard, Helle Bach; Sellebjerg, Finn; Jensen, Poul Erik H; Comabella, Manuel; Montalban, Xavier; Pérez-Boza, Jennifer; Malhotra, Sunny; Lechner-Scott, Jeannette; Broadley, Simon; Slee, Mark; Taylor, Bruce; Kermode, Allan G; Gourraud, Pierre-Antoine; Sawcer, Stephen J; Andreassen, Bettina Kullle; Dubois, Bénédicte; Harbo, Hanne F

    2015-03-01

    Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants. PMID:25616667

  16. Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

    Microsoft Academic Search

    Christopher G. Bell; Sarah Finer; Cecilia M. Lindgren; Gareth A. Wilson; Vardhman K. Rakyan; Andrew E. Teschendorff; Pelin Akan; Elia Stupka; Thomas A. Down; Inga Prokopenko; Ian M. Morison; Jonathan Mill; Ruth Pidsley; Panos Deloukas; Timothy M. Frayling; Andrew T. Hattersley; Mark I. McCarthy; Stephan Beck; Graham A. Hitman; Thorkild I. A. Sorensen

    2010-01-01

    Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci.

  17. Genetic diversity of turmeric germplasm (Curcuma longa; Zingiberaceae) identified by microsatellite markers.

    PubMed

    Sigrist, M S; Pinheiro, J B; Filho, J A Azevedo; Zucchi, M I

    2011-01-01

    Turmeric (Curcuma longa) is a triploid, vegetatively propagated crop introduced early during the colonization of Brazil. Turmeric rhizomes are ground into a powder used as a natural dye in the food industry, although recent research suggests a greater potential for the development of drugs and cosmetics. In Brazil, little is known about the genetic variability available for crop improvement. We examined the genetic diversity among turmeric accessions from a Brazilian germplasm collection comprising 39 accessions collected from the States of Goiás, Mato Grosso do Sul, Minas Gerais, São Paulo, and Pará. For comparison, 18 additional genotypes were analyzed, including samples from India and Puerto Rico. Total DNA was extracted from lyophilized leaf tissue and genetic analysis was performed using 17 microsatellite markers (single-sequence repeats). Shannon-Weiner indexes ranged from 0.017 (Minas Gerais) to 0.316 (São Paulo). Analyses of molecular variance (AMOVA) demonstrated major differences between countries (63.4%) and that most of the genetic diversity in Brazil is found within states (75.3%). Genotypes from São Paulo State were the most divergent and potentially useful for crop improvement. Structure analysis indicated two main groups of accessions. These results can help target future collecting efforts for introduction of new materials needed to develop more productive and better adapted cultivars. PMID:21425092

  18. Identifying genetic loci controlling neonatal passive transfer of immunity using a hybrid genotyping strategy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Colostrum intake is critical to a piglet’s survival and can be measured by precipitating out the gamma-immunoglobulins from serum with ammonium sulfate (immunocrit). Genetic analysis of immunocrits on 5,312 piglets indicated that the heritabilities (se) for direct and maternal effects were 0.13(0.06...

  19. Diverse Genetic Markers Concordantly Identify Bovine Origin Escherichia coli O157 Genotypes Underrepresented in Human Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic markers previously reported to occur at significantly different frequencies in isolates of Escherichia coli O157:H7 obtained from cattle and from clinically affected humans are congruent and delineate at least five groups. Isolates in three of these groups consistently carry one or more mark...

  20. A strategy for identifying serodiagnostically relevant antigens of Leishmania or other pathogens in genetic libraries

    Microsoft Academic Search

    Márcia C. A. Teixeira; Geraldo G. S. Oliveira; Marco A. Silvany; Neuza M. Alcântara-Neves; Milena B. P. Soares; Ricardo Ribeiro-dos-Santos; Selma M. B. Jerônimo; Carlos H. Costa; Washington L. C. dos-Santos; Daniel Eichinger; Lain Pontes-de-Carvalho

    2007-01-01

    Different individuals, when infected with the same parasite, rarely produce antibodies against the same set of antigens. Indeed, unless a particular antigen happens to be recognized by antibodies in all individuals, the use of a single antigen in the serodiagnosis of parasitic diseases leads, invariably, to false-negative results. A straightforward method for pin-pointing, in genetic libraries, the precise antigens that

  1. Genetic analysis of the two zebrafish patched homologues identifies novel roles for the hedgehog signaling pathway

    Microsoft Academic Search

    Marco J Koudijs; Marjo J den Broeder; Evelyn Groot; Fredericus JM van Eeden

    2008-01-01

    BACKGROUND: Aberrant activation of the Hedgehog (Hh) signaling pathway in different organisms has shown the importance of this family of morphogens during development. Genetic screens in zebrafish have assigned specific roles for Hh in proliferation, differentiation and patterning, but mainly as a result of a loss of its activity. We attempted to fully activate the Hh pathway by removing both

  2. Harnessing gene expression to identify the genetic basis of drug resistance

    Microsoft Academic Search

    Bo-Juen Chen; Helen C Causton; Denesy Mancenido; Noel L Goddard; Ethan O Perlstein; Dana Pe'er

    2009-01-01

    The advent of cost-effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants interact with the environment. We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both

  3. A High Through-Put Reverse Genetic Screen Identifies Two Genes Involved in Remote Memory in Mice

    PubMed Central

    Matynia, Anna; Anagnostaras, Stephan G.; Wiltgen, Brian J.; Lacuesta, Maress; Fanselow, Michael S.; Silva, Alcino J.

    2008-01-01

    Previous studies have revealed that the initial stages of memory formation require several genes involved in synaptic, transcriptional and translational mechanisms. In contrast, very little is known about the molecular and cellular mechanisms underlying later stages of memory, including remote memory (i.e. 7-day memory). To identify genes required for remote memory, we screened randomly selected mouse strains harboring known mutations. In our primary reverse genetic screen, we identified 4 putative remote memory mutant strains out of a total of 54 lines analyzed. Additionally, we found 11 other mutant strains with other abnormal profiles. Secondary screens confirmed that mutations of integrin ?2 (Itg?2) and steryl-O-acyl transferase 1 (Soat1) specifically disrupted remote memory. This study identifies some of the first genes required for remote memory, and suggests that screens of targeted mutants may be an efficient strategy to identify molecular requirements for this process. PMID:18464936

  4. Multiplex bead suspension array for screening Neisseria gonorrhoeae antibiotic resistance genetic determinants in noncultured clinical samples.

    PubMed

    Balashov, Sergey; Mordechai, Eli; Adelson, Martin E; Gygax, Scott E

    2013-01-01

    The increasing threat of antibiotic-resistant Neisseria gonorrhoeae highlights the need for new diagnostic options. A high-throughput multiplex bead suspension array assay was developed for profiling 29 N. gonorrhoeae genomic mutations and 2 plasmid genes conferring resistance to 6 antimicrobial agents: penicillin, ciprofloxacin, cefixime, tetracycline, azithromycin, and spectinomycin. The three steps of this assay include amplification of 12 N. gonorrhoeae chromosomal and plasmid loci, multiplex allele-specific primer extension reaction, and multiplex bead suspension array detection. Antibiotic resistance genetic determinants were identified successfully in 239 cervicovaginal N. gonorrhoeae-positive noncultured swab samples. This molecular assay can be used for detection of gonococci in clinical specimens, molecular typing, mutation profiling, and predictive assessment of N. gonorrhoeae susceptibility to antibiotics without the need for culture. PMID:23159594

  5. Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics.

    PubMed

    Koutnikova, Hana; Laakso, Markku; Lu, Lu; Combe, Roy; Paananen, Jussi; Kuulasmaa, Teemu; Kuusisto, Johanna; Häring, Hans-Ulrich; Hansen, Torben; Pedersen, Oluf; Smith, Ulf; Hanefeld, Markolf; Williams, Robert W; Auwerx, Johan

    2009-08-01

    Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.006, respectively and rs2291897: 1.5+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure. PMID:19662162

  6. Identification of the UBP1 Locus as a Critical Blood Pressure Determinant Using a Combination of Mouse and Human Genetics

    PubMed Central

    Koutnikova, Hana; Laakso, Markku; Lu, Lu; Combe, Roy; Paananen, Jussi; Kuulasmaa, Teemu; Kuusisto, Johanna; Häring, Hans-Ulrich; Hansen, Torben; Pedersen, Oluf; Smith, Ulf; Hanefeld, Markolf; Williams, Robert W.; Auwerx, Johan

    2009-01-01

    Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3±0.4 mmHg p<0.001, 0.8±0.3 mmHg p?=?0.006, respectively and rs2291897: 1.5±0.4 mmHg p<0.001, 0.8±0.3 mmHg p?=?0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure. PMID:19662162

  7. 76 FR 63278 - Bayer CropScience LP; Determination of Nonregulated Status for Cotton Genetically Engineered for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-12

    ...Determination of Nonregulated Status for Cotton Genetically Engineered for Insect Resistance...determination that a genetically engineered cotton developed by Bayer CropScience LP, designated as TwinLink TM cotton (events T304-40 and GHB119),...

  8. An unbiased approach to identify genes involved in development in a turtle with temperature-dependent sex determination

    PubMed Central

    2012-01-01

    Background Many reptiles exhibit temperature-dependent sex determination (TSD). The initial cue in TSD is incubation temperature, unlike genotypic sex determination (GSD) where it is determined by the presence of specific alleles (or genetic loci). We used patterns of gene expression to identify candidates for genes with a role in TSD and other developmental processes without making a priori assumptions about the identity of these genes (ortholog-based approach). We identified genes with sexually dimorphic mRNA accumulation during the temperature sensitive period of development in the Red-eared slider turtle (Trachemys scripta), a turtle with TSD. Genes with differential mRNA accumulation in response to estrogen (estradiol-17?; E2) exposure and developmental stages were also identified. Results Sequencing 767 clones from three suppression-subtractive hybridization libraries yielded a total of 581 unique sequences. Screening a macroarray with a subset of those sequences revealed a total of 26 genes that exhibited differential mRNA accumulation: 16 female biased and 10 male biased. Additional analyses revealed that C16ORF62 (an unknown gene) and MALAT1 (a long noncoding RNA) exhibited increased mRNA accumulation at the male producing temperature relative to the female producing temperature during embryonic sexual development. Finally, we identified four genes (C16ORF62, CCT3, MMP2, and NFIB) that exhibited a stage effect and five genes (C16ORF62, CCT3, MMP2, NFIB and NOTCH2) showed a response to E2 exposure. Conclusions Here we report a survey of genes identified using patterns of mRNA accumulation during embryonic development in a turtle with TSD. Many previous studies have focused on examining the turtle orthologs of genes involved in mammalian development. Although valuable, the limitations of this approach are exemplified by our identification of two genes (MALAT1 and C16ORF62) that are sexually dimorphic during embryonic development. MALAT1 is a noncoding RNA that has not been implicated in sexual differentiation in other vertebrates and C16ORF62 has an unknown function. Our results revealed genes that are candidates for having roles in turtle embryonic development, including TSD, and highlight the need to expand our search parameters beyond protein-coding genes. PMID:22793670

  9. Genetic Distances and Variations of Three Geographic Hairtail Populations Identified by PCR Analysis

    PubMed Central

    Yoon, Jong-Man

    2014-01-01

    In the present study, muscle tissues were obtained separately from individuals from Atlantic hairtail population (AHP), Gunsan hairtail population (GHP) and Chinese hairtail population (CHP), respectively. The seven decamer primers were used to generate the shared loci, specific, unique shared loci to each population and shared loci by the three hairtail populations. Here, averagely, a decamer primer generated 64.7 amplified products per primer in the AHP population, 55.7 in GHP population and 56.4 in CHP population. The number of unique shared loci to each population and number of shared loci by the three populations generated by genetic analysis using 7 decamer primers in AHP, GHP and CHP population. 119 unique shared loci to each population, with an average of 17 per primer, were observed in the AHP population, and 28 loci, with an average of 4 per primer, were observed in the CHP population. The hierarchical dendrogram point out three main branches: cluster 1 (ATLANTIC 01 ~ ATLANTIC 07), cluster 2 (GUNSAN 08 ~ GUNSAN 14) and cluster 3 (CHINESE 15 ~ CHINESE 21). The shortest genetic distance displaying significant molecular difference was between individuals’ CHINESE no. 16 and CHINESE no. 18 (0.045). In the long run, individual no. 01 of the AHP population was most distantly related to CHINESE no. 19 (genetic distance = 0.430). Consequently, PCR analysis generated on the genetic data displayed that the geographic AHP population was widely separated from CHP population, while individuals of CHP population were fairly closely related to those of GHP population. PMID:25949186

  10. Identifying indicator species for post-release monitoring of genetically modified, herbicide resistant crops

    Microsoft Academic Search

    Angelika Hilbeck; Matthias Meier; Armin Benzler

    2008-01-01

    In Europe, regulations for release and placing-on-the-market of genetically modified (GM) crops require post-release monitoring\\u000a of their impact on the environment. Monitoring potential adverse effects of GM crops includes direct effects as well as indirect\\u000a effects, e.g. GM crop specific changes in land and pest management. Currently, there is a gap in the pre-release risk assessments\\u000a conducted for regulatory approval

  11. Newly identified genetic risk variants for celiac disease related to the immune response

    Microsoft Academic Search

    Karen A Hunt; Alexandra Zhernakova; Graham Turner; Graham A R Heap; Lude Franke; Marcel Bruinenberg; Jihane Romanos; Lotte C Dinesen; Anthony W Ryan; Davinder Panesar; Rhian Gwilliam; Fumihiko Takeuchi; William M McLaren; Geoffrey K T Holmes; Peter D Howdle; Julian R F Walters; David S Sanders; Raymond J Playford; Gosia Trynka; Chris J J Mulder; M Luisa Mearin; Wieke H M Verbeek; Valerie Trimble; Fiona M Stevens; Colm O'Morain; Nicholas P Kennedy; Dermot Kelleher; Daniel J Pennington; David P Strachan; Wendy L McArdle; Charles A Mein; Martin C Wapenaar; Panos Deloukas; Ralph McGinnis; Ross McManus; Cisca Wijmenga; David A van Heel

    2008-01-01

    Our genome-wide association study of celiac disease previously identified risk variants in the IL2–IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P <

  12. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes

    PubMed Central

    Edwards, Timothy J.; Sherr, Elliott H.; Barkovich, A. James

    2014-01-01

    The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field. PMID:24477430

  13. Genome-wide association study identifies four genetic loci associated with thyroid volume and goiter risk.

    PubMed

    Teumer, Alexander; Rawal, Rajesh; Homuth, Georg; Ernst, Florian; Heier, Margit; Evert, Matthias; Dombrowski, Frank; Völker, Uwe; Nauck, Matthias; Radke, Dörte; Ittermann, Till; Biffar, Reiner; Döring, Angela; Gieger, Christian; Klopp, Norman; Wichmann, H-Erich; Wallaschofski, Henri; Meisinger, Christa; Völzke, Henry

    2011-05-13

    Thyroid disorders such as goiters represent important diseases, especially in iodine-deficient areas. Sibling studies have demonstrated that genetic factors substantially contribute to the interindividual variation of thyroid volume. We performed a genome-wide association study of this phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania (SHIP). Four genetic loci were associated with thyroid volume on a genome-wide level of significance. Of these, two independent loci are located upstream of and within CAPZB, which encodes the ? subunit of the barbed-end F-actin binding protein that modulates actin polymerization, a process crucial in the colloid engulfment during thyroglobulin mobilization in the thyroid. The third locus marks FGF7, which encodes fibroblast growth factor 7. Members of this protein family have been discussed as putative signal molecules involved in the regulation of thyroid development. The fourth locus represents a "gene desert" on chromosome 16q23, located directly downstream of the predicted coding sequence LOC440389, which, however, had already been removed from the NCBI database as a result of the standard genome annotation processing at the time that this study was initiated. Experimental proof of the formerly predicted mature mRNA, however, demonstrates that LOC440389 indeed represents a real gene. All four associations were replicated in an independent sample of 1290 participants of the KORA study. These results increase the knowledge about genetic factors and physiological mechanisms influencing thyroid volume. PMID:21565293

  14. Genetic Differentiation among Recently Diverged Delphinid Taxa Determined

    E-print Network

    Fagan, William

    and mitochondrial DNA (mtDNA) sequences. This species is sympatric with a second species, Delphinus delphis genomes? We used amplified fragment length polymorphism (AFLP) markers to broadly survey the nuclear genomes of these two species to examine the levels of nuclear divergence and genetic diversity between

  15. A Novel Approach to Identify Candidate Prognostic Factors for Hepatitis C Treatment Response Integrating Clinical and Viral Genetic Data

    PubMed Central

    Amadoz, Alicia; González-Candelas, Fernando

    2015-01-01

    The combined therapy of pegylated interferon (IFN) plus ribavirin (RBV) has been for a long time the standard treatment for patients infected with hepatitis C virus (HCV). In the case of genotype 1, only 38%–48% of patients have a positive response to the combined treatment. In previous studies, viral genetic information has been occasionally included as a predictor. Here, we consider viral genetic variation in addition to 11 clinical and 19 viral populations and evolutionary parameters to identify candidate baseline prognostic factors that could be involved in the treatment outcome. We obtained potential prognostic models for HCV subtypes la and lb in combination as well as separately. We also found that viral genetic information is relevant for the combined treatment assessment of patients, as the potential prognostic model of joint subtypes includes 9 viral-related variables out of 11. Our proposed methodology fully characterizes viral genetic information and finds a combination of positions that modulate inter-patient variability. PMID:25780333

  16. Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.

    PubMed

    Herder, Christian; Nuotio, Marja-Liisa; Shah, Sonia; Blankenberg, Stefan; Brunner, Eric J; Carstensen, Maren; Gieger, Christian; Grallert, Harald; Jula, Antti; Kähönen, Mika; Kettunen, Johannes; Kivimäki, Mika; Koenig, Wolfgang; Kristiansson, Kati; Langenberg, Claudia; Lehtimäki, Terho; Luotola, Kari; Marzi, Carola; Müller, Christian; Peters, Annette; Prokisch, Holger; Raitakari, Olli; Rathmann, Wolfgang; Roden, Michael; Salmi, Marko; Schramm, Katharina; Swerdlow, Daniel; Tabak, Adam G; Thorand, Barbara; Wareham, Nick; Wild, Philipp S; Zeller, Tanja; Hingorani, Aroon D; Witte, Daniel R; Kumari, Meena; Perola, Markus; Salomaa, Veikko

    2014-12-01

    The proinflammatory cytokine interleukin (IL)-1? is implicated in the development of insulin resistance and ?-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1?, has been suggested to improve glycemia and ?-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance. PMID:24969107

  17. Genetic determinism of anatomical and hydraulic traits within an apple progeny.

    PubMed

    Lauri, Pierre-Éric; Gorza, Olivier; Cochard, Hervé; Martinez, Sébastien; Celton, Jean-Marc; Ripetti, Véronique; Lartaud, Marc; Bry, Xavier; Trottier, Catherine; Costes, Evelyne

    2011-08-01

    The apple tree is known to have an isohydric behaviour, maintaining rather constant leaf water potential in soil with low water status and/or under high evaporative demand. However, little is known on the xylem water transport from roots to leaves from the two perspectives of efficiency and safety, and on its genetic variability. We analysed 16 traits related to hydraulic efficiency and safety, and anatomical traits in apple stems, and the relationships between them. Most variables were found heritable, and we investigated the determinism underlying their genetic control through a quantitative trait loci (QTL) analysis on 90 genotypes from the same progeny. Principal component analysis (PCA) revealed that all traits related to efficiency, whether hydraulic conductivity, vessel number and area or wood area, were included in the first PC, whereas the second PC included the safety variables, thus confirming the absence of trade-off between these two sets of traits. Our results demonstrated that clustered variables were characterized by common genomic regions. Together with previous results on the same progeny, our study substantiated that hydraulic efficiency traits co-localized with traits identified for tree growth and fruit production. PMID:21477120

  18. Application of Genetic Algorithms and Thermogravimetry to Determine the Kinetics of Polyurethane Foam in Smoldering Combustion 

    E-print Network

    Rein, Guillermo; Lautenberger, Chris; Fernandez-Pello, Carlos; Torero, Jose L; Urban, David

    In this work, the kinetic parameters governing the thermal and oxidative degradation of flexible polyurethane foam are determined using thermogravimetric data and a genetic algorithm. These kinetic parameters are needed ...

  19. Human usage in the native range may determine future genetic structure of an invasion: insights from Acacia pycnantha

    PubMed Central

    2013-01-01

    Background The influence of introduction history and post-introduction dynamics on genetic diversity and structure has been a major research focus in invasion biology. However, genetic diversity and structure in the invasive range can also be affected by human-mediated processes in the native range prior to species introductions, an aspect often neglected in invasion biology. Here we aim to trace the native provenance of the invasive tree Acacia pycnantha by comparing the genetic diversity and structure between populations in the native Australian range and the invasive range in South Africa. This approach also allowed us to explore how human actions altered genetic structure before and after the introduction of A. pycnantha into South Africa. We hypothesized that extensive movement and replanting in A. pycnantha’s Australian range prior to its introduction to South Africa might result in highly admixed genotypes in the introduced range, comparable genetic diversity in both ranges, and therefore preclude an accurate determination of native provenance(s) of invasive populations. Results In the native range Bayesian assignment tests identified three genetic clusters with substantial admixture and could not clearly differentiate previously identified genetic entities, corroborating admixture as a result of replantings within Australia. Assignment tests that included invasive populations from South Africa indicated similar levels of admixture compared to Australian populations and a lack of genetic structure. Invasive populations of A. pycnantha in South Africa are as genetically diverse as native populations, and could not be assigned to particular native range regions. Conclusions Our results indicate that the genetic structure of A. pycnantha in Australia has been greatly altered through various planting initiatives. Specifically, there is little geographic structure and high levels of admixture. While numerous introduction history scenarios may explain the levels of admixture observed in South Africa, planting records of A. pycnantha in Australia suggest that populations were probably already admixed before propagules were introduced to South Africa. These findings have important implications for the management of invasive A. pycnantha populations in South Africa, especially for classical biological control, and more broadly, for studies that aim to understand the evolutionary dynamics of the invasion process. PMID:24083397

  20. Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

    PubMed Central

    Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

    2013-01-01

    Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10?7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

  1. Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans

    E-print Network

    Breitling, Rainer

    - ature-induced sex determination in reptiles [9] and seasonal polyphenism in butterflies [10Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans Yang Li1 the molecular determinants of phenotypic plasticity. Citation: Li Y, Alvarez OA, Gutteling EW, Tijsterman M, Fu

  2. Genetic determination of motor neuron disease and neuropathy.

    PubMed

    Vrebalov Cindro, Pavle; Vrebalov Cindro, Veselin

    2015-03-01

    Following the completion of the Human Genome Project, a lot of progress has been made in understanding the genetic basis of motor neuron diseases (MNDs) and neuropathies. Spinal Muscular Atrophies (SMA) are caused by mutations in the SMN1 gene localized on Chromosome 5q11. Amyotrophic Lateral Sclerosis (ALS) has been found to have at least 18 different types, many of them associated to different genetic loci (e.g. SOD1, ALS2, SETX, FUS, VAPB, ANG, TARDBP and others), but many of the forms have still not been associated with a particular gene. Sensomotoric hereditary neuropathies (Charcot-Marie-Tooth) are a large heterogeneous group of various hereditary neuropathies, which have also been associated with a wide spectrum of genetic mutations, such as PMP22, LITAF, EGR2, P0 protein, KIF1B, MFN2, RAB7 and others. It is also apparent that more genes are being implicated, mutations discovered, and phenotypes recognised and broadened. Therefore, a lot of continuing, additional research effort will be required in the coming years to illuminate pathogenic mechanisms that underlie motor neuron diseases and neuropathies and that could lead to new and improved treatments. PMID:26040103

  3. Genetic implanted fuzzy model for water saturation determination

    NASA Astrophysics Data System (ADS)

    Bagheripour, Parisa; Asoodeh, Mojtaba

    2014-04-01

    The portion of rock pore volume occupied with non-hydrocarbon fluids is called water saturation, which plays a significant role in reservoir description and management. Accurate water saturation, directly measured from special core analysis is highly expensive and time consuming. Furthermore, indirect measurements of water saturation from well log interpretation such as empirical correlations or statistical methods do not provide satisfying results. Recent works showed that fuzzy logic is a robust tool for handling geosciences problems which provide more reliable results compared with empirical correlations or statistical methods. This study goes further to improve fuzzy logic for enhancing accuracy of final prediction. It employs hybrid genetic algorithm-pattern search technique instead of widely held subtractive clustering approach for setting up fuzzy rules and for extracting optimal parameters involved in computational structure of fuzzy model. The proposed strategy, called genetic implanted fuzzy model, was used to formulate conventional well log data, including sonic transit time, neutron porosity, formation bulk density, true resistivity, and gamma ray into water saturation, obtained from subtractive clustering approach. Results indicated genetic implanted fuzzy model performed more satisfyingly compared with traditional fuzzy logic model. The propounded model was successfully applied to one of Iranian carbonate reservoir rocks.

  4. A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses 

    E-print Network

    Conway, David J; Cavanagh, David R; Tanabe, K; Roper, C; Mikes, Z S; Sakihama, N; Bojang, K A; Oduola, A M J; Kremsner, P G; Arnot, D E; Greenwood, B M; McBride, J S

    New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium ...

  5. [Genetic variability of Aedes aegypti determined by mitochondrial gene ND4 analysis in eleven endemic areas for dengue in Peru].

    PubMed

    Yáñez, Pamela; Mamani, Enrique; Valle, Jorge; García, María Paquita; León, Walter; Villaseca, Pablo; Torres, Dina; Cabezas, César

    2013-04-01

    In order to establish the genetic variability of Aedes aegypti determined by the analysis of the MT-ND4 gene, in eleven endemic regions for dengue in Peru, 51 samples of Ae. Aegypti were tested. The genetic variability was determined through the amplification and sequencing of a fragment of 336 base-pairs of MT ND4, the analysis of intra-specific phylogeny was conducted with the Network Ver. 4.6.10 program; and the phylogenetic analysis, with the Neighbor Joining distance method. The presence of five haplotypes of Ae. Aegypti grouped in two lineages was identified: the first one includes haplotypes 1, 3 and 5, and the second one comprises haplotypes 2 and 4. The geographic distribution of each of the haplotypes found is also shown. It is concluded that this variability is caused by the active migration of this vector and the human activity-mediated passive migration. PMID:23949510

  6. A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity.

    PubMed

    Pettitt, Stephen J; Rehman, Farah L; Bajrami, Ilirjana; Brough, Rachel; Wallberg, Fredrik; Kozarewa, Iwanka; Fenwick, Kerry; Assiotis, Ioannis; Chen, Lina; Campbell, James; Lord, Christopher J; Ashworth, Alan

    2013-01-01

    Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such screens have historically been difficult in diploid mammalian cells. The recent derivation of haploid embryonic stem cells provides an opportunity to cause loss of function mutants with a random mutagen in a mammalian cell with a normal genetic background. We describe an approach to genetic screens that exploits the highly active piggyBac transposon in haploid mammalian cells. As an example of haploid transposon (HTP) screening, we apply this approach to identifying determinants of cancer drug toxicity and resistance. In a screen for 6-thioguanine resistance we recovered components of the DNA mismatch repair pathway, a known requirement for toxicity. In a further screen for resistance to the clinical poly(ADP-ribose) polymerase (PARP) inhibitor olaparib we recovered multiple Parp1 mutants. Our results show that olaparib toxicity to normal cells is mediated predominantly via Parp1, and suggest that the clinical side effects of olaparib may be on target. The transposon mutant libraries are stable and can be readily reused to screen other drugs. The screening protocol described has several advantages over other methods such as RNA interference: it is rapid and low cost, and mutations can be easily reverted to establish causality. PMID:23634208

  7. A Genetic Screen Using the PiggyBac Transposon in Haploid Cells Identifies Parp1 as a Mediator of Olaparib Toxicity

    PubMed Central

    Pettitt, Stephen J.; Rehman, Farah L.; Bajrami, Ilirjana; Brough, Rachel; Wallberg, Fredrik; Kozarewa, Iwanka; Fenwick, Kerry; Assiotis, Ioannis; Chen, Lina; Campbell, James; Lord, Christopher J.; Ashworth, Alan

    2013-01-01

    Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such screens have historically been difficult in diploid mammalian cells. The recent derivation of haploid embryonic stem cells provides an opportunity to cause loss of function mutants with a random mutagen in a mammalian cell with a normal genetic background. We describe an approach to genetic screens that exploits the highly active piggyBac transposon in haploid mammalian cells. As an example of haploid transposon (HTP) screening, we apply this approach to identifying determinants of cancer drug toxicity and resistance. In a screen for 6-thioguanine resistance we recovered components of the DNA mismatch repair pathway, a known requirement for toxicity. In a further screen for resistance to the clinical poly(ADP-ribose) polymerase (PARP) inhibitor olaparib we recovered multiple Parp1 mutants. Our results show that olaparib toxicity to normal cells is mediated predominantly via Parp1, and suggest that the clinical side effects of olaparib may be on target. The transposon mutant libraries are stable and can be readily reused to screen other drugs. The screening protocol described has several advantages over other methods such as RNA interference: it is rapid and low cost, and mutations can be easily reverted to establish causality. PMID:23634208

  8. Identifying determinants of effective complementary feeding behaviour change interventions in developing countries

    PubMed Central

    Fabrizio, Cecilia S; van Liere, Marti; Pelto, Gretel

    2014-01-01

    As stunting moves to the forefront of the global agenda, there is substantial evidence that behaviour change interventions (BCI) can improve infant feeding practices and growth. However, this evidence has not been translated into improved outcomes on a national level because we do not know enough about what makes these interventions work, for whom, when, why, at what cost and for how long. Our objective was to examine the design and implementation of complementary feeding BCI, from the peer-reviewed literature, to identify generalisable key determinants. We identified 29 studies that evaluated BCI efficacy or effectiveness, were conducted in developing countries, and reported outcomes on infant and young children aged 6–24 months. Two potential determinants emerged: (1) effective studies used formative research to identify cultural barriers and enablers to optimal feeding practices, to shape the intervention strategy, and to formulate appropriate messages and mediums for delivery; (2) effective studies delineated the programme impact pathway to the target behaviour change and assessed intermediary behaviour changes to learn what worked. We found that BCI that used these developmental and implementation processes could be effective despite heterogeneous approaches and design components. Our analysis was constrained, however, by the limited published data on how design and implementation were carried out, perhaps because of publishing space limits. Information on cost-effectiveness, sustainability and scalability was also very limited. We suggest a more comprehensive reporting process and a more strategic research agenda to enable generalisable evidence to accumulate. PMID:24798264

  9. Integrating EMR-Linked and In Vivo Functional Genetic Data to Identify New Genotype-Phenotype Associations

    PubMed Central

    Mosley, Jonathan D.; Van Driest, Sara L.; Weeke, Peter E.; Delaney, Jessica T.; Wells, Quinn S.; Bastarache, Lisa; Roden, Dan M.; Denny, Josh C.

    2014-01-01

    The coupling of electronic medical records (EMR) with genetic data has created the potential for implementing reverse genetic approaches in humans, whereby the function of a gene is inferred from the shared pattern of morbidity among homozygotes of a genetic variant. We explored the feasibility of this approach to identify phenotypes associated with low frequency variants using Vanderbilt's EMR-based BioVU resource. We analyzed 1,658 low frequency non-synonymous SNPs (nsSNPs) with a minor allele frequency (MAF)<10% collected on 8,546 subjects. For each nsSNP, we identified diagnoses shared by at least 2 minor allele homozygotes and with an association p<0.05. The diagnoses were reviewed by a clinician to ascertain whether they may share a common mechanistic basis. While a number of biologically compelling clinical patterns of association were observed, the frequency of these associations was identical to that observed using genotype-permuted data sets, indicating that the associations were likely due to chance. To refine our analysis associations, we then restricted the analysis to 711 nsSNPs in genes with phenotypes in the On-line Mendelian Inheritance in Man (OMIM) or knock-out mouse phenotype databases. An initial comparison of the EMR diagnoses to the known in vivo functions of the gene identified 25 candidate nsSNPs, 19 of which had significant genotype-phenotype associations when tested using matched controls. Twleve of the 19 nsSNPs associations were confirmed by a detailed record review. Four of 12 nsSNP-phenotype associations were successfully replicated in an independent data set: thrombosis (F5,rs6031), seizures/convulsions (GPR98,rs13157270), macular degeneration (CNGB3,rs3735972), and GI bleeding (HGFAC,rs16844401). These analyses demonstrate the feasibility and challenges of using reverse genetics approaches to identify novel gene-phenotype associations in human subjects using low frequency variants. As increasing amounts of rare variant data are generated from modern genotyping and sequence platforms, model organism data may be an important tool to enable discovery. PMID:24949630

  10. Genetic approaches to chemotype determination in type B-trichothecene producing Fusaria.

    PubMed

    Pasquali, Matias; Migheli, Quirico

    2014-10-17

    This review summarises the genetic methods used for chemotype determination of the main Fusarium type B-trichothecene producing species. Literature on Fusarium chemotype epidemiology over the last 15 years is reviewed in order to describe temporal and spatial chemotype distribution of these fungi worldwide. Genetic approaches used for chemotype determination are also reviewed and discussed, highlighting successes and potential pitfalls of the technique. Results from both genetic and chemical approaches are summarised to compare reliability, advantages and limitations of the two methods. Potential applications of genetic chemotyping to toxigenic Fusarium species are evaluated in the light of improving food safety of agricultural products. The use of chemotype determination in population studies, toxin prediction as well as for breeding purpose is described. PMID:25150674

  11. Genetic analysis of the two zebrafish patched homologues identifies novel roles for the hedgehog signaling pathway

    PubMed Central

    Koudijs, Marco J; den Broeder, Marjo J; Groot, Evelyn; van Eeden, Fredericus JM

    2008-01-01

    Background Aberrant activation of the Hedgehog (Hh) signaling pathway in different organisms has shown the importance of this family of morphogens during development. Genetic screens in zebrafish have assigned specific roles for Hh in proliferation, differentiation and patterning, but mainly as a result of a loss of its activity. We attempted to fully activate the Hh pathway by removing both receptors for the Hh proteins, called Patched1 and 2, which are functioning as negative regulators in this pathway. Results Here we describe a splice-donor mutation in Ptc1, called ptc1hu1602, which in a homozygous state results in a subtle eye and somite phenotype. Since we recently positionally cloned a ptc2 mutant, a ptc1;ptc2 double mutant was generated, showing severely increased levels of ptc1, gli1 and nkx2.2a, confirming an aberrant activation of Hh signaling. As a consequence, a number of phenotypes were observed that have not been reported previously using Shh mRNA overexpression. Somites of ptc1;ptc2 double mutants do not express anteroposterior polarity markers, however initial segmentation of the somites itself is not affected. This is the first evidence that segmentation and anterior/posterior (A/P) patterning of the somites are genetically uncoupled processes. Furthermore, a novel negative function of Hh signaling is observed in the induction of the fin field, acting well before any of the previously reported function of Shh in fin formation and in a way that is different from the proposed early role of Gli3 in limb/fin bud patterning. Conclusion The generation and characterization of the ptc1;ptc2 double mutant assigned novel and unexpected functions to the Hh signaling pathway. Additionally, these mutants will provide a useful system to further investigate the consequences of constitutively activated Hh signaling during vertebrate development. PMID:18284698

  12. Common genetic determinants of vitamin D insufficiency: a genome-wide association study

    PubMed Central

    Wang, Thomas J.; Zhang, Feng; Richards, J. Brent; Kestenbaum, Bryan; van Meurs, Joyce B.; Berry, Diane; Kiel, Douglas; Streeten, Elizabeth A.; Ohlsson, Claes; Koller, Daniel L.; Palotie, Leena; Cooper, Jason D.; O'Reilly, Paul F.; Houston, Denise K.; Glazer, Nicole L.; Vandenput, Liesbeth; Peacock, Munro; Shi, Julia; Rivadeneira, Fernando; McCarthy, Mark I.; Anneli, Pouta; de Boer, Ian H.; Mangino, Massimo; Kato, Bernet; Smyth, Deborah J.; Booth, Sarah L.; Jacques, Paul F.; Burke, Greg L.; Goodarzi, Mark; Cheung, Ching-Lung; Wolf, Myles; Rice, Kenneth; Goltzman, David; Hidiroglou, Nick; Ladouceur, Martin; Hui, Siu L.; Wareham, Nicholas J.; Hocking, Lynne J.; Hart, Deborah; Arden, Nigel K.; Cooper, Cyrus; Malik, Suneil; Fraser, William D.; Hartikainen, Anna-Liisa; Zhai, Guangju; Macdonald, Helen; Forouhi, Nita G.; Loos, Ruth J.F.; Reid, David M.; Hakim, Alan; Dennison, Elaine; Liu, Yongmei; Power, Chris; Stevens, Helen E.; Jaana, Laitinen; Vasan, Ramachandran S.; Soranzo, Nicole; Bojunga, Jörg; Psaty, Bruce M.; Lorentzon, Mattias; Foroud, Tatiana; Harris, Tamara B.; Hofman, Albert; Jansson, John-Olov; Cauley, Jane A.; Uitterlinden, Andre G.; Gibson, Quince; Järvelin, Marjo-Riitta; Karasik, David; Siscovick, David S.; Econs, Michael J.; Kritchevsky, Stephen B.; Florez, Jose C.; Todd, John A.; Dupuis, Josee; Hypponen, Elina; Spector, Timothy D.

    2010-01-01

    Background Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. Methods We performed a genome-wide association study of 25-OH D among ?30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L. Findings Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P?1 × 10-26). Interpretation Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency. PMID:20541252

  13. Myeloperoxidase genetic polymorphisms modulate human neutrophil enzyme activity: Genetic determinants for atherosclerosis?

    Microsoft Academic Search

    Isabelle Chevrier; David-Alexandre Tregouet; Simone Massonnet-Castel; Philippe Beaune; Marie-Anne Loriot

    2006-01-01

    ObjectiveMyeloperoxidase (MPO), an abundant leukocyte hemoprotein has been linked to atherosclerosis and cardiovascular disease. We previously found new genetic polymorphisms in MPO gene. The purpose of this study was to evaluate the influences of these polymorphisms on human neutrophil MPO activity by means of haplotype analysis.

  14. Identifiers Identifiers

    E-print Network

    Brass, Stefan

    , July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] . Uniform://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

  15. Identifiers Identifiers

    E-print Network

    Brass, Stefan

    , July 1998. . Tim Berners­Lee: Cool URIs don't change. [http://www.w3.org/Provider/Style/URI] Stefan://archive.ncsa.uiuc.edu/demoweb/url­primer.html] . T. Berners­Lee, R. Fielding, L. Masinter: Uniform Resource Identifiers (URI): Generic Syntax. RFC Names. RFC 1737, December 1994, 7 pages. . T. Berners­Lee, L. Masinter, M. McCahill: Uniform Resource

  16. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia

    PubMed Central

    Sheehan, Vivien; Linder, Heidi; Howard, Thad A.; Wang, Yong-Dong; Hoppe, Carolyn C.; Aygun, Banu; Adams, Robert J.; Neale, Geoffrey A.; Ware, Russell E.

    2013-01-01

    Stroke is a devastating complication of sickle cell anemia (SCA), occurring in 11% of patients before age 20 years. Previous studies of sibling pairs have demonstrated a genetic component to the development of cerebrovascular disease in SCA, but few candidate genetic modifiers have been validated as having a substantial effect on stroke risk. We performed an unbiased whole-genome search for genetic modifiers of stroke risk in SCA. Genome-wide association studies were performed using genotype data from single-nucleotide polymorphism arrays, whereas a pooled DNA approach was used to perform whole-exome sequencing. In combination, 22 nonsynonymous variants were identified and represent key candidates for further in-depth study. To validate the association of these mutations with the risk for stroke, the 22 candidate variants were genotyped in an independent cohort of control patients (n = 231) and patients with stroke (n = 57) with SCA. One mutation in GOLGB1 (Y1212C) and another mutation in ENPP1 (K173Q) were confirmed as having significant associations with a decreased risk for stroke. These mutations were discovered and validated by an unbiased whole-genome approach, and future studies will focus on how these functional mutations may lead to protection from stroke in the context of SCA. PMID:23422753

  17. Niche Divergence versus Neutral Processes: Combined Environmental and Genetic Analyses Identify Contrasting Patterns of Differentiation in Recently Diverged Pine Species

    PubMed Central

    Moreno-Letelier, Alejandra; Ortíz-Medrano, Alejandra; Piñero, Daniel

    2013-01-01

    Background and Aims Solving relationships of recently diverged taxa, poses a challenge due to shared polymorphism and weak reproductive barriers. Multiple lines of evidence are needed to identify independently evolving lineages. This is especially true of long-lived species with large effective population sizes, and slow rates of lineage sorting. North American pines are an interesting group to test this multiple approach. Our aim is to combine cytoplasmic genetic markers with environmental information to clarify species boundaries and relationships of the species complex of Pinus flexilis, Pinus ayacahuite, and Pinus strobiformis. Methods Mitochondrial and chloroplast sequences were combined with previously obtained microsatellite data and contrasted with environmental information to reconstruct phylogenetic relationships of the species complex. Ecological niche models were compared to test if ecological divergence is significant among species. Key Results and Conclusion Separately, both genetic and ecological evidence support a clear differentiation of all three species but with different topology, but also reveal an ancestral contact zone between P. strobiformis and P. ayacahuite. The marked ecological differentiation of P. flexilis suggests that ecological speciation has occurred in this lineage, but this is not reflected in neutral markers. The inclusion of environmental traits in phylogenetic reconstruction improved the resolution of internal branches. We suggest that combining environmental and genetic information would be useful for species delimitation and phylogenetic studies in other recently diverged species complexes. PMID:24205167

  18. Using molecular genetics to identify immature specimens of the weevil Ceratapion basicorne (Coleoptera, Apionidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A field experiment was conducted to evaluate host plant specificity of the yellow starthistle rosette weevil, Ceratapion basicorne. Larvae infesting plants were preserved in 99% ethanol. Adult specimens of C. basicorne and four closely related species were identified using conventional morphologic...

  19. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.

    PubMed

    Eyre, Steve; Bowes, John; Diogo, Dorothée; Lee, Annette; Barton, Anne; Martin, Paul; Zhernakova, Alexandra; Stahl, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I; Padyukov, Leonid; Toes, Rene E M; Huizinga, Tom W J; Wijmenga, Cisca; Trynka, Gosia; Franke, Lude; Westra, Harm-Jan; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I W; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Pat; Onengut-Gumuscu, Suna; Rich, Stephen S; Deloukas, Panos; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlsetig, Lisbeth; Martin, Javier; Rantapää-Dahlqvist, Solbritt; Plenge, Robert M; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

    2012-12-01

    Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations. PMID:23143596

  20. A forward genetic screen in mice identifies mutants with abnormal cortical patterning.

    PubMed

    Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J; Beier, David R

    2015-01-01

    Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain. PMID:23968836

  1. Multi-locus DNA sequencing of Toxoplasma gondii isolated from Brazilian pigs identifies genetically divergent strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Five Toxoplasma gondii isolates (TgPgBr1-5) were isolated from hearts and brains of pigs freshly purchased at the market of Campos dos Goytacazes, Northern Rio de Janeiro State, Brazil. Four of the five isolates were highly pathogenic in mice. Four genotypes were identified. Multi-locus DNA sequenci...

  2. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis.

    PubMed

    Rahrmann, Eric P; Watson, Adrienne L; Keng, Vincent W; Choi, Kwangmin; Moriarity, Branden S; Beckmann, Dominic A; Wolf, Natalie K; Sarver, Aaron; Collins, Margaret H; Moertel, Christopher L; Wallace, Margaret R; Gel, Bernat; Serra, Eduard; Ratner, Nancy; Largaespada, David A

    2013-07-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/?-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance. PMID:23685747

  3. An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.

    PubMed

    Williams, Charles H; Hempel, Jonathan E; Hao, Jijun; Frist, Audrey Y; Williams, Michelle M; Fleming, Jonathan T; Sulikowski, Gary A; Cooper, Michael K; Chiang, Chin; Hong, Charles C

    2015-04-01

    Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation. PMID:25818300

  4. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

    PubMed

    Berndt, Sonja I; Gustafsson, Stefan; Mägi, Reedik; Ganna, Andrea; Wheeler, Eleanor; Feitosa, Mary F; Justice, Anne E; Monda, Keri L; Croteau-Chonka, Damien C; Day, Felix R; Esko, Tõnu; Fall, Tove; Ferreira, Teresa; Gentilini, Davide; Jackson, Anne U; Luan, Jian'an; Randall, Joshua C; Vedantam, Sailaja; Willer, Cristen J; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Hu, Yi-Juan; Lee, Sang Hong; Liang, Liming; Lin, Dan-Yu; Min, Josine L; Neale, Benjamin M; Thorleifsson, Gudmar; Yang, Jian; Albrecht, Eva; Amin, Najaf; Bragg-Gresham, Jennifer L; Cadby, Gemma; den Heijer, Martin; Eklund, Niina; Fischer, Krista; Goel, Anuj; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jarick, Ivonne; Johansson, Åsa; Johnson, Toby; Kanoni, Stavroula; Kleber, Marcus E; König, Inke R; Kristiansson, Kati; Kutalik, Zoltán; Lamina, Claudia; Lecoeur, Cecile; Li, Guo; Mangino, Massimo; McArdle, Wendy L; Medina-Gomez, Carolina; Müller-Nurasyid, Martina; Ngwa, Julius S; Nolte, Ilja M; Paternoster, Lavinia; Pechlivanis, Sonali; Perola, Markus; Peters, Marjolein J; Preuss, Michael; Rose, Lynda M; Shi, Jianxin; Shungin, Dmitry; Smith, Albert Vernon; Strawbridge, Rona J; Surakka, Ida; Teumer, Alexander; Trip, Mieke D; Tyrer, Jonathan; Van Vliet-Ostaptchouk, Jana V; Vandenput, Liesbeth; Waite, Lindsay L; Zhao, Jing Hua; Absher, Devin; Asselbergs, Folkert W; Atalay, Mustafa; Attwood, Antony P; Balmforth, Anthony J; Basart, Hanneke; Beilby, John; Bonnycastle, Lori L; Brambilla, Paolo; Bruinenberg, Marcel; Campbell, Harry; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Connell, John M; Cookson, William O; de Faire, Ulf; de Vegt, Femmie; Dei, Mariano; Dimitriou, Maria; Edkins, Sarah; Estrada, Karol; Evans, David M; Farrall, Martin; Ferrario, Marco M; Ferrières, Jean; Franke, Lude; Frau, Francesca; Gejman, Pablo V; Grallert, Harald; Grönberg, Henrik; Gudnason, Vilmundur; Hall, Alistair S; Hall, Per; Hartikainen, Anna-Liisa; Hayward, Caroline; Heard-Costa, Nancy L; Heath, Andrew C; Hebebrand, Johannes; Homuth, Georg; Hu, Frank B; Hunt, Sarah E; Hyppönen, Elina; Iribarren, Carlos; Jacobs, Kevin B; Jansson, John-Olov; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Kee, Frank; Khaw, Kay-Tee; Kivimäki, Mika; Koenig, Wolfgang; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Laitinen, Jaana H; Lakka, Timo A; Langenberg, Claudia; Launer, Lenore J; Lind, Lars; Lindström, Jaana; Liu, Jianjun; Liuzzi, Antonio; Lokki, Marja-Liisa; Lorentzon, Mattias; Madden, Pamela A; Magnusson, Patrik K; Manunta, Paolo; Marek, Diana; März, Winfried; Mateo Leach, Irene; McKnight, Barbara; Medland, Sarah E; Mihailov, Evelin; Milani, Lili; Montgomery, Grant W; Mooser, Vincent; Mühleisen, Thomas W; Munroe, Patricia B; Musk, Arthur W; Narisu, Narisu; Navis, Gerjan; Nicholson, George; Nohr, Ellen A; Ong, Ken K; Oostra, Ben A; Palmer, Colin N A; Palotie, Aarno; Peden, John F; Pedersen, Nancy; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Prokopenko, Inga; Pütter, Carolin; Radhakrishnan, Aparna; Raitakari, Olli; Rendon, Augusto; Rivadeneira, Fernando; Rudan, Igor; Saaristo, Timo E; Sambrook, Jennifer G; Sanders, Alan R; Sanna, Serena; Saramies, Jouko; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Shin, So-Youn; Signorini, Stefano; Sinisalo, Juha; Skrobek, Boris; Soranzo, Nicole; Stan?áková, Alena; Stark, Klaus; Stephens, Jonathan C; Stirrups, Kathleen; Stolk, Ronald P; Stumvoll, Michael; Swift, Amy J; Theodoraki, Eirini V; Thorand, Barbara; Tregouet, David-Alexandre; Tremoli, Elena; Van der Klauw, Melanie M; van Meurs, Joyce B J; Vermeulen, Sita H; Viikari, Jorma; Virtamo, Jarmo; Vitart, Veronique; Waeber, Gérard; Wang, Zhaoming; Widén, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Winkelmann, Bernhard R; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Wong, Andrew; Wright, Alan F; Zillikens, M Carola; Amouyel, Philippe; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Chanock, Stephen J; Cupples, L Adrienne; Cusi, Daniele; Dedoussis, George V; Erdmann, Jeanette; Eriksson, Johan G; Franks, Paul W; Froguel, Philippe; Gieger, Christian; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hinney, Anke; Hofman, Albert; Hovingh, Kees G; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kuh, Diana; Laakso, Markku; Lehtimäki, Terho; Levinson, Douglas F; Martin, Nicholas G; Metspalu, Andres; Morris, Andrew D; Nieminen, Markku S

    2013-05-01

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. PMID:23563607

  5. Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function.

    PubMed

    Rawal, Rajesh; Teumer, Alexander; Völzke, Henry; Wallaschofski, Henri; Ittermann, Till; Åsvold, Bjørn O; Bjøro, Trine; Greiser, Karin H; Tiller, Daniel; Werdan, Karl; Meyer zu Schwabedissen, Henriette E; Doering, Angela; Illig, Thomas; Gieger, Christian; Meisinger, Christa; Homuth, Georg

    2012-07-15

    Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the ?-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ?3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function. PMID:22494929

  6. nature genetics | volume 46 | NumBeR 12 | DeCemBeR 2014 1251 new ability to identify upstream regulators of these mutated

    E-print Network

    Kaski, Samuel

    nature genetics | volume 46 | NumBeR 12 | DeCemBeR 2014 1251 Editorial new ability to identify for cancer cell phenotypes as well as an ability to begin to understand the genetic changes driving about for somatic mutations altering transcription, finding TERT promoter mutations in 6 types but surprisingly few

  7. Coupling Genetics and Proteomics To Identify Aphid Proteins Associated with Vector-Specific Transmission of Polerovirus (Luteoviridae)?

    PubMed Central

    Yang, Xiaolong; Thannhauser, T. W.; Burrows, Mary; Cox-Foster, Diana; Gildow, Fred E.; Gray, Stewart M.

    2008-01-01

    Cereal yellow dwarf virus-RPV (CYDV-RPV) is transmitted specifically by the aphids Rhopalosiphum padi and Schizaphis graminum in a circulative nonpropagative manner. The high level of vector specificity results from the vector aphids having the functional components of the receptor-mediated endocytotic pathways to allow virus to transverse the gut and salivary tissues. Studies of F2 progeny from crosses of vector and nonvector genotypes of S. graminum showed that virus transmission efficiency is a heritable trait regulated by multiple genes acting in an additive fashion and that gut- and salivary gland-associated factors are not genetically linked. Utilizing two-dimensional difference gel electrophoresis to compare the proteomes of vector and nonvector parental and F2 genotypes, four aphid proteins (S4, S8, S29, and S405) were specifically associated with the ability of S. graminum to transmit CYDV-RPV. The four proteins were coimmunoprecipitated with purified RPV, indicating that the aphid proteins are capable of binding to virus. Analysis by mass spectrometry identified S4 as a luciferase and S29 as a cyclophilin, both of which have been implicated in macromolecular transport. Proteins S8 and S405 were not identified from available databases. Study of this unique genetic system coupled with proteomic analysis indicated that these four virus-binding aphid proteins were specifically inherited and conserved in different generations of vector genotypes and suggests that they play a major role in regulating polerovirus transmission. PMID:17959668

  8. Whole-Genome Sequencing Identifies Genetic Variances in Culture-Expanded Human Mesenchymal Stem Cells

    PubMed Central

    Cai, Jun; Miao, Xuexia; Li, Yueying; Smith, Cory; Tsang, Kitman; Cheng, Linzhao; Wang, Qian-fei

    2014-01-01

    Summary Culture-expanded human mesenchymal stem cells (MSCs) are increasingly used in clinics, yet full characterization of the genomic compositions of these cells is lacking. We present a whole-genome investigation on the genetic dynamics of cultured MSCs under ex vivo establishment (passage 1 [p1]) and serial expansion (p8 and p13). We detected no significant changes in copy-number alterations (CNAs) and low levels of single-nucleotide changes (SNCs) until p8. Strikingly, a significant number (677) of SNCs were found in p13 MSCs. Using a sensitive Droplet Digital PCR assay, we tested the nonsynonymous SNCs detected by whole-genome sequencing and found that they were preexisting low-frequency mutations in uncultured mononuclear cells (?0.01%) and early-passage MSCs (0.1%–1% at p1 and p8) but reached 17%–36% in p13. Our data demonstrate that human MSCs maintain a stable genomic composition in the early stages of ex vivo culture but are subject to clonal growth upon extended expansion. PMID:25254336

  9. Rank-based tests for identifying multiple genetic variants associated with quantitative traits.

    PubMed

    Li, Zhengbang; Yuan, Ao; Han, Gang; Gao, Guimin; Li, Qizhai

    2014-07-01

    We consider the analysis of multiple genetic variants within a gene or a region that are expected to confer risks to human complex diseases with quantitative traits, where the trait values do not follow the normal distribution even after some transformations. We rank the phenotypic values, calculate a score to measure the trend effect of a particular allele for each marker, and then construct three statistics based on the quadratic frameworks of methods Hotelling T(2) , the summation of squared univariate statistic and the inverse of the square root weighted statistics to combine the scores for different marker loci. Simulation results show that the above three test statistics can control the type I error rate well and are more robust than standard tests constructed based on linear regression. Application to GAW16 data for rheumatoid arthritis successfully detects the association between the HLA-DRB1 gene and anticyclic citrullinated protein measure, while the standard methods based on normal assumption cannot detect this association. PMID:24942081

  10. Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels.

    PubMed

    Draisma, Harmen H M; Pool, René; Kobl, Michael; Jansen, Rick; Petersen, Ann-Kristin; Vaarhorst, Anika A M; Yet, Idil; Haller, Toomas; Demirkan, Ay?e; Esko, Tõnu; Zhu, Gu; Böhringer, Stefan; Beekman, Marian; van Klinken, Jan Bert; Römisch-Margl, Werner; Prehn, Cornelia; Adamski, Jerzy; de Craen, Anton J M; van Leeuwen, Elisabeth M; Amin, Najaf; Dharuri, Harish; Westra, Harm-Jan; Franke, Lude; de Geus, Eco J C; Hottenga, Jouke Jan; Willemsen, Gonneke; Henders, Anjali K; Montgomery, Grant W; Nyholt, Dale R; Whitfield, John B; Penninx, Brenda W; Spector, Tim D; Metspalu, Andres; Eline Slagboom, P; van Dijk, Ko Willems; 't Hoen, Peter A C; Strauch, Konstantin; Martin, Nicholas G; van Ommen, Gert-Jan B; Illig, Thomas; Bell, Jordana T; Mangino, Massimo; Suhre, Karsten; McCarthy, Mark I; Gieger, Christian; Isaacs, Aaron; van Duijn, Cornelia M; Boomsma, Dorret I

    2015-01-01

    Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10(-9)) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research. PMID:26068415

  11. Determination of parameter identifiability in nonlinear biophysical models: A Bayesian approach

    PubMed Central

    Hines, Keegan E.; Middendorf, Thomas R.

    2014-01-01

    A major goal of biophysics is to understand the physical mechanisms of biological molecules and systems. Mechanistic models are evaluated based on their ability to explain carefully controlled experiments. By fitting models to data, biophysical parameters that cannot be measured directly can be estimated from experimentation. However, it might be the case that many different combinations of model parameters can explain the observations equally well. In these cases, the model parameters are not identifiable: the experimentation has not provided sufficient constraining power to enable unique estimation of their true values. We demonstrate that this pitfall is present even in simple biophysical models. We investigate the underlying causes of parameter non-identifiability and discuss straightforward methods for determining when parameters of simple models can be inferred accurately. However, for models of even modest complexity, more general tools are required to diagnose parameter non-identifiability. We present a method based in Bayesian inference that can be used to establish the reliability of parameter estimates, as well as yield accurate quantification of parameter confidence. PMID:24516188

  12. Development of a decision-support tool for identifying the most suitable approach to achieve nitrate source determination.

    PubMed

    Fenech, C; Nolan, K; Rock, L; Morrissey, A

    2014-11-01

    Numerous approaches have been suggested for differentiating point and diffuse sources of nitrate contamination, including nitrate stable isotopes, microbiological analyses, genetic markers and chemical markers. Each approach has its own strengths and limitations. As a result, the most appropriate approach to use largely depends upon the scenario and the context of the study. However, available data on nitrate source determination is highly fragmented and approach dependent, with very little if any interface between the different techniques. This makes it difficult for stakeholders to identify the most suitable approach to adopt in a specific scenario. Therefore, this paper examines the development and application of a decision-support tool to support environmental forensics studies for nitrate contamination. In particular, this tool can support policy makers, regulators and operators within the field in understanding the environmental hazards and processes resulting from nitrate contamination, and to implement appropriate actions for limiting the impacts that may arise from such contamination. The tool was developed using the IDEF0 modeling system, and evaluated by interviewing key stakeholders who suggested a number of important implications for practice. PMID:25232953

  13. Antimicrobial resistance, virulence determinants and genetic profiles of clinical and nonclinical Enterococcus cecorum from poultry.

    PubMed

    Jackson, C R; Kariyawasam, S; Borst, L B; Frye, J G; Barrett, J B; Hiott, L M; Woodley, T A

    2015-02-01

    Enterococcus cecorum has been implicated as a possible cause of disease in poultry. However, the characteristics that contribute to pathogenesis of Ent. cecorum in poultry have not been defined. In this study, Ent. cecorum from carcass rinsates (n = 75) and diseased broilers and broiler breeders (n = 30) were compared based upon antimicrobial resistance phenotype, the presence of virulence determinants and genetic relatedness using pulsed-field gel electrophoresis (PFGE). Of the 16 antimicrobials tested, Ent. cecorum from carcass rinsates and clinical cases were resistant to ten and six of the antimicrobials, respectively. The majority of Ent. cecorum from carcass rinsates was resistant to lincomycin (54/75; 72%) and tetracycline (46/75; 61.3%) while the highest level of resistance among clinical Ent. cecorum was to tetracycline (22/30; 73.3%) and erythromycin (11/30; 36.7%). Multidrug resistance (resistance to ?2 antimicrobials) was identified in Ent. cecorum from carcass rinsates (53/75; 70.7%) and diseased poultry (18/30; 60%). Of the virulence determinants tested, efaAfm was present in almost all of the isolates (104/105; 99%). Using PFGE, the majority of clinical isolates clustered together; however, a few clinical isolates grouped with Ent. cecorum from carcass rinsates. These data suggest that distinguishing the two groups of isolates is difficult based upon the characterization criteria used. PMID:25470229

  14. Mapping the Genetic Determinants of Pathogenicity and Plaque Phenotype in Swine Vesicular Disease Virus

    PubMed Central

    Kanno, Toru; Mackay, David; Inoue, Toru; Wilsden, Ginette; Yamakawa, Makoto; Yamazoe, Reiko; Yamaguchi, Shigeo; Shirai, Junsuke; Kitching, Paul; Murakami, Yosuke

    1999-01-01

    A series of recombinant viruses were constructed using infectious cDNA clones of the virulent J1’73 (large plaque phenotype) and the avirulent H/3’76 (small plaque phenotype) strains of swine vesicular disease virus to identify the genetic determinants of pathogenicity and plaque phenotype. Both traits could be mapped to the region between nucleotides (nt) 2233 and 3368 corresponding to the C terminus of VP3, the whole of VP1, and the N terminus of 2A. In this region, there are eight nucleotide differences leading to amino acid changes between the J1’73 and the H/3’76 strains. Site-directed mutagenesis of individual nucleotides from the virulent to the avirulent genotype and vice versa indicated that A at nt 2832, encoding glycine at VP1-132, and G at nt 3355, encoding arginine at 2APRO-20, correlated with a large-plaque phenotype and virulence in pigs, irrespective of the origin of the remainder of the genome. Of these two sites, 2APRO-20 appeared to be the dominant determinant for the large-plaque phenotype but further studies are required to elucidate their relative importance for virulence in pigs. PMID:10074117

  15. Application of genetic and spatial analyses to identify collection priorities for wild Malus species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The USDA-ARS National Plant Germplasm System has 33 species of wild Malus, many of which were acquired from plant explorations performed over the past 30 years. The phylogenetic relationships among these species were determined by chloroplast sequencing (1681 bp from four regions). Five primary clad...

  16. Genetic determinants of immune-response to a polysaccharide vaccine for typhoid

    PubMed Central

    Staats, Herman F.; Sarkar-Roy, Neeta; Varma, Binuja; Ghosh, Trina; Maiti, Sujit; Narayanasamy, K.; Whisnant, Carol C.; Stephenson, James L.; Wagener, Diane K.

    2010-01-01

    Differences in immunological response among vaccine recipients are determined both by their genetic differences and environmental factors. Knowledge of genetic determinants of immunological response to a vaccine can be used to design a vaccine that circumvents immunogenetic restrictions. The currently available vaccine for typhoid is a pure polysaccharide vaccine, immune response to which is T-cell independent. Little is known about whether genetic variation among vaccinees associates with variation in their antibody response to a polysaccharide vaccine. We conducted a study on 1,000 individuals resident in an area at high-risk for typhoid; vaccinated them with the typhoid vaccine, measured their antibody response to the vaccine, assayed >2,000 curated SNPs chosen from 283 genes that are known to participate in immune-response; and analyzed these data using a strategy to (a) minimize the statistical problems associated with testing of multiple hypotheses, and (b) internally cross-validate inferences, using a half-sample design, with little loss of statistical power. The first stage analysis, using the first half-sample, identified 54 SNPs in 43 genes to be significantly associated with immune response. In the second-stage, these inferences were cross-validated using the second half-sample. First-stage results of only 8 SNPs (out of 54) in 7 genes (out of 43) were cross-validated. We tested additional SNPs in these 7 genes, and found 8 more SNPs to be significantly associated. Haplotypes constructed with these SNPs in these 7 genes also showed significant association. These 7 genes are DEFB1, TLR1, IL1RL1, CTLA4, MAPK8, CD86 and IL17D. The overall picture that has emerged from this study is that (a) immune response to polysaccharide antigens is qualitatively different from that to protein antigens, and (b) polymorphisms in genes involved in polysaccharide recognition, signal transduction, inhibition of T-cell proliferation, pro-inflammatory signaling and eventual production of antimicrobial peptides are associated with antibody response to the polysaccharide vaccine for typhoid. Electronic supplementary material The online version of this article (doi:10.1007/s11568-010-9134-1) contains supplementary material, which is available to authorized users. PMID:21119757

  17. Genetic determinant of pyocin AP41 as an insert in the Pseudomonas aeruginosa chromosome.

    PubMed Central

    Sano, Y; Kageyama, M

    1984-01-01

    The genetic determinant for pyocin AP41 , a bacteriocin produced by Pseudomonas aeruginosa PAF, was transferred to P. aeruginosa PAO and analyzed. By conjugation experiments, the pyocin determinant was found to be located on the chromosome, being closely linked to argG at about 45 min on the genetic map. Cloning of the pyocin AP41 gene into the plasmid R68.45 was attempted in vivo by taking advantage of its linkage at argG. R' argG+ plasmids were isolated by interspecific conjugation between P. aeruginosa and Escherichia coli recA argG strains. Some of the R' argG+ plasmids did contain the pyocin AP41 determinant. Genetic and physical analyses of these R' plasmids indicated that the pyocin AP41 determinant was located within a 2.9-kilobase extra segment found at a certain position of the chromosome of various pyocin AP41 producer strains. Images PMID:6202673

  18. Human Infections with Spirometra decipiens Plerocercoids Identified by Morphologic and Genetic Analyses in Korea

    PubMed Central

    Jeon, Hyeong-Kyu; Park, Hansol; Lee, Dongmin; Choe, Seongjun; Kim, Kyu-Heon; Huh, Sun; Sohn, Woon-Mok; Chai, Jong-Yil; Eom, Keeseon S.

    2015-01-01

    Tapeworms of the genus Spirometra are pseudophyllidean cestodes endemic in Korea. At present, it is unclear which Spirometra species are responsible for causing human infections, and little information is available on the epidemiological profiles of Spirometra species infecting humans in Korea. Between 1979 and 2009, a total of 50 spargana from human patients and 2 adult specimens obtained from experimentally infected carnivorous animals were analyzed according to genetic and taxonomic criteria and classified as Spirometra erinaceieuropaei or Spirometra decipiens depending on the morphology. Morphologically, S. erinaceieuropaei and S. decipiens are different in that the spirally coiled uterus in S. erinaceieuropaei has 5-7 complete coils, while in S. decipiens it has only 4.5 coils. In addition, there is a 9.3% (146/1,566) sequence different between S. erinaceieuropaei and S. decipiens in the cox1 gene. Partial cox1 sequences (390 bp) from 35 Korean isolates showed 99.4% (388/390) similarity with the reference sequence of S. erinaceieuropaei from Korea (G1724; GenBank KJ599680) and an additional 15 Korean isolates revealed 99.2% (387/390) similarity with the reference sequences of S. decipiens from Korea (G1657; GenBank KJ599679). Based on morphologic and molecular databases, the estimated population ratio of S. erinaceieuropaei to S. decipiens was 35: 15. Our results indicate that both S. erinaceieuropaei and S. decipiens found in Korea infect humans, with S. erinaceieuropaei being 2 times more prevalent than S. decipiens. This study is the first to report human sparganosis caused by S. decipiens in humans in Korea. PMID:26174823

  19. Identifying QTL and genetic correlations between fur quality traits in mink (Neovison vison).

    PubMed

    Thirstrup, J P; Anistoroaei, R; Guldbrandtsen, B; Christensen, K; Fredholm, M; Nielsen, V H

    2014-02-01

    Mapping of QTL affecting fur quality traits (guard hair length, guard hair thickness, density of wool, surface of the fur and quality) and skin length was performed in a three-generation mink population (F2 design). In the parental generation, Nordic Brown mink were crossed reciprocally with American Black short nap mink. In all, 1082 mink encompassing three generations were used for the analyses. The mink were genotyped for 104 microsatellites covering all 14 autosomes. The QTL analyses were performed by least-square regression implemented in gridqtl software. Genetic and phenotypic correlations and heritabilities were estimated using the average information-restricted maximum-likelihood method. Evidence was found for QTL affecting fur quality traits on nine autosomes. QTL were detected for guard hair thickness on chromosomes 1, 2, 3, 6 and 13; for guard hair length on chromosomes 2, 3 and 6; for wool density on chromosomes 6 and 13; for surface on chromosomes 7, 12 and 13; for quality on chromosomes 6, 7, 11 and 13; and for skin length on chromosomes 7 and 9. Proximity of locations of QTL for guard hair length, guard hair thickness and for wool density and quality suggests that some of the traits are in part under the influence of the same genes. Traits under the influence of QTL at close or identical positions also were traits that were strongly genotypically correlated. Based on the results of correlation analyses, the most important single traits influencing the quality were found to be density of wool, guard hair thickness and appearance of the surface. PMID:24303917

  20. The ends of a continuum: genetic and temperature-dependent sex determination in reptiles

    Microsoft Academic Search

    Stephen D. Sarre; Arthur Georges; Alex Quinn

    2004-01-01

    Summary Two prevailing paradigms explain the diversity of sex- determining modes in reptiles. Many researchers, parti- cularly those who study reptiles, consider genetic and environmental sex-determining mechanisms to be fun- damentally different, and that one can be demonstrat- ed experimentally to the exclusion of the other. Other researchers, principally those who take a broader taxo- nomic perspective, argue that no

  1. Application of a novel radioimmunoassay to identify baculovirus structural proteins that share interspecies antigenic determinants

    SciTech Connect

    Smith, G.E.; Summers, M.D.

    1981-07-01

    Immunological comparisons were made of baculovirus structural proteins by using a modification of the radioimmunological techniques described by Renart et al. and Towbin et al. Viral proteins were electrophoresed in polyacrylamide gels, transferred to nitrocellulose, and incubated with viral antisera, and the antibodies were detected with /sup 125/I-labeled Staphylococcus aureus protein A. Antisera were prepared to purified and intact virions from five baculoviruses: Autographa californica, Porthetria dispar, Trichoplusia ni, and Heliothis zea nuclear polyhedrosis viruses (NPVs) and T. ni granulosis virus (GV). These antisera were tested against the virion structural polypeptides of 17 different species of baculoviruses. Specific multiple-nucleocapsid NPV (MNPV), single-nucleocapsid NPV (SNPV), and GV virion polypeptides were shown to have similar antigenic determinants and thus be immunologically related. The molecular weights of the virion polypeptides with cross-reacting antigenic determinants were identified. Antisera prepared to purified A. californica and H. zea MNPV polyhedrin recognized antigenic determinants on all the polyhedrins and granulins that were tested. No immunological relationship was detected between A. californica MNPV polyhedrin and any of the A. californica MNPV virion structural polypeptides present on either the virus isolated from occlusion bodies or A. californica MNPV extracellular virus from infected-cell cultures.

  2. Genetic Diversity of Cheju Horses ( Equus caballus ) Determined by Using Mitochondrial DNA D-loop Polymorphism

    Microsoft Academic Search

    Y. H. Yang; K. I. Kim; E. G. Cothran; A. R. Flannery

    2002-01-01

    We used sequence polymorphism of the mitochondrial DNA D-loop (968 bp excluding the tandem repeat region) to determine genetic diversity of horses inhabiting Cheju (a southern island of Korea). Seventeen haplotypes with frequencies from 1.5 to 21.5% were found among 65 Cheju horse samples. Genetic diversity (h) of the 17 haplotypes was calculated to be 0.91, indicating that the extant

  3. Ecological and Genetic Determinants of Pepino Mosaic Virus Emergence

    PubMed Central

    Moreno-Pérez, Manuel G.; Pagán, Israel; Aragón-Caballero, Liliana; Cáceres, Fátima; Fraile, Aurora

    2014-01-01

    ABSTRACT Virus emergence is a complex phenomenon, which generally involves spread to a new host from a wild host, followed by adaptation to the new host. Although viruses account for the largest fraction of emerging crop pathogens, knowledge about their emergence is incomplete. We address here the question of whether Pepino Mosaic Virus (PepMV) emergence as a major tomato pathogen worldwide could have involved spread from wild to cultivated plant species and host adaptation. For this, we surveyed natural populations of wild tomatoes in southern Peru for PepMV infection. PepMV incidence, genetic variation, population structure, and accumulation in various hosts were analyzed. PepMV incidence in wild tomatoes was high, and a strain not yet reported in domestic tomato was characterized. This strain had a wide host range within the Solanaceae, multiplying efficiently in most assayed Solanum species and being adapted to wild tomato hosts. Conversely, PepMV isolates from tomato crops showed evidence of adaptation to domestic tomato, possibly traded against adaptation to wild tomatoes. Phylogenetic reconstructions indicated that the most probable ancestral sequence came from a wild Solanum species. A high incidence of PepMV in wild tomato relatives would favor virus spread to crops and its efficient multiplication in different Solanum species, including tomato, allowing its establishment as an epidemic pathogen. Later, adaptation to tomato, traded off against adaptation to other Solanum species, would isolate tomato populations from those in other hosts. IMPORTANCE Virus emergence is a complex phenomenon involving multiple ecological and genetic factors and is considered to involve three phases: virus encounter with the new host, virus adaptation to the new host, and changes in the epidemiological dynamics. We analyze here if this was the case in the recent emergence of Pepino Mosaic Virus (PepMV) in tomato crops worldwide. We characterized a new strain of PepMV infecting wild tomato populations in Peru. Comparison of this strain with PepMV isolates from tomato crops, plus phylogenetic reconstructions, supports a scenario in which PepMV would have spread to crops from wild tomato relatives, followed by adaptation to the new host and eventually leading to population isolation. Our data, which derive from the analysis of field isolates rather than from experimental evolution approaches, significantly contribute to understanding of plant virus emergence, which is necessary for its anticipation and prevention. PMID:24390328

  4. Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate.

    PubMed

    Krumova, Petranka; Reyniers, Lauran; Meyer, Marc; Lobbestael, Evy; Stauffer, Daniela; Gerrits, Bertran; Muller, Lionel; Hoving, Sjouke; Kaupmann, Klemens; Voshol, Johannes; Fabbro, Doriano; Bauer, Andreas; Rovelli, Giorgio; Taymans, Jean-Marc; Bouwmeester, Tewis; Baekelandt, Veerle

    2015-07-01

    Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant forms of Parkinson's disease. LRRK2 is a modular, multidomain protein containing 2 enzymatic domains, including a kinase domain, as well as several protein-protein interaction domains, pointing to a role in cellular signaling. Although enormous efforts have been made, the exact pathophysiologic mechanisms of LRRK2 are still not completely known. In this study, we used a chemical genetics approach to identify LRRK2 substrates from mouse brain. This approach allows the identification of substrates of 1 particular kinase in a complex cellular environment. Several of the identified peptides are involved in the regulation of microtubule (MT) dynamics, including microtubule-associating protein (MAP)/microtubule affinity-regulating kinase 1 (MARK1). MARK1 is a serine/threonine kinase known to phosphorylate MT-binding proteins such as Tau, MAP2, and MAP4 at KXGS motifs leading to MT destabilization. In vitro kinase assays and metabolic-labeling experiments in living cells confirmed MARK1 as an LRRK2 substrate. Moreover, we also showed that LRRK2 and MARK1 are interacting in eukaryotic cells. Our findings contribute to the identification of physiologic LRRK2 substrates and point to a potential mechanism explaining the reported effects of LRRK2 on neurite morphology.-Krumova, P., Reyniers, L., Meyer, M., Lobbestael, E., Stauffer, D., Gerrits, B., Muller, L., Hoving, S., Kaupmann, K., Voshol, J., Fabbro, D., Bauer, A., Rovelli, G., Taymans, J.-M., Bouwmeester, T., Baekelandt, V. Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate. PMID:25854701

  5. Genetic and molecular characterization of submergence response identifies Subtol6 as a major submergence tolerance locus in maize.

    PubMed

    Campbell, Malachy T; Proctor, Christopher A; Dou, Yongchao; Schmitz, Aaron J; Phansak, Piyaporn; Kruger, Greg R; Zhang, Chi; Walia, Harkamal

    2015-01-01

    Maize is highly sensitive to short term flooding and submergence. Early season flooding reduces germination, survival and growth rate of maize seedlings. We aimed to discover genetic variation for submergence tolerance in maize and elucidate the genetic basis of submergence tolerance through transcriptional profiling and linkage analysis of contrasting genotypes. A diverse set of maize nested association mapping (NAM) founder lines were screened, and two highly tolerant (Mo18W and M162W) and sensitive (B97 and B73) genotypes were identified. Tolerant lines exhibited delayed senescence and lower oxidative stress levels compared to sensitive lines. Transcriptome analysis was performed on these inbreds to provide genome level insights into the molecular responses to submergence. Tolerant lines had higher transcript abundance of several fermentation-related genes and an unannotated Pyrophosphate-Dependent Fructose-6-Phosphate 1-Phosphotransferase gene during submergence. A coexpression network enriched for CBF (C-REPEAT/DRE BINDING FACTOR: C-REPEAT/DRE BINDING FACTOR) genes, was induced by submergence in all four inbreds, but was more activated in the tolerant Mo18W. A recombinant inbred line (RIL) population derived from Mo18W and B73 was screened for submergence tolerance. A major QTL named Subtol6 was mapped to chromosome 6 that explains 22% of the phenotypic variation within the RIL population. We identified two candidate genes (HEMOGLOBIN2 and RAV1) underlying Subtol6 based on contrasting expression patterns observed in B73 and Mo18W. Sources of tolerance identified in this study (Subtol6) can be useful to increase survival rate during flooding events that are predicted to increase in frequency with climate change. PMID:25806518

  6. A Genetic Screen in Myxococcus xanthus Identifies Mutants That Uncouple Outer Membrane Exchange from a Downstream Cellular Response

    PubMed Central

    Dey, Arup

    2014-01-01

    Upon physical contact with sibling cells, myxobacteria transiently fuse their outer membranes (OMs) and exchange OM proteins and lipids. From previous work, TraA and TraB were identified to be essential factors for OM exchange (OME) in donor and recipient cells. To define the genetic complexity of OME, we carried out a comprehensive forward genetic screen. The screen was based on the observation that Myxococcus xanthus nonmotile cells, by a Tra-dependent mechanism, block swarm expansion of motile cells when mixed. Thus, mutants defective in OME or a downstream responsive pathway were readily identified as escape flares from mixed inocula seeded on agar. This screen was surprisingly powerful, as we found >50 mutants defective in OME. Importantly, all of the mutations mapped to the traAB operon, suggesting that there may be few, if any, proteins besides TraA and TraB directly required for OME. We also found a second and phenotypically different class of mutants that exhibited wild-type OME but were defective in a responsive pathway. This pathway is postulated to control inner membrane homeostasis by covalently attaching amino acids to phospholipids. The identified proteins are homologous to the Staphylococcus aureus MprF protein, which is involved in membrane adaptation and antibiotic resistance. Interestingly, we also found that a small number of nonmotile cells were sufficient to block the swarming behavior of a large gliding-proficient population. This result suggests that an OME-derived signal could be amplified from a few nonmotile producers to act on many responder cells. PMID:25266387

  7. Genetic and Molecular Characterization of Submergence Response Identifies Subtol6 as a Major Submergence Tolerance Locus in Maize

    PubMed Central

    Campbell, Malachy T.; Proctor, Christopher A.; Dou, Yongchao; Schmitz, Aaron J.; Phansak, Piyaporn; Kruger, Greg R.; Zhang, Chi; Walia, Harkamal

    2015-01-01

    Maize is highly sensitive to short term flooding and submergence. Early season flooding reduces germination, survival and growth rate of maize seedlings. We aimed to discover genetic variation for submergence tolerance in maize and elucidate the genetic basis of submergence tolerance through transcriptional profiling and linkage analysis of contrasting genotypes. A diverse set of maize nested association mapping (NAM) founder lines were screened, and two highly tolerant (Mo18W and M162W) and sensitive (B97 and B73) genotypes were identified. Tolerant lines exhibited delayed senescence and lower oxidative stress levels compared to sensitive lines. Transcriptome analysis was performed on these inbreds to provide genome level insights into the molecular responses to submergence. Tolerant lines had higher transcript abundance of several fermentation-related genes and an unannotated Pyrophosphate-Dependent Fructose-6-Phosphate 1-Phosphotransferase gene during submergence. A coexpression network enriched for CBF (C-REPEAT/DRE BINDING FACTOR: C-REPEAT/DRE BINDING FACTOR) genes, was induced by submergence in all four inbreds, but was more activated in the tolerant Mo18W. A recombinant inbred line (RIL) population derived from Mo18W and B73 was screened for submergence tolerance. A major QTL named Subtol6 was mapped to chromosome 6 that explains 22% of the phenotypic variation within the RIL population. We identified two candidate genes (HEMOGLOBIN2 and RAV1) underlying Subtol6 based on contrasting expression patterns observed in B73 and Mo18W. Sources of tolerance identified in this study (Subtol6) can be useful to increase survival rate during flooding events that are predicted to increase in frequency with climate change. PMID:25806518

  8. Genetic Features of Resident Biofilms Determine Attachment of Listeria monocytogenes?

    PubMed Central

    Habimana, Olivier; Meyrand, Mickael; Meylheuc, Thierry; Kulakauskas, Saulius; Briandet, Romain

    2009-01-01

    Planktonic Listeria monocytogenes cells in food-processing environments tend most frequently to adhere to solid surfaces. Under these conditions, they are likely to encounter resident biofilms rather than a raw solid surface. Although metabolic interactions between L. monocytogenes and resident microflora have been widely studied, little is known about the biofilm properties that influence the initial fixation of L. monocytogenes to the biofilm interface. To study these properties, we created a set of model resident Lactococcus lactis biofilms with various architectures, types of matrices, and individual cell surface properties. This was achieved using cell wall mutants that affect bacterial chain formation, exopolysaccharide (EPS) synthesis and surface hydrophobicity. The dynamics of the formation of these biofilm structures were analyzed in flow cell chambers using in situ time course confocal laser scanning microscopy imaging. All the L. lactis biofilms tested reduced the initial immobilization of L. monocytogenes compared to the glass substratum of the flow cell. Significant differences were seen in L. monocytogenes settlement as a function of the genetic background of resident lactococcal biofilm cells. In particular, biofilms of the L. lactis chain-forming mutant resulted in a marked increase in L. monocytogenes settlement, while biofilms of the EPS-secreting mutant efficiently prevented pathogen fixation. These results offer new insights into the role of resident biofilms in governing the settlement of pathogens on food chain surfaces and could be of relevance in the field of food safety controls. PMID:19837841

  9. Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes

    PubMed Central

    He, Xin; Sanders, Stephan J.; Liu, Li; De Rubeis, Silvia; Lim, Elaine T.; Sutcliffe, James S.; Schellenberg, Gerard D.; Gibbs, Richard A.; Daly, Mark J.; Buxbaum, Joseph D.; State, Matthew W.; Devlin, Bernie; Roeder, Kathryn

    2013-01-01

    De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support. PMID:23966865

  10. Combining gene expression and genetic analyses to identify candidate genes involved in cold responses in pea.

    PubMed

    Legrand, Sylvain; Marque, Gilles; Blassiau, Christelle; Bluteau, Aurélie; Canoy, Anne-Sophie; Fontaine, Véronique; Jaminon, Odile; Bahrman, Nasser; Mautord, Julie; Morin, Julie; Petit, Aurélie; Baranger, Alain; Rivière, Nathalie; Wilmer, Jeroen; Delbreil, Bruno; Lejeune-Hénaut, Isabelle

    2013-09-01

    Cold stress affects plant growth and development. In order to better understand the responses to cold (chilling or freezing tolerance), we used two contrasted pea lines. Following a chilling period, the Champagne line becomes tolerant to frost whereas the Terese line remains sensitive. Four suppression subtractive hybridisation libraries were obtained using mRNAs isolated from pea genotypes Champagne and Terese. Using quantitative polymerase chain reaction (qPCR) performed on 159 genes, 43 and 54 genes were identified as differentially expressed at the initial time point and during the time course study, respectively. Molecular markers were developed from the differentially expressed genes and were genotyped on a population of 164 RILs derived from a cross between Champagne and Terese. We identified 5 candidate genes colocalizing with 3 different frost damage quantitative trait loci (QTL) intervals and a protein quantity locus (PQL) rich region previously reported. This investigation revealed the role of constitutive differences between both genotypes in the cold responses, in particular with genes related to glycine degradation pathway that could confer to Champagne a better frost tolerance. We showed that freezing tolerance involves a decrease of expression of genes related to photosynthesis and the expression of a gene involved in the production of cysteine and methionine that could act as cryoprotectant molecules. Although it remains to be confirmed, this study could also reveal the involvement of the jasmonate pathway in the cold responses, since we observed that two genes related to this pathway were mapped in a frost damage QTL interval and in a PQL rich region interval, respectively. PMID:23632303

  11. Virulence determinants in the obligate intracellular pathogen Chlamydia trachomatis revealed by forward genetic approaches

    PubMed Central

    Nguyen, Bidong D.; Valdivia, Raphael H.

    2012-01-01

    Chlamydia trachomatis, a pathogen responsible for diseases of significant clinical and public health importance, remains poorly characterized because of its intractability to routine molecular genetic manipulation. We have developed a combinatorial approach to rapidly generate a comprehensive library of genetically defined mutants. Chemical mutagenesis, coupled with whole-genome sequencing (WGS) and a system for DNA exchange within infected cells, was used to generate Chlamydia mutants with distinct phenotypes, map the underlying genetic lesions, and generate isogenic strains. As a result, we identified mutants with altered glycogen metabolism, including an attenuated strain defective for type II secretion. The coupling of chemically induced gene variation and WGS to establish genotype–phenotype associations should be broadly applicable to the large list of medically and environmentally important microorganisms currently intractable to genetic analysis. PMID:22232666

  12. Determining DNA Sequence Specificity of Natural and Artificial Transcription Factors by Cognate Site Identifier Analysis

    NASA Astrophysics Data System (ADS)

    Ozers, Mary S.; Warren, Christopher L.; Ansari, Aseem Z.

    Artificial transcription factors (ATFs) are designed to mimic natural transcription factors in the control of gene expression and are comprised of domains for DNA binding and gene regulation. ATF domains are modular, interchangeable, and can be composed of protein-based or nonpeptidic moieties, yielding DNA-interacting regulatory molecules that can either activate or inhibit transcription. Sequence-specific targeting is a key determinant in ATF activity, and DNA-binding domains such as natural zinc fingers and synthetic polyamides have emerged as useful DNA targeting molecules. Defining the comprehensive DNA binding specificity of these targeting molecules for accurate manipulations of the genome can be achieved using cognate site identifier DNA microarrays to explore the entire sequence space of binding sites. Design of ATFs that regulate gene expression with temporal control will generate important molecular tools to probe cell- and tissue-specific gene regulation and to function as potential therapeutic agents.

  13. Age-Based Differences in the Genetic Determinants of Glycemic Control: A Case of FOXO3 Variations

    PubMed Central

    Sun, Liang; Hu, Caiyou; Qian, Yu; Zheng, Chenguang; Liang, Qinghua; Lv, Zeping; Huang, Zezhi; Qi, Keyan; Huang, Jin; Zhou, Qin; Yang, Ze

    2015-01-01

    Background Glucose homeostasis is a trait of healthy ageing and is crucial to the elderly, but less consideration has been given to the age composition in most studies involving genetics and hyperglycemia. Methods Seven variants in FOXO3 were genotyped in three cohorts (n = 2037; LLI, MI_S and MI_N; mean age: 92.5±3.6, 45.9±8.2 and 46.8±10.3, respectively) to compare the contribution of FOXO3 to fasting hyperglycemia (FH) between long-lived individuals (LLI, aged over 90 years) and middle-aged subjects (aged from 35–65 years). Results A different genetic predisposition of FOXO3 alleles to FH was observed between LLI and both of two middle-aged cohorts. In the LLI cohort, the longevity beneficial alleles of three variants with the haplotype “AGGC” in block 1 were significantly protective to FH, fasting glucose, hemoglobin A1C and HOMA-IR. Notably, combining multifactor dimensionality reduction and logistic regression, we identified a significant 3-factor interaction model (rs2802288, rs2802292 and moderate physical activity) associated with lower FH risk. However, not all of the findings were replicated in the two middle-aged cohorts. Conclusion Our data provides a novel insight into the inconsistent genetic determinants between middle-aged and LLI subjects. FOXO3 might act as a shared genetic predisposition to hyperglycemia and lifespan. PMID:25993007

  14. Global Genetic Determinants of Mitochondrial DNA Copy Number

    PubMed Central

    Zhang, Hengshan; Singh, Keshav K.

    2014-01-01

    Many human diseases including development of cancer is associated with depletion of mitochondrial DNA (mtDNA) content. These diseases are collectively described as mitochondrial DNA depletion syndrome (MDS). High similarity between yeast and human mitochondria allows genomic study of the budding yeast to be used to identify human disease genes. In this study, we systematically screened the pre-existing respiratory-deficient Saccharomyces cerevisiae yeast strains using fluorescent microscopy and identified 102 nuclear genes whose deletions result in a complete mtDNA loss, of which 52 are not reported previously. Strikingly, these genes mainly encode protein products involved in mitochondrial protein biosynthesis process (54.9%). The rest of these genes either encode protein products associated with nucleic acid metabolism (14.7%), oxidative phosphorylation (3.9%), or other protein products (13.7%) responsible for bud-site selection, mitochondrial intermembrane space protein import, assembly of cytochrome-c oxidase, vacuolar protein sorting, protein-nucleus import, calcium-mediated signaling, heme biosynthesis and iron homeostasis. Thirteen (12.7%) of the genes encode proteins of unknown function. We identified human orthologs of these genes, conducted the interaction between the gene products and linked them to human mitochondrial disorders and other pathologies. In addition, we screened for genes whose defects affect the nuclear genome integrity. Our data provide a systematic view of the nuclear genes involved in maintenance of mitochondrial DNA. Together, our studies i) provide a global view of the genes regulating mtDNA content; ii) provide compelling new evidence toward understanding novel mechanism involved in mitochondrial genome maintenance and iii) provide useful clues in understanding human diseases in which mitochondrial defect and in particular depletion of mitochondrial genome plays a critical role. PMID:25170845

  15. Genome-Wide Reverse Genetics Framework to Identify Novel Functions of the Vertebrate Secretome

    PubMed Central

    Pickart, Michael A.; Klee, Eric W.; Nielsen, Aubrey L.; Sivasubbu, Sridhar; Mendenhall, Eric M.; Bill, Brent R.; Chen, Eleanor; Eckfeldt, Craig E.; Knowlton, Michelle; Robu, Mara E.; Larson, Jon D.; Deng, Yun; Schimmenti, Lisa A.; Ellis, Lynda B.M.; Verfaillie, Catherine M.; Hammerschmidt, Matthias; Farber, Steven A.; Ekker, Stephen C.

    2006-01-01

    Background Understanding the functional role(s) of the more than 20,000 proteins of the vertebrate genome is a major next step in the post-genome era. The approximately 4,000 co-translationally translocated (CTT) proteins – representing the vertebrate secretome – are important for such vertebrate-critical processes as organogenesis. However, the role(s) for most of these genes is currently unknown. Results We identified 585 putative full-length zebrafish CTT proteins using cross-species genomic and EST-based comparative sequence analyses. We further investigated 150 of these genes (Figure 1) for unique function using morpholino-based analysis in zebrafish embryos. 12% of the CTT protein-deficient embryos resulted in specific developmental defects, a notably higher rate of gene function annotation than the 2%–3% estimate from random gene mutagenesis studies. Conclusion(s) This initial collection includes novel genes required for the development of vascular, hematopoietic, pigmentation, and craniofacial tissues, as well as lipid metabolism, and organogenesis. This study provides a framework utilizing zebrafish for the systematic assignment of biological function in a vertebrate genome. PMID:17218990

  16. MLVA and SNP analysis identified a unique genetic cluster in Bulgarian Bacillus anthracis strains.

    PubMed

    Antwerpen, M; Ilin, D; Georgieva, E; Meyer, H; Savov, E; Frangoulidis, D

    2011-07-01

    A collection of 40 Bacillus anthracis strains mostly isolated from soil in Bulgaria between 1960 and 1980 were investigated. All strains were proven to be B. anthracis by culture and amplification of a B. anthracis-specific chromosomal marker. PCR demonstrated that in nine strains both virulence plasmids (pX01+/pX02+) and in four strains only one plasmid (pX02+) were present, whereas the majority of strains (n = 27) lacked both plasmids (pX01-/pX02-). Multi-locus-variable number of tandem repeat-analysis (MLVA) using 15 markers differentiated three genotypes. Comparison with typing data of more than 1,000 different B. anthracis strains revealed that Bulgarian genotypes affiliated with the A1.a cluster and form their own unique cluster different from clusters containing strains isolated in geographical proximity, e.g., Turkey, Georgia, Hungary, Albania or Italy. In addition, a new allele of one marker (vrrC2) was identified. Canonical single nucleotide polymorphisms analysis allocated 31 Bulgarian strains into the A.Br.008/009 and nine strains into the A.Br.WNA group, which is the first description of B. anthracis strains of the A.Br.WNA group on the Eurasian continent. PMID:21279731

  17. Coupled biophysical global ocean model and molecular genetic analyses identify multiple introductions of cryptogenic species

    PubMed Central

    Dawson, Michael N; Gupta, Alex Sen; England, Matthew H.

    2005-01-01

    The anthropogenic introduction of exotic species is one of the greatest modern threats to marine biodiversity. Yet exotic species introductions remain difficult to predict and are easily misunderstood because knowledge of natural dispersal patterns, species diversity, and biogeography is often insufficient to distinguish between a broadly dispersed natural population and an exotic one. Here we compare a global molecular phylogeny of a representative marine meroplanktonic taxon, the moon-jellyfish Aurelia, with natural dispersion patterns predicted by a global biophysical ocean model. Despite assumed high dispersal ability, the phylogeny reveals many cryptic species and predominantly regional structure with one notable exception: the globally distributed Aurelia sp.1, which, molecular data suggest, may occasionally traverse the Pacific unaided. This possibility is refuted by the ocean model, which shows much more limited dispersion and patterns of distribution broadly consistent with modern biogeographic zones, thus identifying multiple introductions worldwide of this cryptogenic species. This approach also supports existing evidence that (i) the occurrence in Hawaii of Aurelia sp. 4 and other native Indo-West Pacific species with similar life histories is most likely due to anthropogenic translocation, and (ii) there may be a route for rare natural colonization of northeast North America by the European marine snail Littorina littorea, whose status as endemic or exotic is unclear. PMID:16103373

  18. In Vivo RNAi Screening Identifies Regulators of Actin Dynamics as Key Determinants of Lymphoma Progression

    E-print Network

    Ho, Emily E.

    Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report ...

  19. Determination of genetic variation and taxonomy in lentil (Lens Miller) species by chloroplast DNA polymorphism

    Microsoft Academic Search

    D. G. Muench; A. E. Slinkard; G. J. Scoles

    1991-01-01

    Chloroplast DNA restriction fragment lenght polymorphisms (RFLP) were used to examine the taxonomic relationships of cultivated and wild lentil (Lens Miller) species and identify the extent of genetic variation in this genus. Twelve accessions representing all Lens subspecies were digested with four hexanucleotide-recognizing restriction endonucleases. These digests randomly surveyed 540 base pairs, or 0.4% of the approximately 125 kilobase lentil

  20. Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk

    PubMed Central

    Zhang, Ben; Jia, Wei-Hua; Matsuda, Koichi; Kweon, Sun-Seog; Matsuo, Keitaro; Xiang, Yong-Bing; Shin, Aesun; Jee, Sun Ha; Kim, Dong-Hyun; Cai, Qiuyin; Long, Jirong; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Zhang, Yanfeng; Li, Chun; Li, Bingshan; Guo, Yan; Ren, Zefang; Ji, Bu-Tian; Pan, Zhi-Zhong; Takahashi, Atsushi; Shin, Min-Ho; Matsuda, Fumihiko; Gao, Yu-Tang; Oh, Jae Hwan; Kim, Soriul; Ahn, Yoon-Ok; Chan, Andrew T; Chang-Claude, Jenny; Slattery, Martha L.; Gruber, Stephen B.; Schumacher, Fredrick R.; Stenzel, Stephanie L.; Casey, Graham; Kim, Hyeong-Rok; Jeong, Jin-Young; Park, Ji Won; Li, Hong-Lan; Hosono, Satoyo; Cho, Sang-Hee; Kubo, Michiaki; Shu, Xiao-Ou; Zeng, Yi-Xin; Zheng, Wei

    2014-01-01

    Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10?8 to 9.22 × 10?21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways. PMID:24836286

  1. Cystic fibrosis in Korean children:a case report identified by a quantitative pilocarpine iontophoresis sweat test and genetic analysis.

    PubMed

    Ahn, Kang Mo; Park, Hwa Young; Lee, Ji Hyun; Lee, Min Goo; Kim, Jeong Ho; Kang, Im Ju; Lee, Sang Il

    2005-02-01

    Cystic fibrosis (CF) is inherited as an autosomal recessive trait, and the mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene contributes to the CF syndrome. Although CF is common in Caucasians, it is known to be rare in Asians. Recently, we experienced two cases of CF in Korean children. The patients were girls with chronic productive cough since early infancy. Chest computed tomography showed the diffuse bronchiectasis in both lungs, and their diagnosis was confirmed by the repeated analysis of a quantitative pilocarpine iontophoresis test (QPIT). The sweat chloride concentrations of the first patient were 108.1 mM/L and 96.7 mM/L. The genetic analysis revealed that she was the compound heterozygote of Q1291X and IVS8 T5-M470V. In the second case, the sweat chloride concentrations were 95.0 mM/L and 77.5 mM/L. Although we performed a comprehensive search for the coding regions and exon-intron splicing junctions of CFTR gene, no obvious disease-related mutations were detected in the second case. To our knowledge, this is the first report of CF in Korean children identified by a QPIT and genetic analysis. The possibility of CF should be suspected in those patients with chronic respiratory symptoms even in Korea. PMID:15716623

  2. Cystic Fibrosis in Korean Children: A Case Report Identified by a Quantitative Pilocarpine Iontophoresis Sweat Test and Genetic Analysis

    PubMed Central

    Ahn, Kang-Mo; Park, Hwa-Young; Lee, Ji-Hyun; Lee, Min-Goo; Kim, Jeong-Ho; Kang, Im-Ju

    2005-01-01

    Cystic fibrosis (CF) is inherited as an autosomal recessive trait, and the mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene contributes to the CF syndrome. Although CF is common in Caucasians, it is known to be rare in Asians. Recently, we experienced two cases of CF in Korean children. The patients were girls with chronic productive cough since early infancy. Chest computed tomography showed the diffuse bronchiectasis in both lungs, and their diagnosis was confirmed by the repeated analysis of a quantitative pilocarpine iontophoresis test (QPIT). The sweat chloride concentrations of the first patient were 108.1 mM/L and 96.7 mM/L. The genetic analysis revealed that she was the compound heterozygote of Q1291X and IVS8 T5-M470V. In the second case, the sweat chloride concentrations were 95.0 mM/L and 77.5 mM/L. Although we performed a comprehensive search for the coding regions and exon-intron splicing junctions of CFTR gene, no obvious disease-related mutations were detected in the second case. To our knowledge, this is the first report of CF in Korean children identified by a QPIT and genetic analysis. The possibility of CF should be suspected in those patients with chronic respiratory symptoms even in Korea. PMID:15716623

  3. Natural genetic variation in Arabidopsis identifies BREVIS RADIX, a novel regulator of cell proliferation and elongation in the root

    PubMed Central

    Mouchel, Céline F.; Briggs, Georgette C.; Hardtke, Christian S.

    2004-01-01

    Mutant analysis has been tremendously successful in deciphering the genetics of plant development. However, less is known about the molecular basis of morphological variation within species, which is caused by naturally occurring alleles. In this study, we succeeded in isolating a novel regulator of root growth by exploiting natural genetic variation in the model plant Arabidopsis. Quantitative trait locus analysis of a cross between isogenized accessions revealed that a single locus is responsible for ?80% of the variance of the observed difference in root length. This gene, named BREVIS RADIX (BRX), controls the extent of cell proliferation and elongation in the growth zone of the root tip. We isolated BRX by positional cloning. BRX is a member of a small group of highly conserved genes, the BRX gene family, which is only found in multicellular plants. Analyses of Arabidopsis single and double mutants suggest that BRX is the only gene of this family with a role in root development. The BRX protein is nuclear localized and activates transcription in a heterologous yeast system, indicating that BRX family proteins represent a novel class of transcription factors. Thus, we have identified a novel regulatory factor controlling quantitative aspects of root growth. PMID:15031265

  4. Alteration of Genetic Make-up in Karnal Bunt Pathogen (Tilletia indica) of Wheat in Presence of Host Determinants

    PubMed Central

    Gupta, Atul K.; Seneviratne, J. M.; Bala, Ritu; Jaiswal, J. P.; Kumar, Anil

    2015-01-01

    Alteration of genetic make-up of the isolates and monosporidial strains of Tilletia indica causing Karnal bunt (KB) disease in wheat was analyzed using DNA markers and SDS-PAGE. The generation of new variation with different growth characteristics is not a generalized feature and is not only dependant on the original genetic make up of the base isolate/monosporidial strains but also on interaction with host. Host determinant(s) plays a significant role in the generation of variability and the effect is much pronounced in monosporidial strains with narrow genetic base as compared to broad genetic base. The most plausible explanation of genetic variation in presence of host determinant(s) are the recombination of genetic material from two different mycelial/sporidia through sexual mating as well as through para-sexual means. The morphological and development dependent variability further suggests that the variation in T. indica strains predominantly derived through the genetic rearrangements. PMID:26060428

  5. Structural imaging in the presymptomatic stage of genetically determined parkinsonism.

    PubMed

    Reetz, Kathrin; Tadic, Vera; Kasten, Meike; Brüggemann, Norbert; Schmidt, Alexander; Hagenah, Johann; Pramstaller, Peter P; Ramirez, Alfredo; Behrens, Maria I; Siebner, Hartwig R; Klein, Christine; Binkofski, Ferdinand

    2010-09-01

    Several genes associated with monogenic forms of Parkinson's disease (PD) have been discovered, opening up new avenues for the investigation of presymptomatic stages of PD. Using voxel-based morphometry in 30 asymptomatic mutation carriers (MC) with mutations in four different genes for PD and 100 healthy controls, we identified an increase in gray matter volume (GMV) in the striatum in asymptomatic Parkin, PINK1, ATP13A2 and, to a much lesser extent, in LRRK2 MC. Moreover, an increase in GMV was found in the parieto-temporo-occipital association cortex in asymptomatic Parkin and ATP13A2 MC. The observed striatal GMV increase might be the common structural correlate of compensatory mechanisms due to the latent dopaminergic deficit, reflecting the different, but probably interrelated pathogenic pathways resulting in nigral cell death. Asymptomatic PINK1 and LRRK2 MC also revealed smaller GMV in the hippocampal region, which might play a role in the observed psychiatric disorders. PMID:20483373

  6. A clinical genetic method to identify mechanisms by which pain causes depression and anxiety

    PubMed Central

    Max, Mitchell B; Wu, Tianxia; Atlas, Steven J; Edwards, Robert R; Haythornthwaite, Jennifer A; Bollettino, Antonella F; Hipp, Heather S; McKnight, Colin D; Osman, Inge A; Crawford, Erin N; Pao, Maryland; Nejim, Jemiel; Kingman, Albert; Aisen, Daniel C; Scully, Michele A; Keller, Robert B; Goldman, David; Belfer, Inna

    2006-01-01

    Background Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. Results We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood – the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. Conclusion Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts. PMID:16623937

  7. Genetics

    MedlinePLUS

    Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  8. Postprandial lipemia and cardiovascular disease risk: Interrelationships between dietary, physiological and genetic determinants.

    PubMed

    Jackson, Kim G; Poppitt, Sally D; Minihane, Anne M

    2012-01-01

    Although the independence of the association and causality has not been fully established, non-fasting (postprandial) triglyceride (TG) concentrations have emerged as a clinically significant cardiovascular disease (CVD) risk factor. In the current review, findings from three insightful prospective studies in the area, namely the Women's Health Study, the Copenhagen City Heart Study and the Norwegian Counties Study, are discussed. An overview is provided as to the likely etiological basis for the association between postprandial TG and CVD, with a focus on both lipid and non-lipid (inflammation, hemostasis and vascular function) risk factors. The impact of various lifestyle and physiological determinants are considered, in particular genetic variation and meal fat composition. Furthermore, although data is limited some information is provided as to the relative and interactive impact of a number of modulators of lipemia. It is evident that relative to age, gender and body mass index (known modulators of postprandial lipemia), the contribution of identified gene variants to the heterogeneity observed in the postprandial response is likely to be relatively small. Finally, we highlight the need for the development of a standardised 'fat tolerance test' for use in clinical trials, to allow the integration and comparison of data from individual studies. PMID:21955695

  9. Determinants of Genetic Structure in a Nonequilibrium Metapopulation of the Plant Silene latifolia

    PubMed Central

    Fields, Peter D.; Taylor, Douglas R.

    2014-01-01

    Population genetic differentiation will be influenced by the demographic history of populations, opportunities for migration among neighboring demes and founder effects associated with repeated extinction and recolonization. In natural populations, these factors are expected to interact with each other and their magnitudes will vary depending on the spatial distribution and age structure of local demes. Although each of these effects has been individually identified as important in structuring genetic variance, their relative magnitude is seldom estimated in nature. We conducted a population genetic analysis in a metapopulation of the angiosperm, Silene latifolia, from which we had more than 20 years of data on the spatial distribution, demographic history, and extinction and colonization of demes. We used hierarchical Bayesian methods to disentangle which features of the populations contributed to among population variation in allele frequencies, including the magnitude and direction of their effects. We show that population age, long-term size and degree of connectivity all combine to affect the distribution of genetic variance; small, recently-founded, isolated populations contributed most to increase FST in the metapopulation. However, the effects of population size and population age are best understood as being modulated through the effects of connectivity to other extant populations, i.e. FST diminishes as populations age, but at a rate that depends how isolated the population is. These spatial and temporal correlates of population structure give insight into how migration, founder effect and within-deme genetic drift have combined to enhance and restrict genetic divergence in a natural metapopulation. PMID:25198341

  10. Determinants of genetic structure in a nonequilibrium metapopulation of the plant Silene latifolia.

    PubMed

    Fields, Peter D; Taylor, Douglas R

    2014-01-01

    Population genetic differentiation will be influenced by the demographic history of populations, opportunities for migration among neighboring demes and founder effects associated with repeated extinction and recolonization. In natural populations, these factors are expected to interact with each other and their magnitudes will vary depending on the spatial distribution and age structure of local demes. Although each of these effects has been individually identified as important in structuring genetic variance, their relative magnitude is seldom estimated in nature. We conducted a population genetic analysis in a metapopulation of the angiosperm, Silene latifolia, from which we had more than 20 years of data on the spatial distribution, demographic history, and extinction and colonization of demes. We used hierarchical Bayesian methods to disentangle which features of the populations contributed to among population variation in allele frequencies, including the magnitude and direction of their effects. We show that population age, long-term size and degree of connectivity all combine to affect the distribution of genetic variance; small, recently-founded, isolated populations contributed most to increase FST in the metapopulation. However, the effects of population size and population age are best understood as being modulated through the effects of connectivity to other extant populations, i.e. FST diminishes as populations age, but at a rate that depends how isolated the population is. These spatial and temporal correlates of population structure give insight into how migration, founder effect and within-deme genetic drift have combined to enhance and restrict genetic divergence in a natural metapopulation. PMID:25198341

  11. Tryptophan Scanning Mutagenesis Identifies the Molecular Determinants of Distinct Barttin Functions.

    PubMed

    Wojciechowski, Daniel; Fischer, Martin; Fahlke, Christoph

    2015-07-24

    CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the ?-subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9-26 and 35-55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC-K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC-K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. PMID:26063802

  12. Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response.

    PubMed

    Halappanavar, Sabina; Saber, Anne Thoustrup; Decan, Nathalie; Jensen, Keld Alstrup; Wu, Dongmei; Jacobsen, Nicklas Raun; Guo, Charles; Rogowski, Jacob; Koponen, Ismo K; Levin, Marcus; Madsen, Anne Mette; Atluri, Rambabu; Snitka, Valentinas; Birkedal, Renie K; Rickerby, David; Williams, Andrew; Wallin, Håkan; Yauk, Carole L; Vogel, Ulla

    2015-03-01

    We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ? 0.05; fold change ? 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials. PMID:25504612

  13. Molecular genetic approach for identifying markers associated with yield traits in the silkworm, Bombyx mori using RFLP-STS primers.

    PubMed

    Mohandas, T P; Sethuraman, B N; Saratchandra, B; Chatterjee, S N

    2004-10-01

    Bombyx mori, the mulberry silkworm, exhibits wide variability in yield and developmental attributes. The genetics of yield expression, shown to be of polygenic nature, is poorly studied in silkworm. To identify markers associated with 10 selected yield traits, multiple regression analysis (MRA) and discriminant function analysis (DFA) were applied on 64 markers generated with eight RFLP-derived sequence-tagged-site (STS) primers on the genomic DNA of 20 silkworm stocks of different origin and diverse yield potential. The analyses led to the identification of ten markers showing significant association with the different yield traits. The markers could classify the stocks according to yield potential, irrespective of their origin and status of diapause. Trait means were significantly different for stocks with and with out the associated marker. The inheritance of a marker G2(1300bp), selected at the first step of MRA for five yield traits was shown to segregate in 1:1 ratio in the F2 progeny from a cross between two divergent stocks. The relevance of the STS primers is discussed in the context of applying multiple regression model for identifying markers associated with yield expression and suitability for molecular breeding work in B. mori for yield improvement. PMID:15609576

  14. Pathways to obesity: identifying local, modifiable determinants of physical activity and diet.

    PubMed

    Stafford, Mai; Cummins, Steven; Ellaway, Anne; Sacker, Amanda; Wiggins, Richard D; Macintyre, Sally

    2007-11-01

    Many studies document small area inequalities in morbidity and mortality and show associations between area deprivation and health. However, few studies unpack the "black box" of area deprivation to show which specific local social and physical environmental characteristics impact upon health, and might be amenable to modification. We theorised a model of the potential causal pathways to obesity and employed path analysis using a rich data set from national studies in England and Scotland to test the model empirically. Significant associations between obesity and neighbourhood disorder and access to local high street facilities (local shops, financial services and health-related stores found in a typical small UK town) were found. There was a tendency for lower levels of obesity in areas with more swimming pools and supermarkets. In turn, policing levels, physical dereliction and recorded violent crime were associated with neighbourhood disorder. The analysis identifies several factors that are associated with (and are probably determinants of) obesity and which are outside the standard remit of the healthcare sector. They highlight the role that public and private sector organisations have in promoting the nation's health. Public health professionals should seek to work alongside or within these organisations to capitalise on opportunities to improve health. PMID:17640787

  15. Nickel-Resistance Determinants in Acidiphilium sp. PM Identified by Genome-Wide Functional Screening

    PubMed Central

    San Martin-Uriz, Patxi; Mirete, Salvador; Alcolea, Pedro J.; Gomez, Manuel J.; Amils, Ricardo; Gonzalez-Pastor, Jose E.

    2014-01-01

    Acidiphilium spp. are conspicuous dwellers of acidic, metal-rich environments. Indeed, they are among the most metal-resistant organisms; yet little is known about the mechanisms behind the metal tolerance in this genus. Acidiphilium sp. PM is an environmental isolate from Rio Tinto, an acidic, metal-laden river located in southwestern Spain. The characterization of its metal resistance revealed a remarkable ability to tolerate high Ni concentrations. Here we report the screening of a genomic library of Acidiphilium sp. PM to identify genes involved in Ni resistance. This approach revealed seven different genes conferring Ni resistance to E. coli, two of which form an operon encoding the ATP-dependent protease HslVU (ClpQY). This protease was found to enhance resistance to both Ni and Co in E. coli, a function not previously reported. Other Ni-resistance determinants include genes involved in lipopolysaccharide biosynthesis and the synthesis of branched amino acids. The diversity of molecular functions of the genes recovered in the screening suggests that Ni resistance in Acidiphilium sp. PM probably relies on different molecular mechanisms. PMID:24740277

  16. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

    PubMed Central

    van Roosmalen, Wies; Le Dévédec, Sylvia E.; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; van de Water, Bob

    2015-01-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin ?3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

  17. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

    PubMed

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

    2015-04-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin ?3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

  18. Electronic Supplementary Material Kolbe et al. "Admixture determines genetic diversity and population differentiation

    E-print Network

    Losos, Jonathan B.

    1 Electronic Supplementary Material Kolbe et al. "Admixture determines genetic diversity and Houston in Texas, New Orleans, Louisiana, USA, and George Town, Grand Cayman (Kolbe et al. 2007). We also), Portillo (N=11), Soroa (N=6), and S. Esmeralda (N=6) in Cuba (Kolbe et al. 2004). These represent all

  19. Teachers' Conceptions about the Genetic Determinism of Human Behaviour: A Survey in 23 Countries

    ERIC Educational Resources Information Center

    Castéra, Jérémy; Clément, Pierre

    2014-01-01

    This work analyses the answers to a questionnaire from 8,285 in-service and pre-service teachers from 23 countries, elaborated by the Biohead-Citizen research project, to investigate teachers' conceptions related to the genetic determinism of human behaviour. A principal components analysis is used to assess the main trends in all the…

  20. The HapMap project has raised high hopes for mapping genetic determinants of complex human

    E-print Network

    Rosenberg, Noah

    The HapMap project has raised high hopes for mapping genetic determinants of complex human disease for mapping studies in human populations around the world. The HapMap project has characterized haplotype structures across the genome for four human populations with the goal of enabling genome-wide sets of SNPs

  1. The Stability of Genetic Determination from Age 2 to Age 9: A Longitudinal Twin Study.

    ERIC Educational Resources Information Center

    Lytton, Hugh; And Others

    A longitudinal investigation of the social and cognitive development of male twins was conducted when twins were 2.5 years of age, and again when they were 8- to 10-years-old. This study was designed to re-examine the heritability of the traits studied at the earlier age and, thus, to address the question of the stability of genetic determination.…

  2. Teachers' Conceptions About the Genetic Determinism of Human Behaviour: A Survey in 23 Countries

    NASA Astrophysics Data System (ADS)

    Castéra, Jérémy; Clément, Pierre

    2012-07-01

    This work analyses the answers to a questionnaire from 8,285 in-service and pre-service teachers from 23 countries, elaborated by the Biohead-Citizen research project, to investigate teachers' conceptions related to the genetic determinism of human behaviour. A principal components analysis is used to assess the main trends in all the interviewed teachers' conceptions. This illustrates that innatism is present in two distinct ways: in relation to individuals (e.g. genetic determinism to justify intellectual likeness between individuals such as twins) or in relation to groups of humans (e.g. genetic determinism to justify gender differences or the superiority of some human ethnic groups). A between-factor analysis discriminates between countries, showing very significant differences. There is more innatism among teachers' conceptions in African countries and Lebanon than in European countries, Brazil and Australia. Among the other controlled parameters, only two are significantly independent of the country: the level of training and the level of knowledge of biology. A co-inertia analysis shows a strong correlation between non-citizen attitudes towards and innatist conceptions of genetic determinism regarding human groups. We discuss these findings and their implications for education.

  3. Genetic Factors Are Relevant and Independent Determinants of Antihypertensive Drug Effects in a Multiracial Population

    Microsoft Academic Search

    Petra C. van Rijn-Bikker; Gideon Mairuhu; Gert A. van Montfrans; Eric J. G. Sijbrands; Aeilko H. Zwinderman; Henk-Jan Guchelaar; Richard P. Koopmans

    2009-01-01

    BackgroundThe success of antihypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to antihypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental,

  4. Genetic determinants of sensitivity to beryllium in mice.

    PubMed

    Tarantino-Hutchison, Lauren M; Sorrentino, Claudio; Nadas, Arthur; Zhu, Yiwen; Rubin, Edward M; Tinkle, Sally S; Weston, Ainsley; Gordon, Terry

    2009-06-01

    Chronic beryllium disease (CBD), an irreversible, debilitating granulomatous lung disease is caused by exposure to beryllium. This occupational hazard occurs in primary production and machining of Be-metal, BeO, beryllium - containing alloys, and other beryllium products. CBD begins as an MHC Class II-restricted, T(H)1 hypersensitivity, and the Human Leukocyte Antigen, HLA-DPB1E(69), is associated with risk of developing CBD. Because inbred strains of mice have not provided good models of CBD to date, three strains of HLA-DPB1 transgenic mice in an FVB/N background were developed; each contains a single allele of HLA-DPB1 that confers a different magnitude of risk for chronic beryllium disease: HLA-DPB1*0401 (OR approximately 0.2), HLA-DPB1*0201 (OR approximately 3), and HLA-DPB1*1701 (OR approximately 46). The mouse ear swelling test (MEST) was employed to determine if these different alleles would support a hypersensitivity response to beryllium. Mice were first sensitized on the back and subsequently challenged on the ear. In separate experiments, mice were placed into one of three groups (sensitization/challenge): C/C, C/Be, and Be/Be. In the HLA-DPB1*1701 mice, the strain with the highest risk transgene, the Be/Be group was the only group that displayed significant maximum increased ear thickness of 19.6% +/- 3.0% over the baseline measurement (p < 0.05). No significant changes were observed in the other transgenic strains for any treatment condition. In addition, inter-strain differences in response to beryllium in seven inbred strains were investigated through use of the MEST, these included: FVB/N, AKR, Balb/c, C3H/HeJ, C57/BL6, DBA/2, and SJL/J. The FVB/N strain was least responsive, while the SJL/J and C57/BL6 strains were the highest responders. Our results suggest that the HLA-DPB1*1701 transgene product is an important risk factor for induction of the beryllium-sensitive phenotype. This model should be a useful tool for investigating beryllium sensitization. PMID:19589099

  5. Environmental versus genetic sex determination: a possible factor in dinosaur extinction?

    Microsoft Academic Search

    David Miller; Jonathan Summers; Sherman Silber

    2004-01-01

    This study examined the possibility that genetically based sex-determination mechanisms have evolved to ensure a balanced male\\/female ratio and that this temperature-independent checkpoint might have been unavailable to long-extinct reptiles, notably the dinosaurs. A review of the literature on molecular and phylogenetic relationships between modes of reproduction and sex determination in extant animals was conducted. Mammals, birds, all snakes and

  6. Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus

    PubMed Central

    Wilson, Gareth A.; Rakyan, Vardhman K.; Teschendorff, Andrew E.; Akan, Pelin; Stupka, Elia; Down, Thomas A.; Prokopenko, Inga; Morison, Ian M.; Mill, Jonathan; Pidsley, Ruth; Deloukas, Panos; Frayling, Timothy M.; Hattersley, Andrew T.; McCarthy, Mark I.; Beck, Stephan; Hitman, Graham A.

    2010-01-01

    Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p?=?9.40×10?4, permutation p?=?1.0×10?3). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p?=?1.13×10?7). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases. PMID:21124985

  7. Application of Genomic and Quantitative Genetic Tools to Identify Candidate Resistance Genes for Brown Rot Resistance in Peach

    PubMed Central

    Martínez-García, Pedro J.; Parfitt, Dan E.; Bostock, Richard M.; Fresnedo-Ramírez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A.; Gradziel, Thomas M.; Crisosto, Carlos H.

    2013-01-01

    The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar ‘Dr. Davis’ and a brown rot resistant introgression line, ‘F8,1–42’, derived from an initial almond × peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329

  8. Two Different High Throughput Sequencing Approaches Identify Thousands of De Novo Genomic Markers for the Genetically Depleted Bornean Elephant

    PubMed Central

    Sharma, Reeta; Goossens, Benoit; Kun-Rodrigues, Célia; Teixeira, Tatiana; Othman, Nurzhafarina; Boone, Jason Q.; Jue, Nathaniel K.; Obergfell, Craig; O'Neill, Rachel J.; Chikhi, Lounès

    2012-01-01

    High throughput sequencing technologies are being applied to an increasing number of model species with a high-quality reference genome. The application and analyses of whole-genome sequence data in non-model species with no prior genomic information are currently under way. Recent sequencing technologies provide new opportunities for gathering genomic data in natural populations, laying the empirical foundation for future research in the field of conservation and population genomics. Here we present the case study of the Bornean elephant, which is the most endangered subspecies of Asian elephant and exhibits very low genetic diversity. We used two different sequencing platforms, the Roche 454 FLX (shotgun) and Illumina, GAIIx (Restriction site associated DNA, RAD) to evaluate the feasibility of the two methodologies for the discovery of de novo markers (single nucleotide polymorphism, SNPs and microsatellites) using low coverage data. Approximately, 6,683 (shotgun) and 14,724 (RAD) SNPs were detected within our elephant sequence dataset. Genotyping of a representative sample of 194 SNPs resulted in a SNP validation rate of ? 83 to 94% and 17% of the loci were polymorphic with a low diversity (Ho?=?0.057). Different numbers of microsatellites were identified through shotgun (27,226) and RAD (868) techniques. Out of all di-, tri-, and tetra-microsatellite loci, 1,706 loci had sufficient flanking regions (shotgun) while only 7 were found with RAD. All microsatellites were monomorphic in the Bornean but polymorphic in another elephant subspecies. Despite using different sample sizes, and the well known differences in the two platforms used regarding sequence length and throughput, the two approaches showed high validation rate. The approaches used here for marker development in a threatened species demonstrate the utility of high throughput sequencing technologies as a starting point for the development of genomic tools in a non-model species and in particular for a species with low genetic diversity. PMID:23185354

  9. Identity-by-descent approaches identify regions of importance for genetic susceptibility to hereditary esophageal squamous cell carcinoma.

    PubMed

    Ko, Josephine My; Zhang, Peng; Law, Simon; Fan, Yanhui; Song, You-Qiang; Zhao, Xue Ke; Wong, Elibe H W; Tang, Sa; Song, Xin; Lung, Maria Li; Wang, Li Dong

    2014-08-01

    Worldwide, the highest prevalence of esophageal cancer (EC) occurs in Northern China. High-density SNP arrays allow identification of identity-by-descent (IBD) segments in genomic DNAs representative of shared common ancestral regions. We utilized IBD approaches to map susceptibility loci associated with low-penetrance SNPs in high-risk Henan hereditary esophageal squamous cell carcinoma (ESCC) patients. Affymetrix GeneChip Human mapping SNP array IBD analysis was performed in 32 Henan family history-positive (FH+) ESCC patients, 18 Henan healthy unrelated individuals, and 45 Chinese individuals from a CHB HapMap dataset using PLink (scoring IBD segments individually) and Beagle (scoring of shared IBD segments among case/case vs. control/control pairs) software. Both analyses identified longer IBD segment lengths associated with FH+ ESCC compared to controls. However, there was no strong evidence for a genetic founder effect. Pairing IBD analysis with BEAGLE identified 8 critical IBD segments residing at 2q32.1-q32.2, 3p22.3-p22.2, 4q21.1-q21.21, 7p22.2, 8q23.2-q23.3, 10q23.33-q24.1, 14q24.3 and 16q11.2-q12.1, which were more significantly shared among case/case compared to control/control. The shared IBD segments in FH+ ESCC samples with no overlap with control/CHB Hapmap may encompass potential cancer susceptibility loci. Selected targeted genes, PLCE1, GPT2, SIAH1 and CYP2C-18, residing within the IBD segments at 10q23.33-q24.1 and 16q11.2-q12.1, had statistically significant differential expression in primary ESCC tissues and are likely involved in ESCC carcinogenesis. The importance of these IBD segments to the etiology and development of ESCC in high-risk areas requires further study with expanded sample sizes. This is the first report employing the pairing IBD approach for elucidation of the genetic basis of hereditary ESCC in Henan by applying high throughput SNP array analysis. PMID:24890309

  10. A Genome-wide Association Study of Host Genetic Determinants of the Antibody Response to Anthrax Vaccine Adsorbed

    PubMed Central

    Pajewski, Nicholas M.; Shrestha, Sadeep; Quinn, Conrad P.; Parker, Scott D.; Wiener, Howard; Aissani, Brahim; McKinney, Brett A.; Poland, Gregory A.; Edberg, Jeffrey C.; Kimberly, Robert P.; Tang, Jianming; Kaslow, Richard A.

    2012-01-01

    Several lines of evidence have supported a host genetic contribution to vaccine response, but genome-wide assessments for specific determinants have been sparse. Here we describe a genome-wide association study (GWAS) of protective antigen-specific antibody (AbPA) responses among 726 European-Americans who received Anthrax Vaccine Adsorbed (AVA) as part of a clinical trial. After quality control, 736,996 SNPs were tested for association with the AbPA response to 3 or 4 AVA vaccinations given over a 6-month period. No SNP achieved the threshold of genome-wide significance (p=5x10?8), but suggestive associations (p<1x10?5) were observed for SNPs in or near the class II region of the major histocompatibility complex (MHC), in the promoter region of SPSB1, and adjacent to MEX3C. Multivariable regression modeling suggested that much of the association signal within the MHC corresponded to previously identified HLA DR-DQ haplotypes involving component HLA-DRB1 alleles of *15:01, *01:01, or *01:02. We estimated the proportion of additive genetic variance explained by common SNP variation for the AbPA response after the 6 month vaccination. This analysis indicated a significant, albeit imprecisely estimated, contribution of variation tagged by common polymorphisms (p=0.032). Future studies will be required to replicate these findings in European Americans and to further elucidate the host genetic factors underlying variable immune response to AVA. PMID:22658931

  11. Patient responses to genetic information: studies of patients with hereditary cancer syndromes identify issues for use of genetic testing in nephrology practice.

    PubMed

    Kaphingst, Kimberly A; McBride, Colleen M

    2010-03-01

    Advances in the genetic basis of kidney disease may mean that genetic testing is increasingly important in reducing disease morbidity and mortality among patients. However, there is little research examining patient responses to genetic information for Mendelian and common kidney diseases. Existing research on kidney and other hereditary cancer syndromes can inform three major issues relevant to the nephrology context as follows: (1) how patients understand their risk of disease after genetic counseling and testing, (2) their emotional responses to the information, and (3) their uptake of recommended risk-reducing strategies. Prior research suggests that genetic counseling and testing may improve patient understanding of genetics, but patients still might not fully understand the meaning of their results for disease risk. Genetic counseling and testing does not appear to result in long-term negative emotional effects among patients who carry mutations or those who do not. Finally, although genetic counseling and testing may improve adherence to recommended screening strategies, adherence varies substantially across different risk-reduction options. Previous research also suggests that computer-based interventions might be a useful adjunct to genetic counseling approaches. Examining whether and how these prior findings relate to the context of hereditary kidney disease is an important area for future research. PMID:20347649

  12. Patient responses to genetic information: studies of patients with hereditary cancer syndromes identify issues for use of genetic testing in nephrology practice

    PubMed Central

    Kaphingst, Kimberly A.; McBride, Colleen M.

    2010-01-01

    Advances in the genetic basis of kidney disease may mean that genetic testing is increasingly important in reducing disease morbidity and mortality among patients. However, there is little research examining patient responses to genetic information for Mendelian and common kidney diseases. Existing research on kidney and other hereditary cancer syndromes can inform three major issues relevant to the nephrology context: (1) how patients understand their risk of disease following genetic counseling and testing; (2) their emotional responses to the information; and (3) their uptake of recommended risk-reducing strategies. Prior research suggests that genetic counseling and testing may improve patient understanding of genetics, but patients still might not fully understand the meaning of their results for disease risk. Genetic counseling and testing does not appear to result in long-term negative emotional effects among patients who carry mutations or those who do not. Finally, while genetic counseling and testing may improve adherence to recommended screening strategies, adherence varies substantially across different risk-reduction options. Previous research also suggests that computer-based interventions might be a useful adjunct to genetic counseling approaches. Examining whether and how these prior findings relate to the context of hereditary kidney disease is an important area for future research. PMID:20347649

  13. Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis

    PubMed Central

    Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

    2014-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count. PMID:25329635

  14. An Iterative Genetic and Dynamical Modelling Approach Identifies Novel Features of the Gene Regulatory Network Underlying Melanocyte Development

    PubMed Central

    Greenhill, Emma R.; Rocco, Andrea; Vibert, Laura; Nikaido, Masataka; Kelsh, Robert N.

    2011-01-01

    The mechanisms generating stably differentiated cell-types from multipotent precursors are key to understanding normal development and have implications for treatment of cancer and the therapeutic use of stem cells. Pigment cells are a major derivative of neural crest stem cells and a key model cell-type for our understanding of the genetics of cell differentiation. Several factors driving melanocyte fate specification have been identified, including the transcription factor and master regulator of melanocyte development, Mitf, and Wnt signalling and the multipotency and fate specification factor, Sox10, which drive mitf expression. While these factors together drive multipotent neural crest cells to become specified melanoblasts, the mechanisms stabilising melanocyte differentiation remain unclear. Furthermore, there is controversy over whether Sox10 has an ongoing role in melanocyte differentiation. Here we use zebrafish to explore in vivo the gene regulatory network (GRN) underlying melanocyte specification and differentiation. We use an iterative process of mathematical modelling and experimental observation to explore methodically the core melanocyte GRN we have defined. We show that Sox10 is not required for ongoing differentiation and expression is downregulated in differentiating cells, in response to Mitfa and Hdac1. Unexpectedly, we find that Sox10 represses Mitf-dependent expression of melanocyte differentiation genes. Our systems biology approach allowed us to predict two novel features of the melanocyte GRN, which we then validate experimentally. Specifically, we show that maintenance of mitfa expression is Mitfa-dependent, and identify Sox9b as providing an Mitfa-independent input to melanocyte differentiation. Our data supports our previous suggestion that Sox10 only functions transiently in regulation of mitfa and cannot be responsible for long-term maintenance of mitfa expression; indeed, Sox10 is likely to slow melanocyte differentiation in the zebrafish embryo. More generally, this novel approach to understanding melanocyte differentiation provides a basis for systematic modelling of differentiation in this and other cell-types. PMID:21909283

  15. Genetic modifiers of Hb E/?0 thalassemia identified by a two-stage genome-wide association study

    PubMed Central

    2010-01-01

    Background Patients with Hb E/?0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/?0 thalassemia and normal ?-globin genes. Methods First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P < 0.02 by pooling were selected for individual genotyping. Results After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P < 0.05) after Bonferroni adjustment for multiple testing. Forty-one SNPs in a large LD block within the ?-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 × 10-13). Seven SNPs in two distinct LD blocks within a region centromeric to the ?-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 × 10-11). Several previously unreported SNPs were also significantly associated with disease severity. Conclusions These results suggest that there may be an additional regulatory region centromeric to the ?-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression. PMID:20353593

  16. Identifying some determinants of "jet lag" and its symptoms: a study of athletes and other travellers

    PubMed Central

    Waterhouse, J; Edwards, B; Nevill, A; Carvalho, S; Atkinson, G; Buckley, P; Reilly, T; Godfrey, R; Ramsay, R

    2002-01-01

    Background: Travelling across multiple time zones disrupts normal circadian rhythms and induces "jet lag". Possible effects of this on training and performance in athletes were concerns before the Sydney Olympic Games. Objective: To identify some determinants of jet lag and its symptoms. Methods: A mixture of athletes, their coaches, and academics attending a conference (n = 85) was studied during their flights from the United Kingdom to Australia (two flights with a one hour stopover in Singapore), and for the first six days in Australia. Subjects differed in age, sex, chronotype, flexibility of sleeping habits, feelings of languor, fitness, time of arrival in Australia, and whether or not they had previous experience of travel to Australia. These variables and whether the body clock adjusted to new local time by phase advance or delay were tested as predictors for jet lag and some of its symptoms by stepwise multiple regression analyses. Results: The amount of sleep in the first flight was significantly greater in those who had left the United Kingdom in the evening than the morning (medians of 5.5 hours and 1.5 hours respectively; p = 0.0002, Mann-Whitney), whereas there was no significant difference on the second flight (2.5 hours v 2.8 hours; p = 0.72). Only the severity of jet lag and assessments of sleep and fatigue were commonly predicted significantly (p<0.05) by regression analysis, and then by only some of the variables. Thus increasing age and a later time of arrival in Australia were associated with less jet lag and fatigue, and previous experience of travel to Australia was associated with an earlier time of getting to sleep. Subjects who had adjusted by phase advance suffered worse jet lag during the 5th and 6th days in Australia. Conclusions: These results indicate the importance of an appropriate choice of itinerary and lifestyle for reducing the negative effects of jet lag in athletes and others who wish to perform optimally in the new time zone. PMID:11867494

  17. Exploration of genetically determined resistance against hepatitis C infection in high-risk injecting drug users.

    PubMed

    Sugden, P B; Cameron, B; Luciani, F; Lloyd, A R

    2014-08-01

    Genetic resistance to specific infections is well recognized. In hepatitis C virus (HCV) infection, genetic polymorphisms in IL-28B and the killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands have been shown to affect clearance of the virus following infection. There are limited data regarding resistance to established HCV infection. Reliable quantification of repeated exposure in high-risk populations, such as injecting drug users (IDU), is a key limitation of previous studies of resistance. Behavioural data and DNA from IDU (n = 210) in the Hepatitis C Incidence and Transmission Study in prisons (HITS-p) cohort were genotyped for polymorphisms in: IL-28B, peptidyl-prolyl isomerase A (PPIA), HLA-C and KIR2. To quantify risk, a composite risk index based on factors predictive of incident HCV infection was derived. Logistic regression analysis revealed the risk index was strongly associated with incident HCV infection (P < 0.0001). The upper tertile of the uninfected individuals had risk indices comparable to the incident cases, but remained uninfected. There were no significant differences in the frequencies of IL-28B or PPIA polymorphisms between these exposed-uninfected cases, or in the frequencies of KIR2-DL3, HLA-C1, or their combination. A framework for the investigation of genetic determinants of resistance to HCV infection has been developed. Several candidate gene associations were investigated and excluded. Further investigation of genetic determinants of resistance to HCV infection is warranted. PMID:24612442

  18. Environmental versus genetic sex determination: a possible factor in dinosaur extinction?

    PubMed

    Miller, David; Summers, Jonathan; Silber, Sherman

    2004-04-01

    This study examined the possibility that genetically based sex-determination mechanisms have evolved to ensure a balanced male/female ratio and that this temperature-independent checkpoint might have been unavailable to long-extinct reptiles, notably the dinosaurs. A review of the literature on molecular and phylogenetic relationships between modes of reproduction and sex determination in extant animals was conducted. Mammals, birds, all snakes and most lizards, amphibians, and some gonochoristic fish use specific sex-determining chromosomes or genes (genetic sex determination, GSD). Some reptiles, however, including all crocodilians studied to date, many turtle and tortoise species, and some lizards, use environmental or temperature-dependent sex determination (TSD). We show that various modes of GSD have evolved many times, independently in different orders. Animals using TSD would be at risk of rapid reproductive failure due to a skewed sex ratio favoring males in response to sustained environmental temperature change and favoring the selection of sex-determining genes. The disadvantage to the evolving male sex-determining chromosome, however, is its decay due to nonrecombination and the subsequent loss of spermatogenesis genes. Global temperature change can skew the sex ratio of TSD animals and might have played a significant role in the demise of long-extinct species, notably the dinosaurs, particularly if the temperature change resulted in a preponderance of males. Current global warming also represents a risk for extant TSD species. PMID:15066448

  19. Genetic analysis to identify good combiners for ToLCV resistance and yield components in tomato using interspecific hybridization.

    PubMed

    Singh, Ramesh K; Rai, N; Singh, Major; Singh, S N; Srivastava, K

    2014-12-01

    The interspecific hybridization for tomato leaf curl virus (ToLCV) resistance was carried out among 10 genetically diverse tomato genotypes (diversified by 50 SSR markers). Among the 10 parents, four susceptible cultivars of Solanum lycopersicum were crossed with six resistant wilds, such as S. pimpinellifolium, S. habrochaites, S. chemielewskii, S. ceraseforme, S. peruvianum and S. chilense in a line x tester mating design. All the 24 hybrids and their parents were grown in the field and glasshouse conditions to determine the general-combining abilities (GCA) and specific-combining abilities (SCA). The variances due to SCA and GCA showed both additive and nonadditive gene effects. Based on GCA estimates, EC-520061 and WIR-5032 were good general combiners while based on SCA estimates, PBC x EC-520061 and PBC x EC-521080 were best specific combiners for coefficient of infection and fruit yield per plant in both the environments. These lines could be selected and utilized in ToLCV resistance and high yield breeding programme for improving the traits. PMID:25572221

  20. Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing

    PubMed Central

    Brookes, Clare; Lai, Stella; Doherty, Elaine; Love, Donald R.

    2015-01-01

    Objectives: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. Methods: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub) for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. Results: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. Conclusion: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible.

  1. Identifying Determinants of Cullin Binding Specificity Among the Three Functionally Different Drosophila melanogaster Roc Proteins via Domain Swapping

    PubMed Central

    Reynolds, Patrick J.; Simms, Jeffrey R.; Duronio, Robert J.

    2008-01-01

    Background Cullin-dependent E3 ubiquitin ligases (CDL) are key regulators of protein destruction that participate in a wide range of cell biological processes. The Roc subunit of CDL contains an evolutionarily conserved RING domain that binds ubiquitin charged E2 and is essential for ubiquitylation. Drosophila melanogaster contains three highly related Roc proteins: Roc1a and Roc2, which are conserved in vertebrates, and Roc1b, which is specific to Drosophila. Our previous genetic data analyzing Roc1a and Roc1b mutants suggested that Roc proteins are functionally distinct, but the molecular basis for this distinction is not known. Methodology/Principal Findings Using co-immunoprecipitation studies we show that Drosophila Roc proteins bind specific Cullins: Roc1a binds Cul1-4, Roc1b binds Cul3, and Roc2 binds Cul5. Through domain swapping experiments, we demonstrate that Cullin binding specificity is strongly influenced by the Roc NH2-terminal domain, which forms an inter-molecular ? sheet with the Cullin. Substitution of the Roc1a RING domain with that of Roc1b results in a protein with similar Cullin binding properties to Roc1a that is active as an E3 ligase but cannot complement Roc1a mutant lethality, indicating that the identity of the RING domain can be an important determinant of CDL function. In contrast, the converse chimeric protein with a substitution of the Roc1b RING domain with that of Roc1a can rescue the male sterility of Roc1b mutants, but only when expressed from the endogenous Roc1b promoter. We also identified mutations of Roc2 and Cul5 and show that they cause no overt developmental phenotype, consistent with our finding that Roc2 and Cul5 proteins are exclusive binding partners, which others have observed in human cells as well. Conclusions The Drosophila Roc proteins are highly similar, but have diverged during evolution to bind a distinct set of Cullins and to utilize RING domains that have overlapping, but not identical, function in vivo. PMID:18698375

  2. Robust Flight Path Determination for Mars Precision Landing Using Genetic Algorithms

    NASA Technical Reports Server (NTRS)

    Bayard, David S.; Kohen, Hamid

    1997-01-01

    This paper documents the application of genetic algorithms (GAs) to the problem of robust flight path determination for Mars precision landing. The robust flight path problem is defined here as the determination of the flight path which delivers a low-lift open-loop controlled vehicle to its desired final landing location while minimizing the effect of perturbations due to uncertainty in the atmospheric model and entry conditions. The genetic algorithm was capable of finding solutions which reduced the landing error from 111 km RMS radial (open-loop optimal) to 43 km RMS radial (optimized with respect to perturbations) using 200 hours of computation on an Ultra-SPARC workstation. Further reduction in the landing error is possible by going to closed-loop control which can utilize the GA optimized paths as nominal trajectories for linearization.

  3. USGS Genetics and Genomics Showcase

    USGS Multimedia Gallery

    The USGS Biology Resources Discipline showcased research in the fields of genetics and genomics on March 10, 2010 in the South Interior Building of the Department of the Interior. Topics included genetics to determine populations and recover endangered species, genetics that can identify wildlife in...

  4. Using the Social Communication Questionnaire to Identify "Autistic Spectrum" Disorders Associated with Other Genetic Conditions: Findings from a Study of Individuals with Cohen Syndrome

    ERIC Educational Resources Information Center

    Howlin, Patricia; Karpf, Janne

    2004-01-01

    Increasingly, recent research has identified relatively high rates of autistic types of symptoms in a variety of genetic conditions, such as fragile X (Turk and Graham, 1997), tuberous sclerosis (Bolton and Griffiths, 1997), Angelman syndrome (Trillingsgaard and Ostergaard, this issue) and others (see Gillberg and Coleman, 2000). Detailed…

  5. Dynamic Structure-Based Neural Network Determination Using Orthogonal Genetic Algorithm with Quantization

    Microsoft Academic Search

    Liling Xing; Wentao Zhao

    2007-01-01

    It proposed a novel dynamic structure-based neural network determination approach using orthogonal genetic algorithm with\\u000a quantization in this paper. Both the parameter (the threshold of each neuron and the weight between two neurons) and the transfer\\u000a function (the transfer function of each layer and the network training function) of the dynamic structure-based neural network\\u000a were optimized in this proposed approach.

  6. Genetic determinants of Pseudomonas aeruginosa colonization in cystic fibrosis patients in Canada

    Microsoft Academic Search

    M. De Braekeleer; C. Allard; J.-P. Leblanc; G. Aubin; F. Simard

    1998-01-01

    The present study was aimed at analyzing whether the rate of colonization and the age at colonization withPseudomonas aeruginosa was genetically determined in cystic fibrosis (CF) patients. These two variables were calculated among 127 CF patients whose genotypes were known and who were monitored at the Clinique de Fibrose Kystique in Saguenay Lac-Saint-Jean. No statistically significant differences were found in

  7. A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.

    PubMed

    Angus, Simon D; Piotrowska, Monika Joanna

    2014-01-01

    Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17-18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy. PMID:25460164

  8. A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes

    PubMed Central

    Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

    2014-01-01

    Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n?=?228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. PMID:25411967

  9. Extensive Genetic Diversity Identified among Sporadic Methicillin-Resistant Staphylococcus aureus Isolates Recovered in Irish Hospitals between 2000 and 2012

    PubMed Central

    Kinnevey, Peter M.; Shore, Anna C.; Brennan, Grainne I.; Sullivan, Derek J.; Ehricht, Ralf; Monecke, Stefan

    2014-01-01

    Clonal replacement of predominant nosocomial methicillin-resistant Staphylococcus aureus (MRSA) strains has occurred several times in Ireland during the last 4 decades. However, little is known about sporadically occurring MRSA in Irish hospitals or in other countries. Eighty-eight representative pvl-negative sporadic MRSA isolates recovered in Irish hospitals between 2000 and 2012 were investigated. These yielded unusual pulsed-field gel electrophoresis and antibiogram-resistogram typing patterns distinct from those of the predominant nosocomial MRSA clone, ST22-MRSA-IV, during the study period. Isolates were characterized by spa typing and DNA microarray profiling for multilocus sequence type (MLST) clonal complex (CC) and/or sequence type (ST) and SCCmec type assignment, as well as for detection of virulence and antimicrobial resistance genes. Conventional PCR-based SCCmec subtyping was undertaken when necessary. Extensive diversity was detected, including 38 spa types, 13 MLST-CCs (including 18 STs among 62 isolates assigned to STs), and 25 SCCmec types (including 2 possible novel SCCmec elements and 7 possible novel SCCmec subtypes). Fifty-four MLST-spa-SCCmec type combinations were identified. Overall, 68.5% of isolates were assigned to nosocomial lineages, with ST8-t190-MRSA-IID/IIE ± SCCM1 predominating (17.4%), followed by CC779/ST779-t878-MRSA-?SCCmec-SCC-SCCCRISPR (7.6%) and CC22/ST22-t032-MRSA-IVh (5.4%). Community-associated clones, including CC1-t127/t386/t2279-MRSA-IV, CC59-t216-MRSA-V, CC8-t008-MRSA-IVa, and CC5-t002/t242-MRSA-IV/V, and putative animal-associated clones, including CC130-t12399-MRSA-XI, ST8-t064-MRSA-IVa, ST398-t011-MRSA-IVa, and CC6-t701-MRSA-V, were also identified. In total, 53.3% and 47.8% of isolates harbored genes for resistance to two or more classes of antimicrobial agents and two or more mobile genetic element-encoded virulence-associated factors, respectively. Effective ongoing surveillance of sporadic nosocomial MRSA is warranted for early detection of emerging clones and reservoirs of virulence, resistance, and SCCmec genes. PMID:24395241

  10. Phylogenomics of Xanthomonas field strains infecting pepper and tomato reveals diversity in effector repertoires and identifies determinants of host specificity

    PubMed Central

    Schwartz, Allison R.; Potnis, Neha; Timilsina, Sujan; Wilson, Mark; Patané, José; Martins, Joaquim; Minsavage, Gerald V.; Dahlbeck, Douglas; Akhunova, Alina; Almeida, Nalvo; Vallad, Gary E.; Barak, Jeri D.; White, Frank F.; Miller, Sally A.; Ritchie, David; Goss, Erica; Bart, Rebecca S.; Setubal, João C.; Jones, Jeffrey B.; Staskawicz, Brian J.

    2015-01-01

    Bacterial spot disease of pepper and tomato is caused by four distinct Xanthomonas species and is a severely limiting factor on fruit yield in these crops. The genetic diversity and the type III effector repertoires of a large sampling of field strains for this disease have yet to be explored on a genomic scale, limiting our understanding of pathogen evolution in an agricultural setting. Genomes of 67 Xanthomonas euvesicatoria (Xe), Xanthomonas perforans (Xp), and Xanthomonas gardneri (Xg) strains isolated from diseased pepper and tomato fields in the southeastern and midwestern United States were sequenced in order to determine the genetic diversity in field strains. Type III effector repertoires were computationally predicted for each strain, and multiple methods of constructing phylogenies were employed to understand better the genetic relationship of strains in the collection. A division in the Xp population was detected based on core genome phylogeny, supporting a model whereby the host-range expansion of Xp field strains on pepper is due, in part, to a loss of the effector AvrBsT. Xp-host compatibility was further studied with the observation that a double deletion of AvrBsT and XopQ allows a host range expansion for Nicotiana benthamiana. Extensive sampling of field strains and an improved understanding of effector content will aid in efforts to design disease resistance strategies targeted against highly conserved core effectors. PMID:26089818

  11. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.

    PubMed

    Wen, C C; Yee, S W; Liang, X; Hoffmann, T J; Kvale, M N; Banda, Y; Jorgenson, E; Schaefer, C; Risch, N; Giacomini, K M

    2015-05-01

    The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug. PMID:25676789

  12. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response

    PubMed Central

    Wen, CC; Yee, SW; Liang, X; Hoffmann, TJ; Kvale, MN; Banda, Y; Jorgenson, E; Schaefer, C; Risch, N; Giacomini, KM

    2015-01-01

    The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente’s Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10?8), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10?7) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug. PMID:25676789

  13. Determination of genetic relationships among shape Phaseolus vulgaris populations in a conical cross from RAPD marker analyses

    Microsoft Academic Search

    Yonghe Bai; T. E. Michaels; K. P. Pauls

    1998-01-01

    Random-amplified polymorphic DNA (RAPD) markers were used to determine genetic relationships among Phaseolus vulgaris breeding populations. Genetic distances were calculated from the distribution of 317 RAPD markers among 8 parents, 10 individuals from 8 cycle-one populations, 10 individuals from 6 cycle-two populations and 10 individuals from 2 cycle-three populations of a conical cross. Genetic distances between populations and parents were

  14. Genetic Determinants of Cardio-Metabolic Risk: A Proposed Model for Phenotype Association and Interaction

    PubMed Central

    Blackett, Piers R; Sanghera, Dharambir K

    2012-01-01

    This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes and ? cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus it follows that the genetics of dyslipidemia, obesity, and non-alcoholic fatty liver (NAFLD) disease are central in triggering progression of the syndrome to overt expression of disease traits, and have become a key focus of interest for early detection and for designing prevention and treatments. To support the “birds’ eye view” approach we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacological targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. PMID:23351585

  15. Genetic diversity and geographic population structure of bovine Neospora caninum determined by microsatellite genotyping analysis.

    PubMed

    Regidor-Cerrillo, Javier; Díez-Fuertes, Francisco; García-Culebras, Alicia; Moore, Dadín P; González-Warleta, Marta; Cuevas, Carmen; Schares, Gereon; Katzer, Frank; Pedraza-Díaz, Susana; Mezo, Mercedes; Ortega-Mora, Luis M

    2013-01-01

    The cyst-forming protozoan parasite Neosporacaninum is one of the main causes of bovine abortion worldwide and is of great economic importance in the cattle industry. Recent studies have revealed extensive genetic variation among N. caninum isolates based on microsatellite sequences (MSs). MSs may be suitable molecular markers for inferring the diversity of parasite populations, molecular epidemiology and the basis for phenotypic variations in N. caninum, which have been poorly defined. In this study, we evaluated nine MS markers using a panel of 11 N. caninum-derived reference isolates from around the world and 96 N. caninum bovine clinical samples and one ovine clinical sample collected from four countries on two continents, including Spain, Argentina, Germany and Scotland, over a 10-year period. These markers were used as molecular tools to investigate the genetic diversity, geographic distribution and population structure of N. caninum. Multilocus microsatellite genotyping based on 7 loci demonstrated high levels of genetic diversity in the samples from all of the different countries, with 96 microsatellite multilocus genotypes (MLGs) identified from 108 N. caninum samples. Geographic sub-structuring was present in the country populations according to pairwise F(ST). Principal component analysis (PCA) and Neighbor Joining tree topologies also suggested MLG segregation partially associated with geographical origin. An analysis of the MLG relationships, using eBURST, confirmed that the close genetic relationship observed between the Spanish and Argentinean populations may be the result of parasite migration (i.e., the introduction of novel MLGs from Spain to South America) due to cattle movement. The eBURST relationships also revealed genetically different clusters associated with the abortion. The presence of linkage disequilibrium, the co-existence of specific MLGs to individual farms and eBURST MLG relationships suggest a predominant clonal propagation for Spanish N. caninum MLGs in cattle. PMID:23940816

  16. Genetically Determined Amerindian Ancestry Correlates with Increased Frequency of Risk Alleles for Systemic Lupus Erythematosus

    PubMed Central

    Sanchez, E; Webb, R; Rasmussen, A.; Kelly, J.A; Riba, L.; Kaufman, K.M.; Garcia-de la Torre, I.; Moctezuma, J.F.; Maradiaga-Ceceña, M.A.; Cardiel, M.; Acevedo, E.; Cucho-Venegas, M.; Garcia, M.A.; Gamron, S.; Pons-Estel, B.A.; Vasconcelos, C.; Martin, J.; Tusié-Luna, T.; Harley, J.B.; Richardson, B.; Sawalha, A.H.; Alarcón-Riquelme, M.E.

    2011-01-01

    Objectives To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus. Methods Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression. Results A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele. Conclusion Amerindian ancestry increased the number of risk alleles for lupus. PMID:20848568

  17. Determination of Timed Transitions in Identified Discrete-Event Models for Fault Detection

    E-print Network

    Boyer, Edmond

    is to model large-scale Discrete Event Systems (DESs) with little a-priori knowledge. For this class approaches are knowledge based and therefore comprehensive a-priori in- formation is required. For large-scale generic method for time guard determination of large-scale DESs affected by dis- turbances. Known

  18. Genetic Variation Within Adrenergic Pathways Determines In Vivo Effects of Presynaptic Stimulation in Humans

    PubMed Central

    Fung, Maple M.; Nguyen, Carie; Mehtani, Parag; Salem, Rany M.; Perez, Brandon; Thomas, Brenda; Das, Madhusudan; Schork, Nicholas J.; Mahata, Sushil K.; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Background Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. Methods and Results To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase ?-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype. Conclusions Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may influence the complex heritability of adrenergic responses and perhaps hypertension. PMID:18180394

  19. Castra J. & Clment P., 2014 -Teachers' conceptions about genetic determinism of human behaviour: a survey in 23 Countries. Science & Education, 23 (2), 417-443.

    E-print Network

    Paris-Sud XI, Université de

    1 Castéra J. & Clément P., 2014 - Teachers' conceptions about genetic determinism of human-012-9494-0) Teachers' Conceptions about the Genetic Determinism of Human Behaviour: A Survey in 23 Countries (Preprint to the genetic determinism of human behaviour. A principal components analysis is used to assess the main trends

  20. Dozens of new de novo genetic mutations in schizophrenia identified http://www.sciencedaily.com/releases/2012/10/121003132420.htm[10/9/2012 1:10:35 PM

    E-print Network

    ) -- Researchers have shown that new, or "de novo," protein-altering mutations -- genetic errors that are presentDozens of new de novo genetic mutations in schizophrenia identified http spontaneous genetic mutations that play a significant role in the development of schizophrenia, adding

  1. Genome-wide association identifies ATOH7 as a major gene determining human optic disc size.

    PubMed

    Macgregor, Stuart; Hewitt, Alex W; Hysi, Pirro G; Ruddle, Jonathan B; Medland, Sarah E; Henders, Anjali K; Gordon, Scott D; Andrew, Toby; McEvoy, Brian; Sanfilippo, Paul G; Carbonaro, Francis; Tah, Vikas; Li, Yi Ju; Bennett, Sonya L; Craig, Jamie E; Montgomery, Grant W; Tran-Viet, Khanh-Nhat; Brown, Nadean L; Spector, Timothy D; Martin, Nicholas G; Young, Terri L; Hammond, Christopher J; Mackey, David A

    2010-07-01

    Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P=6.2x10(-10), near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P=3.4x10(-10). Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P=1.3x10(-10) to 4.3x10(-11), top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P=1.5x10(-7), in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P=0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls. PMID:20395239

  2. In the name of the migrant father--analysis of surname origins identifies genetic admixture events undetectable from genealogical records.

    PubMed

    Larmuseau, M H D; Vanoverbeke, J; Gielis, G; Vanderheyden, N; Larmuseau, H F M; Decorte, R

    2012-08-01

    Patrilineal heritable surnames are widely used to select autochthonous participants for studies on small-scale population genetic patterns owing to the unique link between the surname and a genetic marker, the Y-chromosome (Y-chr). Today, the question arises as to whether the surname origin will be informative on top of in-depth genealogical pedigrees. Admixture events that happened in the period after giving heritable surnames but before the start of genealogical records may be informative about the additional value of the surname origin. In this context, an interesting historical event is the demic migration from French-speaking regions in Northern France to the depopulated and Dutch-speaking region Flanders at the end of the sixteenth century. Y-chr subhaplogroups of individuals with a French/Roman surname that could be associated with this migration event were compared with those of a group with autochthonous Flemish surnames. Although these groups could not be differentiated based on in-depth genealogical data, they were significantly genetically different from each other. Moreover, the observed genetic divergence was related to the differences in the distributions of main Y-subhaplogroups between contemporary populations from Northern France and Flanders. Therefore, these results indicate that the surname origin can be an important feature on top of in-depth genealogical results to select autochthonous participants for a regional population genetic study based on Y-chromosomes. PMID:22511074

  3. New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers

    PubMed Central

    Hendig, Doris; Knabbe, Cornelius; Götting, Christian

    2013-01-01

    Screening of the adenosine triphosphate binding cassette transporter protein subfamily C member 6 gene (ABCC6) in pseudoxanthoma elasticum (PXE) revealed a mutation detection rate of approximately 87%. Although 25% of the unidentified disease alleles underlie deletions/insertions, there remain several PXE patients with no clear genotype. The recent identification of PXE-related diseases and the high intra-familiar and inter-individual clinical variability of PXE led to the assumption that secondary genetic co-factors exist. Here, we summarize current knowledge of the genetics underlying PXE and PXE-related disorders based on human and animal studies. Furthermore, we discuss the role of genetic interactions and modifier genes in PXE and PXE-related diseases characterized by soft tissue calcification. PMID:23802012

  4. Dynamic Genetic Interactions Determine Odor-Guided Behavior in Drosophila melanogaster

    PubMed Central

    Sambandan, Deepa; Yamamoto, Akihiko; Fanara, Juan-José; Mackay, Trudy F. C.; Anholt, Robert R. H.

    2006-01-01

    Understanding the genetic architecture of complex traits requires identification of the underlying genes and characterization of gene-by-gene and genotype-by-environment interactions. Behaviors that mediate interactions between organisms and their environment are complex traits expected to be especially sensitive to environmental conditions. Previous studies on the olfactory avoidance response of Drosophila melanogaster showed that the genetic architecture of this model behavior depends on epistatic networks of pleiotropic genes. We performed a screen of 1339 co-isogenic p[GT1]-element insertion lines to identify novel genes that contribute to odor-guided behavior and identified 55 candidate genes with known p[GT1]-element insertion sites. Characterization of the expression profiles of 10 p[GT1]-element insertion lines showed that the effects of the transposon insertions are often dependent on developmental stage and that hypomorphic mutations in developmental genes can elicit profound adult behavioral deficits. We assessed epistasis among these genes by constructing all possible double heterozygotes and measuring avoidance responses under two stimulus conditions. We observed enhancer and suppressor effects among subsets of these P-element-tagged genes, and surprisingly, epistatic interactions shifted with changes in the concentration of the olfactory stimulus. Our results show that the manifestation of epistatic networks dynamically changes with alterations in the environment. PMID:17028343

  5. Genetics

    NSDL National Science Digital Library

    Jennifer Doherty

    This activity helps students to understand basic principles of genetics, including relationships of genotype to phenotype, concepts of recessive and dominant alleles, and how understanding meiosis and fertilization provides the basis for understanding inheritance, as summarized in Punnett squares. The Student Handout includes an analysis of the inheritance of albinism that teaches all of these concepts, a Coin Toss Genetics activity that helps students understand the probabilistic nature of Punnett square predictions, and an analysis of the inheritance of sickle cell anemia that reinforces the basic concepts and introduces some of the complexities of genetics. The Genetics Supplement includes two additional activities, an analysis of student data on the sex makeup of sibships and pedigree analyses of recessive and dominant alleles with challenge questions that introduce the role of mutations and an evaluation of Punnett squares and pedigrees as models of inheritance.

  6. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency.

    PubMed

    Pike, Gillian N; Cumming, Anthony M; Hay, Charles R M; Bolton-Maggs, Paula H B; Burthem, John

    2015-07-16

    Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations. When contact activation was inhibited and platelets were absent, FXI:C levels did not correlate with thrombin generation parameters, and control and FXI-deficient individuals were not distinguished. In all other sample types, the best discrimination was obtained using TF 0.5 pM and assay measures: endogenous thrombin potential (ETP) and peak height. We showed that although a number of conditions could distinguish differences between the groups tested, TGA measured in PRP with CTI best differentiated between bleeders and nonbleeders. These measures provided high sensitivity and specificity (peak height receiver operating characteristic [ROC] area under the curve [AUC] = 0.9362; P < .0001) (ETP ROC AUC = 0.9362; P < .0001). We conclude that by using sample conditions directed to test specific pathways of FXI activation, the TGA can identify bleeding phenotype in FXI deficiency. PMID:25911238

  7. Structural distribution of dipeptides that are identified to be determinants of intracellular protein stability.

    PubMed

    Reddy, B V

    1996-10-01

    The dipeptides that had been previously implicated as determinants of in vivo protein stability (Guruprasad, K., Reddy, B.V.B. and Pandit, M.W., 1990. Protein Eng. 4, 155-161) have been reassessed on a latest data set and about 25% dipeptide combinations (102 dipeptides) were found to play significant role in determining the intracellular protein stability. These were classified as stabilizing dipeptides (Stb), destabilizing dipeptides (Dst) and normal dipeptides (Nor). By different theoretical approaches we have investigated the global localization of these dipeptides in a set of 303 best resolved (< or = 2.0A) non-homologous X-ray defined protein structures. The Dst dipeptides are found to be more of hydrophilic combinations where as Stb dipeptides are more of hydrophobic combinations. We observed a significant difference in overall frequency of occurrence of Stb and Dst dipeptides in different secondary structural regions. The sensitive dipeptides (Stb + Dst) are less in beta-strands and more in coils. A high frequency of occurrence of Stb are observed in the regions closer to the molecular surface compared to the Dst and Nor dipeptides. A significantly high dipole interactions are observed in the Dst dipeptides. The studies indicate that though the Dst dipeptides are more of hydrophilic nature they are localized significantly more in the buried regions of protein structures, on the other hand Stb are more of hydrophobic nature but relatively more accessible to the solvent. These dipeptides therefore increasing sensitivity of the protein to external environment, any alteration in their occurrence in the sequence could increase or decrease intracellular stability of the protein. These observations are useful to select mutations to alter intracellular stability of a given protein and therefore have implications in protein engineering. PMID:8913856

  8. Population genetics of sex determination in Mytilus mussels: reanalyses and a model.

    PubMed

    Yusa, Yoichi; Breton, Sophie; Hoeh, Walter R

    2013-01-01

    Large variations in offspring sex ratio have been reported in Mytilus mussels, which show doubly uniparental inheritance of mitochondria (DUI). Here, we reanalyzed the published sex ratio data, using simple population genetics concepts and logistic regression. Contrary to previous studies that detected only maternal effects, we found both paternal and maternal effects on the offspring sex ratio. We propose that sex in Mytilus is controlled by a pair of nuclear sex ratio alleles expressed in the mother and by minor sex-determining genes inherited from the father and also possibly from the mother. PMID:23505313

  9. Molecular Screening of Enterococcus Virulence Determinants and Potential for Genetic Exchange between Food and Medical Isolates

    PubMed Central

    Eaton, Tracy J.; Gasson, Michael J.

    2001-01-01

    Enterococci are used as starter and probiotic cultures in foods, and they occur as natural food contaminants. The genus Enterococcus is of increased significance as a cause of nosocomial infections, and this trend is exacerbated by the development of antibiotic resistance. In this study, we investigated the incidence of known virulence determinants in starter, food, and medical strains of Enterococcus faecalis, E. faecium, and E. durans. PCR and gene probe strategies were used to screen enterococcal isolates from both food and medical sources. Different and distinct patterns of incidence of virulence determinants were found for the E. faecalis and E. faecium strains. Medical E. faecalis strains had more virulence determinants than did food strains, which, in turn, had more than did starter strains. All of the E. faecalis strains tested possessed multiple determinants (between 6 and 11). E. faecium strains were generally free of virulence determinants, with notable exceptions. Significantly, esp and gelE determinants were identified in E. faecium medical strains. These virulence determinants have not previously been identified in E. faecium strains and may result from regional differences or the evolution of pathogenic E. faecium. Phenotypic testing revealed the existence of apparently silent gelE and cyl genes. In E. faecalis, the trend in these silent genes mirrors that of the expressed determinants. The potential for starter strains to acquire virulence determinants by natural conjugation mechanisms was investigated. Transconjugation in which starter strains acquired additional virulence determinants from medical strains was demonstrated. In addition, multiple pheromone-encoding genes were identified in both food and starter strains, indicating their potential to acquire other sex pheromone plasmids. These results suggest that the use of Enterococcus spp. in foods requires careful safety evaluation. PMID:11282615

  10. Genetically determined neuromuscular disorders of some Roma families living in Hungary.

    PubMed

    Aranka, Laszlo; Peter, Mayer; Jeno, Kobor; Katalin, Racz; Gyula, Talosi; Emoke, Endreffy; Agnes, Herczegfalvi; Tibor, Hortobagyi; Laszlo, Tiszlavicz; Edit, Bereg; Marta, Katona; Janos, Szabo; Veronika, Karcagi

    2009-01-30

    The authors discuss the clinical and molecular genetic aspects of genetically determined neuromuscular disorders of some Roma families living in Hungary. Among the autosomal recessively inherited spinal muscular atrophic (SMA) group, 8 Caucasian children had the typical 7-8 exonal deletions of the SMA gene, but only 2 patients belonged to the Roma population. There was no difference in the molecular genetic findings among the Caucasian and the Roma SMA patients. All of them had 7-8 exonal deletions of the SMA gene. We wanted to call attention to the founder mutation of the Roma population in 7 patients suffering from congenital myasthenia (CMS) from 3 Roma families. The 1267G deletion for CMS was detected by molecular genetic method. Clinical onset was pubertal and relatively slow progression of specific and phenotypic features for this founder mutation of acetyl-cholin receptor epsylon gene. In 2 patients (sister and brother) the sarcoglycanopathy 2C type C283Q mutation was proven in one Roma family suffering from limb-girdle muscular dystrophy (LGMD). Two out of the three facioscapular-humeral dystrophy (FSHD) Roma families carried 21.8 kb and 18.5 kb alleles in FSHD A1 gene (D4S139). In one family together with prenatal diagnosis founder mutation in FSHD A1 gene was detected, according to the autosomal dominant (AD) inheritance. In (F2) prenatal diagnosis was carried out, 18.5 kb/18.5 kb homozygosity was proven in the fetus, so the pregnancy was interrupted. In the CMS, LGMD and FSHD Roma patients ancient typical Roma founder mutations were found. PMID:19248726

  11. Genetic Diversity among Clinical Isolates of Acremonium strictum Determined during an Investigation of a Fatal Mycosis

    PubMed Central

    Novicki, Thomas J.; LaFe, Karen; Bui, Lynda; Bui, Uyen; Geise, Robert; Marr, Kieren; Cookson, Brad T.

    2003-01-01

    Primarily saprophytic in nature, fungi of the genus Acremonium are a well-documented cause of mycetoma and other focal diseases. More recently, a number of Acremonium spp. have been implicated in invasive infections in the setting of severe immunosuppression. During the course of routine microbiological studies involving a case of fatal mycosis in a nonmyeloablative hematopoietic stem cell transplant patient, we identified a greater-than-expected variation among strains previously identified as Acremonium strictum by clinical microbiologists. Using DNA sequence analysis of the ribosomal DNA intergenic transcribed spacer (ITS) regions and the D1-D2 variable domain of the 28S ribosomal DNA gene (28S), the case isolate and four other clinical isolates phenotypically identified as A. strictum were found to have <99% homology to the A. strictum type strain, CBS 346.70, at the ITS and 28S loci, while a sixth isolate phenotypically identified only as Acremonium sp. had >99% homology to the type strain at both loci. These results suggest that five out of the six clinical isolates belong to species other than A. strictum or that the A. strictum taxon is genetically diverse. Based upon these sequence data, the clinical isolates were placed into three genogroups. PMID:12791889

  12. Researchers identify dozens of new de novo genetic mutations in schizophrenia http://www.eurekalert.org/pub_releases/2012-10/cumc-rid100312.php[10/9/2012 1:11:24 PM

    E-print Network

    the United States and South Africa. Each trio consisted of a patient and both of his or her parents, who wereResearchers identify dozens of new de novo genetic mutations in schizophrenia http Medical Center Researchers identify dozens of new de novo genetic mutations in schizophrenia Many newly

  13. A molecular genetic linkage map identifying the St and H sub-genomes of Elymus wheatgrass (Poaceae: Triticeae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elymus L. is the largest and most complex genus in the Triticeae with approximately 150 polyploid perennial grass species occurring worldwide. We report here the first genetic linkage map for Elymus. Backcross mapping populations were created by crossing caespitose Elymus wawawaiensis (EW) (Snake ...

  14. Identifying and selecting for genetic diversity in Papua New Guinea sweetpotato Ipomoea batatas (L.) Lam. germplasm collected as botanical seed

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic analysis was conducted on 141 "Ipomoea batatas" L. (Lam.) Genotypes derived from botanical seed originally collected from 26 sites in 4 provinces in Papua New Guinea. Relatedness among accessions was estimated by analysis of the AFLP data using the Dice coefficient of similarity and UPGMA. ...

  15. Copyright 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death Mutation Identify Genes

    E-print Network

    Dangl, Jeff

    Copyright © 1999 by the Genetics Society of America Suppressors of the Arabidopsis lsd5 Cell Death hypersensitive reaction (HR). Arabidopsis lsd mutants that spontaneously exhibit cell death reminiscent of the HR disease resistance, one of these mutants, lsd5, was used to isolate new mutations that suppress its cell

  16. Identifying microbial fitness determinants by Insertion Sequencing (INSeq) using genome-wide transposon mutant libraries

    PubMed Central

    Goodman, Andrew L.; Wu, Meng; Gordon, Jeffrey I.

    2012-01-01

    Insertion Sequencing (INSeq) is a method for determining the insertion site and relative abundance of large numbers of transposon mutants in a mixed population of isogenic mutants of a sequenced microbial species. INSeq is based on a modified mariner transposon containing MmeI sites at its ends, allowing cleavage at chromosomal sites 16–17bp from the inserted transposon. Genomic regions adjacent to the transposons are amplified by linear PCR with a biotinylated primer. Products are bound to magnetic beads, digested with MmeI, and barcoded with sample-specific linkers appended to each restriction fragment. After limited PCR amplification, fragments are sequenced using a high-throughput instrument. The sequence of each read can be used to map the location of a transposon in the genome. Read count measures the relative abundance of that mutant in the population. Solid-phase library preparation makes this protocol rapid (18h), easy to scale-up, amenable to automation, and useful for a variety of samples. A protocol for characterizing libraries of transposon mutant strains clonally arrayed in multi-well format is provided. PMID:22094732

  17. A high-throughput forward genetic screen identifies genes required for virulence of Pseudomonas syringae pv. maculicola ES4326 on Arabidopsis.

    PubMed

    Schreiber, Karl J; Ye, David; Fich, Eric; Jian, Allen; Lo, Timothy; Desveaux, Darrell

    2012-01-01

    Successful pathogenesis requires a number of coordinated processes whose genetic bases remain to be fully characterized. We utilized a high-throughput, liquid media-based assay to screen transposon disruptants of the phytopathogen Pseudomonas syringae pv. maculicola ES4326 to identify genes required for virulence on Arabidopsis. Many genes identified through this screen were involved in processes such as type III secretion, periplasmic glucan biosynthesis, flagellar motility, and amino acid biosynthesis. A small set of genes did not fall into any of these functional groups, and their disruption resulted in context-specific effects on in planta bacterial growth. PMID:22870224

  18. A High-Throughput Forward Genetic Screen Identifies Genes Required for Virulence of Pseudomonas syringae pv. maculicola ES4326 on Arabidopsis

    PubMed Central

    Schreiber, Karl J.; Ye, David; Fich, Eric; Jian, Allen; Lo, Timothy; Desveaux, Darrell

    2012-01-01

    Successful pathogenesis requires a number of coordinated processes whose genetic bases remain to be fully characterized. We utilized a high-throughput, liquid media-based assay to screen transposon disruptants of the phytopathogen Pseudomonas syringae pv. maculicola ES4326 to identify genes required for virulence on Arabidopsis. Many genes identified through this screen were involved in processes such as type III secretion, periplasmic glucan biosynthesis, flagellar motility, and amino acid biosynthesis. A small set of genes did not fall into any of these functional groups, and their disruption resulted in context-specific effects on in planta bacterial growth. PMID:22870224

  19. Model-based identifiable parameter determination applied to a simultaneous saccharification and fermentation process model for bio-ethanol production.

    PubMed

    López C, Diana C; Barz, Tilman; Peñuela, Mariana; Villegas, Adriana; Ochoa, Silvia; Wozny, Günter

    2013-01-01

    In this work, a methodology for the model-based identifiable parameter determination (MBIPD) is presented. This systematic approach is proposed to be used for structure and parameter identification of nonlinear models of biological reaction networks. Usually, this kind of problems are over-parameterized with large correlations between parameters. Hence, the related inverse problems for parameter determination and analysis are mathematically ill-posed and numerically difficult to solve. The proposed MBIPD methodology comprises several tasks: (i) model selection, (ii) tracking of an adequate initial guess, and (iii) an iterative parameter estimation step which includes an identifiable parameter subset selection (SsS) algorithm and accuracy analysis of the estimated parameters. The SsS algorithm is based on the analysis of the sensitivity matrix by rank revealing factorization methods. Using this, a reduction of the parameter search space to a reasonable subset, which can be reliably and efficiently estimated from available measurements, is achieved. The simultaneous saccharification and fermentation (SSF) process for bio-ethanol production from cellulosic material is used as case study for testing the methodology. The successful application of MBIPD to the SSF process demonstrates a relatively large reduction in the identified parameter space. It is shown by a cross-validation that using the identified parameters (even though the reduction of the search space), the model is still able to predict the experimental data properly. Moreover, it is shown that the model is easily and efficiently adapted to new process conditions by solving reduced and well conditioned problems. PMID:23749438

  20. [Remote signaling of radiation damage to the extracellular space in mice with various levels of genetically determined radio sensitivity].

    PubMed

    Senuk, O F; Kovalev, V A; Krul', N I; Zhidkov, A V; Chemerski?, G F; Kireev, S S; Gorovo?, L F; Gerge?, T

    2013-01-01

    The search results of "bystander" signals are presented at different model of influence of IR on Balb/c and C57bl/6 mice, characterized by different levels of genetically determined sensitivity to IR influence. We used the following models of IR influence: 1) external gamma-quanta influence from small samples of nuclear fuel from the CNPP 4th power unit modified in the course of the accident in 1986, which are 99% connected with 137Cs, with the total dose of irradiation of about 5.0 Gy for 16 hours and accumulated dose of 0.290 Gy for 231 day of exposure, 2) internal intake of 137Cs with water for 40 days. It is shown that cells of different types (splenocytes, hepatocytes, bone marrow and astroglia cells) irrespective of a model of IR influence produce the factors, which failed to be identified in this research, raising the SSF levels in the DNA of non-irradiated cells. Under conditions of a single exposure to gamma-field external irradiation at a dose of about 5.0 Gy, the intensity of production of "bystander" signals is higher in the mice with the raised level of genetically determined sensitivity to RI (Balb/c). Under the same conditions of gamma-field exposure, induction of additional levels of SSF in the DNA of non-irradiated cells is detected for at least one month after IR exposure. Intraperitoneal injection of melanin in the melanin-glucan complex from fungus F. fomentarius before irradiation exposure promotes an essential decrease in the production of "bystander" signals, testifying in favor of the free radical nature of their certain part. PMID:23700833

  1. A simulation study of mutations in the genetic regulatory hierarchy for butterfly eyespot focus determination.

    PubMed

    Marcus, Jeffrey M; Evans, Travis M

    2008-09-01

    The color patterns on the wings of butterflies have been an important model system in evolutionary developmental biology. A recent computational model tested genetic regulatory hierarchies hypothesized to underlie the formation of butterfly eyespot foci [Evans, T.M., Marcus, J.M., 2006. A simulation study of the genetic regulatory hierarchy for butterfly eyespot focus determination. Evol. Dev. 8, 273-283]. The computational model demonstrated that one proposed hierarchy was incapable of reproducing the known patterns of gene expression associated with eyespot focus determination in wild-type butterflies, but that two slightly modified alternative hierarchies were capable of reproducing all of the known gene expressions patterns. Here we extend the computational models previously implemented in Delphi 2.0 to two mutants derived from the squinting bush brown butterfly (Bicyclus anynana). These two mutants, comet and Cyclops, have aberrantly shaped eyespot foci that are produced by different mechanisms. The comet mutation appears to produce a modified interaction between the wing margin and the eyespot focus that results in a series of comet-shaped eyespot foci. The Cyclops mutation causes the failure of wing vein formation between two adjacent wing-cells and the fusion of two adjacent eyespot foci to form a single large elongated focus in their place. The computational approach to modeling pattern formation in these mutants allows us to make predictions about patterns of gene expression, which are largely unstudied in butterfly mutants. It also suggests a critical experiment that will allow us to distinguish between two hypothesized genetic regulatory hierarchies that may underlie all butterfly eyespot foci. PMID:18586070

  2. Genome-Wide Association Mapping Combined with Reverse Genetics Identifies New Effectors of Low Water Potential-Induced Proline Accumulation in Arabidopsis1[W][OPEN

    PubMed Central

    Verslues, Paul E.; Lasky, Jesse R.; Juenger, Thomas E.; Liu, Tzu-Wen; Kumar, M. Nagaraj

    2014-01-01

    Arabidopsis (Arabidopsis thaliana) exhibits natural genetic variation in drought response, including varying levels of proline (Pro) accumulation under low water potential. As Pro accumulation is potentially important for stress tolerance and cellular redox control, we conducted a genome-wide association (GWAS) study of low water potential-induced Pro accumulation using a panel of natural accessions and publicly available single-nucleotide polymorphism (SNP) data sets. Candidate genomic regions were prioritized for subsequent study using metrics considering both the strength and spatial clustering of the association signal. These analyses found many candidate regions likely containing gene(s) influencing Pro accumulation. Reverse genetic analysis of several candidates identified new Pro effector genes, including thioredoxins and several genes encoding Universal Stress Protein A domain proteins. These new Pro effector genes further link Pro accumulation to cellular redox and energy status. Additional new Pro effector genes found include the mitochondrial protease LON1, ribosomal protein RPL24A, protein phosphatase 2A subunit A3, a MADS box protein, and a nucleoside triphosphate hydrolase. Several of these new Pro effector genes were from regions with multiple SNPs, each having moderate association with Pro accumulation. This pattern supports the use of summary approaches that incorporate clusters of SNP associations in addition to consideration of individual SNP probability values. Further GWAS-guided reverse genetics promises to find additional effectors of Pro accumulation. The combination of GWAS and reverse genetics to efficiently identify new effector genes may be especially applicable for traits difficult to analyze by other genetic screening methods. PMID:24218491

  3. Genetics, genomics, and molecular biology of sex determination in small animals

    Microsoft Academic Search

    Vicki N. Meyers-Wallen

    2006-01-01

    The genomic revolution is beginning to facilitate advances in canine and feline medicine, as illustrated in our research. Our studies are focused upon identifying the gene mutation that causes canine Sry-negative XX sex reversal, a disorder of sex determination in which chromosomal females (78,XX) develop testicular tissue, becoming either XX true hermaphrodites with ovotestes, or XX males with bilateral testes.

  4. Biased Random-Key Genetic Algorithms for the Winner Determination Problem in Combinatorial Auctions.

    PubMed

    de Andrade, Carlos Eduardo; Toso, Rodrigo Franco; Resende, Mauricio G C; Miyazawa, Flávio Keidi

    2015-01-01

    In this paper we address the problem of picking a subset of bids in a general combinatorial auction so as to maximize the overall profit using the first-price model. This winner determination problem assumes that a single bidding round is held to determine both the winners and prices to be paid. We introduce six variants of biased random-key genetic algorithms for this problem. Three of them use a novel initialization technique that makes use of solutions of intermediate linear programming relaxations of an exact mixed integer linear programming model as initial chromosomes of the population. An experimental evaluation compares the effectiveness of the proposed algorithms with the standard mixed linear integer programming formulation, a specialized exact algorithm, and the best-performing heuristics proposed for this problem. The proposed algorithms are competitive and offer strong results, mainly for large-scale auctions. PMID:25299242

  5. Evidence for genetically influenced caste determination in phylogenetically diverse species of the termite genus Reticulitermes

    PubMed Central

    Kitade, Osamu; Hoshi, Masahiro; Odaira, Shiori; Asano, Akiko; Shimizu, Manami; Hayashi, Yoshinobu; Lo, Nathan

    2011-01-01

    A number of social insect species have recently been shown to have genetically influenced caste determination (GCD), challenging the conventional view that caste determination should be strictly environmental. To date, GCD has been found in phylogenetically isolated species; examples of GCD being present in multiple species of a genus are lacking. Through crossing experiments of neotenic (juvenile) reproductives, we have recently provided the first evidence for a royal versus worker GCD in the termite Reticulitermes speratus. To elucidate whether this system is more widespread, we performed crossing experiments using three additional Reticulitermes species. Offspring caste and sex ratios were found to be highly similar to those found previously in R. speratus, raising the possibility that GCD was present in an ancestral lineage of Reticulitermes, and subsequently maintained throughout several episodes of speciation. PMID:20980291

  6. Piezoelectric Sensor for Determination of Genetically Modified Soybean Roundup Ready® in Samples not Amplified by PCR

    PubMed Central

    Stobiecka, Magdalena; Cie?la, Jaros?aw M.; Janowska, Beata; Tudek, Barbara; Radecka, Hanna

    2007-01-01

    The chemically modified piezoelectrodes were utilized to develop relatively cheap and easy to use biosensor for determination of genetically modified Roundup Ready soybean (RR soybean). The biosensor relies on the immobilization onto gold piezoelectrodes of the 21-mer single stranded oligonucleotide (probes) related to 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene, which is an active component of an insert integrated into RR soybean genome. The hybridization reaction between the probe and the target complementary sequence in solution was monitored. The system was optimized using synthetic oligonucleotides, which were applied for EPSPS gene detection in DNA samples extracted from animal feed containing 30% RR soybean amplified by the PCR and nonamplified by PCR. The detection limit for genomic DNA was in the range of 4.7·105 numbers of genom copies contained EPSPS gene in the QCM cell. The properties such as sensitivity and selectivity of piezoelectric senor presented here indicated that it could be applied for the direct determination of genetically modified RR soybean in the samples non-amplified by PCR.

  7. Genetic Variation Determines PPAR? Function and Anti-diabetic Drug Response In Vivo.

    PubMed

    Soccio, Raymond E; Chen, Eric R; Rajapurkar, Satyajit R; Safabakhsh, Pegah; Marinis, Jill M; Dispirito, Joanna R; Emmett, Matthew J; Briggs, Erika R; Fang, Bin; Everett, Logan J; Lim, Hee-Woong; Won, Kyoung-Jae; Steger, David J; Wu, Ying; Civelek, Mete; Voight, Benjamin F; Lazar, Mitchell A

    2015-07-01

    SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPAR?, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPAR? or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPAR? accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPAR? binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPAR? motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPAR? genomic occupancy determines individual disease risk and drug response. PMID:26140591

  8. Mutilocus genetic determinants of LDL particle size in coronary artery disease families

    SciTech Connect

    Rotter, J.I.; Bu, X.; Cantor, R.M. [and others

    1996-03-01

    Recent interest in atherosclerosis has focused on the genetic determinants of low-density lipoprotein (LDL) particle size, because of (1) the association of small dense LDL particles with a three-fold increased risk for coronary artery disease (CAD) and (2) the recent report of linkage of the trait to the LDL receptor (chromosome 19). By utilizing nonparametric quantitative sib-pair and relative-pair-analysis methods in CAD families, we tested for linkage of a gene or genes controlling LDL particle sizes with the genetic loci for the major apolipoproteins and enzymes participating in lipoprotein metabolism. We confirmed evidence for linkage to the LDL receptor locus (P = .008). For six candidate gene loci, including apolipoprotein(apo)B, apoAII, apo(a), apoE-CI-CII, lipoprotein lipase, and high-density lipoprotein-binding protein, no evidence for linkage was observed by sib-pair linkage analyses (P values ranged from .24 to .81). However, in addition, we did find tentative evidence for linkage with the apoAI-CIII-AIV locus (chromosome 11) (P = .06) and significant evidence for linkage of the cholesteryl ester transfer protein locus (chromosome 16) (P = .01) and the manganese superoxide dismutase locus (chromosome 6) (P = .001), thus indicating multilocus determination of this atherogenic trait. 73 refs., 3 figs., 4 tabs.

  9. Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca²? dependence and differential modulation by norepinephrine.

    PubMed

    Guan, Dongxu; Armstrong, William E; Foehring, Robert C

    2015-04-01

    We studied neocortical pyramidal neurons from two lines of bacterial artificial chromosome mice (etv1 and glt; Gene Expression Nervous System Atlas: GENSAT project), each of which expresses enhanced green fluorescent protein (EGFP) in a different subpopulation of layer 5 pyramidal neurons. In barrel cortex, etv1 and glt pyramidal cells were previously reported to differ in terms of their laminar distribution, morphology, thalamic inputs, cellular targets, and receptive field size. In this study, we measured the laminar distribution of etv1 and glt cells. On average, glt cells were located more deeply; however, the distributions of etv1 and glt cells extensively overlap in layer 5. To test whether these two cell types differed in electrophysiological properties that influence firing behavior, we prepared acute brain slices from 2-4-wk-old mice, where EGFP-positive cells in somatosensory cortex were identified under epifluorescence and then studied using whole cell current- or voltage-clamp recordings. We studied the details of action potential parameters and repetitive firing, characterized by the larger slow afterhyperpolarizations (AHPs) in etv1 neurons and larger medium AHPs (mAHPS) in glt cells, and compared currents underlying the mAHP and slow AHP (sAHP) in etv1 and glt neurons. Etv1 cells exhibited lower dV/dt for spike polarization and repolarization and reduced direct current (DC) gain (lower f-I slope) for repetitive firing than glt cells. Most importantly, we found that 1) differences in the expression of Ca(2+)-dependent K(+) conductances (small-conductance calcium-activated potassium channels and sAHP channels) determine major functional differences between etv1 and glt cells, and 2) there is differential modulation of etv1 and glt neurons by norepinephrine. PMID:25568159

  10. Pooled Sequencing and Rare Variant Association Tests for Identifying the Determinants of Emerging Drug Resistance in Malaria Parasites

    PubMed Central

    Cheeseman, Ian H.; McDew-White, Marina; Phyo, Aung Pyae; Sriprawat, Kanlaya; Nosten, François; Anderson, Timothy J.C.

    2015-01-01

    We explored the potential of pooled sequencing to swiftly and economically identify selective sweeps due to emerging artemisinin (ART) resistance in a South-East Asian malaria parasite population. ART resistance is defined by slow parasite clearance from the blood of ART-treated patients and mutations in the kelch gene (chr. 13) have been strongly implicated to play a role. We constructed triplicate pools of 70 slow-clearing (resistant) and 70 fast-clearing (sensitive) infections collected from the Thai–Myanmar border and sequenced these to high (?150-fold) read depth. Allele frequency estimates from pools showed almost perfect correlation (Lin’s concordance = 0.98) with allele frequencies at 93 single nucleotide polymorphisms measured directly from individual infections, giving us confidence in the accuracy of this approach. By mapping genome-wide divergence (FST) between pools of drug-resistant and drug-sensitive parasites, we identified two large (>150 kb) regions (on chrs. 13 and 14) and 17 smaller candidate genome regions. To identify individual genes within these genome regions, we resequenced an additional 38 parasite genomes (16 slow and 22 fast-clearing) and performed rare variant association tests. These confirmed kelch as a major molecular marker for ART resistance (P = 6.03 × 10?6). This two-tier approach is powerful because pooled sequencing rapidly narrows down genome regions of interest, while targeted rare variant association testing within these regions can pinpoint the genetic basis of resistance. We show that our approach is robust to recurrent mutation and the generation of soft selective sweeps, which are predicted to be common in pathogen populations with large effective population sizes, and may confound more traditional gene mapping approaches. PMID:25534029

  11. Genetics

    NSDL National Science Digital Library

    National Science Teachers Association (NSTA)

    2005-04-01

    What affects how physical characteristics are transmitted from parent to offspring? This is a question that can be answered at many levels. Molecular biologists examine the pattern of nucleotides in deoxyribonucleic acid (DNA) and the effect of mutations on the proteins produced. Classical geneticists explore the patterns by which traits are transmitted through families. Medical geneticists attempt to describe and develop treatments for diseases that have a genetic component. Genetic engineers analyze how traits can be altered in organisms through modern technology. These are only a few of the strategies that scientists employ to explain the nature of heredity. Explore historical perspectives on the study of genetics and investigate how cutting-edge technology is being used to expand our understanding of heredity.

  12. Genome-wide association study in RPGRIP1?/? dogs identifies a modifier locus that determines the onset of retinal degeneration

    PubMed Central

    Kato, Kumiko; Boursnell, Mike; Mellersh, Cathryn S.; Sargan, David R.

    2014-01-01

    Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1?/? dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1?/? MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10?13) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ?11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1?/? alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD. PMID:22193413

  13. Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene

    PubMed Central

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P?=?0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF?=?0.042] and rs116541814 [MAF?=?0.021], combined P?=?3.2×10?6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P?=?0.049 for C-alpha test and P?=?0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

  14. A genome-wide association identified the common genetic variants influence disease severity in ? 0 -thalassemia\\/hemoglobin E

    Microsoft Academic Search

    Manit Nuinoon; Wattanan Makarasara; Taisei Mushiroda; Iswari Setianingsih; Pustika Amalia Wahidiyat; Orapan Sripichai; Natsuhiko Kumasaka; Atsushi Takahashi; Saovaros Svasti; Thongperm Munkongdee; Surakameth Mahasirimongkol; Chayanon Peerapittayamongkol; Vip Viprakasit; Naoyuki Kamatani; Pranee Winichagoon; Michiaki Kubo; Yusuke Nakamura; Suthat Fucharoen

    2010-01-01

    ?-Thalassemia\\/HbE disease is clinically variable. In searching for genetic factors modifying the disease severity, patients\\u000a were selected based on their disease severities, and a genome-wide association study (GWAS) was performed. Genotyping was\\u000a conducted with the Illumina Human 610-Quad BeadChips array using DNAs from 618 Thai ?0-thalassemia\\/HbE patients who were classified as 383 severe and 235 mild phenotypes by a validated

  15. A High-Resolution Genetic Map of Yellow Monkeyflower Identifies Chemical Defense QTLs and Recombination Rate Variation

    E-print Network

    Holeski, Liza M.; Monnahan, Patrick; Koseva, Boryana S.; McCool, Nick; Lindroth, Richard L.; Kelly, John K.

    2014-05-04

    sequencing data. Genome Res. 20: 1297– 1303. Mølgaard, P., 1986 Population genetics and geographical distribution of caffeic acid esters in leaves of Plantago major in Denmark. J. Ecol. 74: 1127–1137. Mølgaard, P., and H. Ravn, 1988 Evolutionary aspects...- ulations or species, typically via quantitative trait loci (QTL) mapping. A second major goal is to characterize broad patterns and features of genomes, including linkage, recombination rate variation, and major chromosomal polymorphisms such as inversions...

  16. A genetic screen for modifiers of drosophila Src42A identifies mutations in Egfr, rolled and a novel signaling gene.

    PubMed Central

    Zhang, Q; Zheng, Q; Lu, X

    1999-01-01

    Drosophila Src42A, a close relative of the vertebrate c-Src, has been implicated in the Ras-Mapk signaling cascade. An allele of Src42A, Su(Raf)1, dominantly suppresses the lethality of partial loss-of-function Raf mutations. To isolate genes involved in the same pathway where Src42A functions, we carried out genetic screens for dominant suppressor mutations that prevented Su(Raf)1 from suppressing Raf. Thirty-six mutations representing at least five genetic loci were recovered from the second chromosome. These are Drosophila EGF Receptor (Egfr), rolled, Src42A, and two other new loci, one of which was named semang (sag). During embryogenesis, sag affects the development of the head, tail, and tracheal branches, suggesting that it participates in the pathways of Torso and DFGF-R1 receptor tyrosine kinases. sag also disrupts the embryonic peripheral nervous system. During the development of imaginal discs, sag affects two processes known to require Egfr signaling: the recruitment of photoreceptor cells and wing vein formation. Thus sag functions in several receptor tyrosine kinase (RTK)-mediated processes. In addition, sag dominantly enhances the phenotypes associated with loss-of-function Raf and rl, but suppresses those of activated Ras1(V12) mutation. This work provides the first genetic evidence that both Src42A and sag are modulators of RTK signaling. PMID:9927462

  17. Finding Markers That Make a Difference: DNA Pooling and SNP-Arrays Identify Population Informative Markers for Genetic Stock Identification

    PubMed Central

    Ozerov, Mikhail; Vasemägi, Anti; Wennevik, Vidar; Diaz-Fernandez, Rogelio; Kent, Matthew; Gilbey, John; Prusov, Sergey; Niemelä, Eero; Vähä, Juha-Pekka

    2013-01-01

    Genetic stock identification (GSI) using molecular markers is an important tool for management of migratory species. Here, we tested a cost-effective alternative to individual genotyping, known as allelotyping, for identification of highly informative SNPs for accurate genetic stock identification. We estimated allele frequencies of 2880 SNPs from DNA pools of 23 Atlantic salmon populations using Illumina SNP-chip. We evaluated the performance of four common strategies (global FST, pairwise FST, Delta and outlier approach) for selection of the most informative set of SNPs and tested their effectiveness for GSI compared to random sets of SNP and microsatellite markers. For the majority of cases, SNPs selected using the outlier approach performed best followed by pairwise FST and Delta methods. Overall, the selection procedure reduced the number of SNPs required for accurate GSI by up to 53% compared with randomly chosen SNPs. However, GSI accuracy was more affected by populations in the ascertainment group rather than the ranking method itself. We demonstrated for the first time the compatibility of different large-scale SNP datasets by compiling the largest population genetic dataset for Atlantic salmon to date. Finally, we showed an excellent performance of our top SNPs on an independent set of populations covering the main European distribution range of Atlantic salmon. Taken together, we demonstrate how combination of DNA pooling and SNP arrays can be applied for conservation and management of salmonids as well as other species. PMID:24358184

  18. The computer program STRUCTURE does not reliably identify the main genetic clusters within species: simulations and implications for human population structure

    PubMed Central

    Kalinowski, S T

    2011-01-01

    One of the primary goals of population genetics is to succinctly describe genetic relationships among populations, and the computer program STRUCTURE is one of the most frequently used tools for doing so. The mathematical model used by STRUCTURE was designed to sort individuals into Hardy–Weinberg populations, but the program is also frequently used to group individuals from a large number of populations into a small number of clusters that are supposed to represent the main genetic divisions within species. In this study, I used computer simulations to examine how well STRUCTURE accomplishes this latter task. Simulations of populations that had a simple hierarchical history of fragmentation showed that when there were relatively long divergence times within evolutionary lineages, the clusters created by STRUCTURE were frequently not consistent with the evolutionary history of the populations. These difficulties can be attributed to forcing STRUCTURE to place individuals into too few clusters. Simulations also showed that the clusters produced by STRUCTURE can be strongly influenced by variation in sample size. In some circumstances, STRUCTURE simply put all of the individuals from the largest sample in the same cluster. A reanalysis of human population structure suggests that the problems I identified with STRUCTURE in simulations may have obscured relationships among human populations—particularly genetic similarity between Europeans and some African populations. PMID:20683484

  19. Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval

    PubMed Central

    Seyerle, Amanda A.; Young, Alicia M.; Jeff, Janina M.; Melton, Phillip E.; Jorgensen, Neal W.; Lin, Yi; Carty, Cara L.; Deelman, Ewa; Heckbert, Susan R.; Hindorff, Lucia A.; Jackson, Rebecca D.; Martin, Lisa W.; Okin, Peter M; Perez, Marco V.; Psaty, Bruce M.; Soliman, Elsayed Z.; Whitsel, Eric A.; North, Kari E; Laston, Sandra; Kooperberg, Charles; Avery, Christy L.

    2015-01-01

    Background QT-interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. Methods Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n=16,398), African (n=5,437), American Indian (n=5,032), Hispanic (n=1,143), and Asian (n=932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. Results Of 21 SNPs, seven showed consistent direction of effect across all five populations, and an additional nine had estimated effects that were consistent across four populations. Despite consistent direction of effect, nine of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. Conclusions These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT. PMID:25166880

  20. A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy

    Microsoft Academic Search

    Kevin Pethe; Patricia C. Sequeira; Sanjay Agarwalla; Kyu Rhee; Kelli Kuhen; Wai Yee Phong; Viral Patel; David Beer; John R. Walker; Jeyaraj Duraiswamy; Jan Jiricek; Thomas H. Keller; Arnab Chatterjee; Mai Ping Tan; Manjunatha Ujjini; Srinivasa P. S. Rao; Luis Camacho; Pablo Bifani; Puiying A. Mak; Ida Ma; S. Whitney Barnes; Zhong Chen; David Plouffe; Pamela Thayalan; Seow Hwee Ng; Melvin Au; Boon Heng Lee; Bee Huat Tan; Sindhu Ravindran; Mahesh Nanjundappa; Xiuhua Lin; Anne Goh; Suresh B. Lakshminarayana; Carolyn Shoen; Michael Cynamon; Barry Kreiswirth; Veronique Dartois; Eric C. Peters; Richard Glynne; Sydney Brenner; Thomas Dick

    2010-01-01

    Candidate antibacterials are usually identified on the basis of their in vitro activity. However, the apparent inhibitory activity of new leads can be misleading because most culture media do not reproduce an environment relevant to infection in vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism can affect antimicrobial activity. Novel pyrimidine-imidazoles (PIs) were identified

  1. Toenail iron, genetic determinants of iron status and the risk of glioma

    PubMed Central

    Anic, Gabriella M.; Madden, Melissa H.; Thompson, Reid C.; Nabors, L. Burton; Olson, Jeffrey J.; LaRocca, Renato V.; Browning, James E.; Brockman, John D.; Forsyth, Peter A.; Egan, Kathleen M.

    2013-01-01

    Purpose Iron is essential for oxygen transport and oxidative metabolism; however, elevated iron stores can trigger overproduction of reactive oxygen species and induce DNA damage. Little is known about the association between body iron stores and glioma risk. This study examined associations of iron levels measured in toenails and genetic variants linked to body iron stores with risk of glioma in a clinic-based case-control study. Methods Samples were collected a median of 24 days following glioma diagnosis in the cases (10th-90th percentile range: 10-44 days). Nail iron levels were measured in 300 cases and 300 controls using neutron-activation analysis. A total of 24 genetic variants associated with iron status were genotyped in 622 cases and 628 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to toenail iron and the examined genotypes. Results No association was observed between toenail iron and glioma risk when restricting to cases with nails collected within ~3 weeks of diagnosis (OR=0.93; 95% CI: 0.46, 1.87 comparing those with high (? 14 ?g/g) versus low (<6 ?g/g) iron levels). In contrast, an inverse association with increasing iron was observed after restricting to cases with a delay of 3 weeks or greater (OR=0.42; 95% CI: 0.19, 0.95) reflecting potentially insidious effects of advancing disease on iron levels among the cases. No associations were observed for any of the examined genetic variants. Conclusion The results do not support a role for body iron stores as a determinant of glioma risk. PMID:23996192

  2. The effect of cytokinins on in vitro cultured inbred lines of Raphanus sativus var. radicula Pers. with genetically determined tumorigenesis

    Microsoft Academic Search

    E. L. Il’ina; I. E. Dodueva; N. M. Ivanova; L. A. Lutova

    2006-01-01

    The higher plant tumors are convenient models for studying the genetic control mechanism of plant cell division. There are\\u000a two types of tumors: induced by the pathogenic factor and genetically determined. The development of both tumor types was\\u000a related to the changes in cytokinin metabolism and\\/or signal transduction. In this work, the effect of synthetic cytokinins\\u000a on the in vitro

  3. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

    PubMed

    Do, Chuong B; Tung, Joyce Y; Dorfman, Elizabeth; Kiefer, Amy K; Drabant, Emily M; Francke, Uta; Mountain, Joanna L; Goldman, Samuel M; Tanner, Caroline M; Langston, J William; Wojcicki, Anne; Eriksson, Nicholas

    2011-06-01

    Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered. PMID:21738487

  4. Determination of Slope Safety Factor with Analytical Solution and Searching Critical Slip Surface with Genetic-Traversal Random Method

    PubMed Central

    2014-01-01

    In the current practice, to determine the safety factor of a slope with two-dimensional circular potential failure surface, one of the searching methods for the critical slip surface is Genetic Algorithm (GA), while the method to calculate the slope safety factor is Fellenius' slices method. However GA needs to be validated with more numeric tests, while Fellenius' slices method is just an approximate method like finite element method. This paper proposed a new method to determine the minimum slope safety factor which is the determination of slope safety factor with analytical solution and searching critical slip surface with Genetic-Traversal Random Method. The analytical solution is more accurate than Fellenius' slices method. The Genetic-Traversal Random Method uses random pick to utilize mutation. A computer automatic search program is developed for the Genetic-Traversal Random Method. After comparison with other methods like slope/w software, results indicate that the Genetic-Traversal Random Search Method can give very low safety factor which is about half of the other methods. However the obtained minimum safety factor with Genetic-Traversal Random Search Method is very close to the lower bound solutions of slope safety factor given by the Ansys software. PMID:24782679

  5. Plant genetics. A Y-chromosome-encoded small RNA acts as a sex determinant in persimmons.

    PubMed

    Akagi, Takashi; Henry, Isabelle M; Tao, Ryutaro; Comai, Luca

    2014-10-31

    In plants, multiple lineages have evolved sex chromosomes independently, providing a powerful comparative framework, but few specific determinants controlling the expression of a specific sex have been identified. We investigated sex determinants in the Caucasian persimmon, Diospyros lotus, a dioecious plant with heterogametic males (XY). Male-specific short nucleotide sequences were used to define a male-determining region. A combination of transcriptomics and evolutionary approaches detected a Y-specific sex-determinant candidate, OGI, that displays male-specific conservation among Diospyros species. OGI encodes a small RNA targeting the autosomal MeGI gene, a homeodomain transcription factor regulating anther fertility in a dosage-dependent fashion. This identification of a feminizing gene suppressed by a Y-chromosome-encoded small RNA contributes to our understanding of the evolution of sex chromosome systems in higher plants. PMID:25359977

  6. Contraselectable streptomycin susceptibility determinant for genetic manipulation and analysis of Helicobacter pylori.

    PubMed

    Dailidiene, Daiva; Dailide, Giedrius; Kersulyte, Dangeruta; Berg, Douglas E

    2006-09-01

    Many Helicobacter pylori genetic studies would benefit from an ability to move DNA sequences easily between strains by transformation and homologous recombination, without needing to leave a conventional drug resistance determinant at the targeted locus. Presented here is a two-gene cassette that can be selected both (i) against, due to a Campylobacter jejuni rpsL gene (dominant streptomycin susceptibility in cells also carrying an rpsL-str(r) allele), and (ii) for, due to an erm gene (erythromycin resistance). This rpsL,erm cassette's utility was assessed by using it to replace four gene loci (mdaB, frxA, fur, and nikR) in four streptomycin-resistant [Str(r)] strain backgrounds (derivatives of 26695, SS1, X47, and G27MA). The resultant 16 strains (phenotypically erythromycin resistant [Erm(r)] and Str(s)) were each transformed with wild-type genomic DNAs, and Str(r) derivatives were selected. The desired Erm(s) Str(r) isolates were obtained at frequencies that ranged from 17 to 96% among Str(r) transformants, with the Erm(s) yield apparently depending on the strain background and genome location of the targeted locus. The ease of isolating unmarked transformants described here should be valuable for many H. pylori molecular genetic and evolutionary analyses. PMID:16957210

  7. Defining genes using "blueprint" versus "instruction" metaphors: effects for genetic determinism, response efficacy, and perceived control.

    PubMed

    Parrott, Roxanne; Smith, Rachel A

    2014-01-01

    Evidence supports mixed attributions aligned with personal and/or clinical control and gene expression for health in this era of genomic science and health care. We consider variance in these attributions and possible relationships to individual mind sets associated with essentialist beliefs that genes determine health versus threat beliefs that genes increase susceptibility for disease and severity linked to gene-environment interactions. Further, we contribute to theory and empirical research to evaluate the use of metaphors to define genes. Participants (N?=?324) read a message that varied the introduction by providing a definition of genes that used either an "instruction" metaphor or a "blueprint" metaphor. The "instruction" metaphor compared to the "blueprint" metaphor promoted stronger threat perceptions, which aligned with both belief in the response efficacy of genetic research for health and perceived behavioral control linked to genes and health. The "blueprint" metaphor compared to the "instruction" metaphor promoted stronger essentialist beliefs, which aligned with more intense positive regard for the efficacy of genetic research and human health. Implications for health communicators include societal effects aligned with stigma and discrimination that such findings portend. PMID:23448621

  8. Genetic determination of telomere size in humans: A twin study of three age groups

    SciTech Connect

    Slagboom, P.E.; Droog, S. [TNO-PG, Leiden (Netherlands); Boomsma, D.I. [Free Univ., Amsterdam (Netherlands)

    1994-11-01

    Reduction of telomere length has been postulated to be a casual factor in cellular aging. Human telomeres terminate in tandemly arranged repeat arrays consisting of the (TTAGGG) motif. The length of these arrays in cells from human mitotic tissues is inversely related to the age of the donor, indicating telomere reduction with age. In addition to telemore length differences between different age cohorts, considerable variation is present among individuals of the same age. To investigate whether this variation can be ascribed to genetic influences, we have measured the size of terminal restriction fragments (TRFs) in HaeIII-digested genomic DNA from 123 human MZ and DZ twin pairs 2-95 years of age. The average rate of telomere shortening was 31 bp/year, which is similar to that observed by others. Statistical analysis in 115 pairs 2-63 years of age indicates a 78% heritability for mean TRF length in this age cohort. The individual differences in mean TRF length in blood, therefore, seem to a large extent to be genetically determined. 24 refs., 4 figs., 2 tabs.

  9. Genome-wide linkage scan identifies two novel genetic loci for coronary artery disease: in GeneQuest families.

    PubMed

    Gao, Hanxiang; Li, Lin; Rao, Shaoqi; Shen, Gongqing; Xi, Quansheng; Chen, Shenghan; Zhang, Zheng; Wang, Kai; Ellis, Stephen G; Chen, Qiuyun; Topol, Eric J; Wang, Qing K

    2014-01-01

    Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of "missing heritability". Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL ?=?5.49) and 3q29 (NPL ?=?6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL ?=?3.18-4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD. PMID:25485937

  10. Genome-Wide Linkage Scan Identifies Two Novel Genetic Loci for Coronary Artery Disease: In GeneQuest Families

    PubMed Central

    Shen, Gongqing; Xi, Quansheng; Chen, Shenghan; Zhang, Zheng; Wang, Kai; Ellis, Stephen G.; Chen, Qiuyun; Topol, Eric J.; Wang, Qing K.

    2014-01-01

    Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of “missing heritability”. Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL ?=?5.49) and 3q29 (NPL ?=?6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL ?=?3.18–4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD. PMID:25485937

  11. A Genome Scan Conducted in a Multigenerational Pedigree with Convergent Strabismus Supports a Complex Genetic Determinism

    PubMed Central

    Georges, Anouk; Cambisano, Nadine; Ahariz, Naïma; Karim, Latifa; Georges, Michel

    2013-01-01

    A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree. PMID:24376720

  12. Genes determining yeast replicative life span in a long-lived genetic background

    E-print Network

    Dunham, Maitreya

    (three genetic models of calorie restriction) significantly enhanced longevity. In addition, over reserved. Keywords: Yeast aging; Caloric restriction; Genetic pathways 1. Introduction The budding yeast longevity genes and pathways whose counterparts can be examined in higher eukaryotes (Kaeberlein et al

  13. 77 FR 41350 - Monsanto Co.; Determination of Nonregulated Status of Soybean Genetically Engineered To Produce...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-13

    ...Soybean Genetically Engineered To Produce Stearidonic Acid AGENCY: Animal and Plant Health Inspection Service...been genetically engineered to produce stearidonic acid, an omega-3 fatty acid not found in conventional soybean, is no longer...

  14. Determinants of vitamin D status in Caucasian adults: influence of sun exposure, dietary intake, sociodemographic, lifestyle, anthropometric, and genetic factors.

    PubMed

    Touvier, Mathilde; Deschasaux, Mélanie; Montourcy, Marion; Sutton, Angela; Charnaux, Nathalie; Kesse-Guyot, Emmanuelle; Assmann, Karen E; Fezeu, Léopold; Latino-Martel, Paule; Druesne-Pecollo, Nathalie; Guinot, Christiane; Latreille, Julie; Malvy, Denis; Galan, Pilar; Hercberg, Serge; Le Clerc, Sigrid; Souberbielle, Jean-Claude; Ezzedine, Khaled

    2015-02-01

    Very few studies have investigated the determinants of serum vitamin D levels using a set of variables that include simultaneously sun exposure, phototype, dietary intake, sociodemographics, anthropometric, lifestyle data, and genetic polymorphisms. Our objective was to investigate the associations between all these parameters and vitamin D status in a large sample of French adults. This cross-sectional survey was based on 1,828 middle-aged Caucasian adults from the SU.VI.MAX (SUpplémentation en VItamines et Minéraux AntioXydants) study. Plasma 25-hydroxyvitamin D (25OHD) concentration was lower among women (P<0.0001), older subjects (P=0.04), obese/underweight (P<0.0001), those living at higher latitudes (P<0.0001), those whose blood draw occurred in early spring (P<0.0001), less physically active (P<0.0001), with low sun exposure (P<0.0001), and with no-to-low alcohol intake (P=0.0001). Mutant GC rs4588 and rs7041 single nucleotide polymorphisms were associated with lower and higher 25OHD concentrations, respectively (P<0.0001). Dietary intake was not a major determinant of vitamin D status (P=0.7). This study provides an overall picture of determinants of vitamin D status. Several modifiable factors were identified, such as daily-life moderate sun exposure, physical activity, and normal-weight maintenance, which should be targeted by public health policies in order to improve vitamin D status in the general population, while avoiding active/intensive sun exposure, in line with recommendations for skin cancer prevention. PMID:25211176

  15. Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study

    PubMed Central

    Narayanan, B; Soh, P; Calhoun, V D; Ruaño, G; Kocherla, M; Windemuth, A; Clementz, B A; Tamminga, C A; Sweeney, J A; Keshavan, M S; Pearlson, G D

    2015-01-01

    Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10?422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development. PMID:26101851

  16. Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study.

    PubMed

    Narayanan, B; Soh, P; Calhoun, V D; Ruaño, G; Kocherla, M; Windemuth, A; Clementz, B A; Tamminga, C A; Sweeney, J A; Keshavan, M S; Pearlson, G D

    2015-01-01

    Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10?422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development. PMID:26101851

  17. Twin studies of immunogenicity — determining the genetic contribution to vaccine failure

    Microsoft Academic Search

    Poh-Lin Tan; Robert M Jacobson; Gregory A Poland; Steven J Jacobsen; V. Shane Pankratz

    2001-01-01

    Context: Estimating the magnitude of the genetic contribution to the overall variation of antibody levels among individuals should help clarify the role of genetic association in the biological mechanism of vaccine response and failure. This, in turn, should help guide the design of improved vaccines with enhanced efficacy. Objective: To explore the magnitude of genetic influence on antibody levels following

  18. ABSTRACTS | Carcinogenesis and Cancer Genetics Chromothripsis and focal copy number alterations determine poor outcome in malignant

    E-print Network

    Cai, Long

    ABSTRACTS | Carcinogenesis and Cancer Genetics 326 Chromothripsis and focal copy number alterations Meltzer1 and T Ried1 1 Genetics Branch, National Institutes of Health, Bethesda, MD, 2 Institute, Germany Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study

  19. Analysis of Genetic Diversity in Cultivated Jute Determined by Means of SSR Markers and AFLP Profiling

    Microsoft Academic Search

    A. Basu; M. Ghosh; R. Meyer; W. Powell; S. L. Basak; S. K. Sen

    2004-01-01

    a few common accessions. It has also been indicated that each of the two jute species contain very limited genetic Genetic improvement of the cultivars of jute (Corchorus olitorius variability with respect to (i) adaptability to different agro- L. and Corchorus capsularis L.) is needed to broaden the genetic base nomic environments, (ii) fiber quality, (iii) fiber yield, of new

  20. PROTEOMIC AND GENETIC APPROACHES TO IDENTIFYING DEFENSE-RELATED PROTEINS IN RICE CHALLENGED WITH THE FUNGAL PATHOGEN RHIZOCTONIA SOLANI

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sheath blight, caused by the fungus Rhizoctonia solani, is a major disease of rice worldwide, but little is known about the host response to infection. The objective of this study was to identify proteins and DNA markers in resistant and susceptible rice associated with response to infection by R. s...

  1. Full Genome Sequencing and Genetic Characterization of Eubenangee Viruses Identify Pata Virus as a Distinct Species within the Genus Orbivirus

    Microsoft Academic Search

    Manjunatha N. Belaganahalli; Sushila Maan; Narender S. Maan; Kyriaki Nomikou; Ian Pritchard; Ross Lunt; Peter D. Kirkland; Houssam Attoui; Joe Brownlie; Peter P. C. Mertens

    2012-01-01

    Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels

  2. Am. J. Hum. Genet. 76:934949, 2005 Joint Modeling of Linkage and Association: Identifying SNPs Responsible

    E-print Network

    Abecasis, Goncalo

    unaffected family members. Introduction Positional cloning is widely used for identification of genes involved in human diseases. To date, hundreds of disease genes have been identified solely on the basis. 2002). The first step in a traditional positional-cloning approach involves a genomewide linkage

  3. A High Through-Put Reverse Genetic Screen Identifies Two Genes Involved in Remote Memory in Mice

    Microsoft Academic Search

    Anna Matynia; Stephan G. Anagnostaras; Brian J. Wiltgen; Maress Lacuesta; Michael S. Fanselow; Alcino J. Silva

    2008-01-01

    Previous studies have revealed that the initial stages of memory formation require several genes involved in synaptic, transcriptional and translational mechanisms. In contrast, very little is known about the molecular and cellular mechanisms underlying later stages of memory, including remote memory (i.e. 7-day memory). To identify genes required for remote memory, we screened randomly selected mouse strains harboring known mutations.

  4. Genetics

    NSDL National Science Digital Library

    The Tech Museum of Innovation

    2004-01-01

    This online tutorial from the TheTech Museum of Innovation focuses on genetics. The interactive topics will initially introduce the user to the DNA, chromosomes, and the make up of human genes. Further topics will examine forensic science, the history of forensics, fingerprinting, and cloning background research and community response to cloning. Finally, the resource provides connections to gallery exhibits, science labs, and a design challenge that engages the learner to write a persuasive letter to a group or organization responsible for cloning or DNA decision making. Copyright 2005 International Technology Education Association

  5. Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples.

    PubMed

    Solovieff, Nadia; Roberts, Andrea L; Ratanatharathorn, Andrew; Haloosim, Michelle; De Vivo, Immaculata; King, Anthony P; Liberzon, Israel; Aiello, Allison; Uddin, Monica; Wildman, Derek E; Galea, Sandro; Smoller, Jordan W; Purcell, Shaun M; Koenen, Karestan C

    2014-07-01

    The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. PMID:24525708

  6. Risk of genome-wide association study newly identified genetic variants for breast cancer in Chinese women of Heilongjiang Province

    Microsoft Academic Search

    Yongdong JiangJiguang; Jiguang Han; Jing Liu; Guoqiang Zhang; Lihong Wang; Feng Liu; Xianyu Zhang; Yashuang Zhao; Da Pang

    2011-01-01

    Recent genome-wide association studies have identified seven single nucleotide polymorphisms (SNPs) associated with breast\\u000a cancer, but mainly in Europeans. In this study, the authors evaluated the effect of these loci on breast cancer and its disease\\u000a characteristics in women from northeast of China, Heilongjiang Province. Seven SNPs were successfully genotyped in 492 breast\\u000a cancer patients and 510 healthy controls using

  7. A genetic screen for suppressors and enhancers of the Drosophila cdk1-cyclin B identifies maternal factors that regulate microtubule and microfilament stability.

    PubMed Central

    Ji, Jun-Yuan; Haghnia, Marjan; Trusty, Cory; Goldstein, Lawrence S B; Schubiger, Gerold

    2002-01-01

    Coordination between cell-cycle progression and cytoskeletal dynamics is important for faithful transmission of genetic information. In early Drosophila embryos, increasing maternal cyclin B leads to higher Cdk1-CycB activity, shorter microtubules, and slower nuclear movement during cycles 5-7 and delays in nuclear migration to the cortex at cycle 10. Later during cycle 14 interphase of six cycB embryos, we observed patches of mitotic nuclei, chromosome bridges, abnormal nuclear distribution, and small and large nuclei. These phenotypes indicate disrupted coordination between the cell-cycle machinery and cytoskeletal function. Using these sensitized phenotypes, we performed a dosage-sensitive genetic screen to identify maternal proteins involved in this process. We identified 10 suppressors classified into three groups: (1) gene products regulating Cdk1 activities, cdk1 and cyclin A; (2) gene products interacting with both microtubules and microfilaments, Actin-related protein 87C; and (3) gene products interacting with microfilaments, chickadee, diaphanous, Cdc42, quail, spaghetti-squash, zipper, and scrambled. Interestingly, most of the suppressors that rescue the astral microtubule phenotype also reduce Cdk1-CycB activities and are microfilament-related genes. This suggests that the major mechanism of suppression relies on the interactions among Cdk1-CycB, microtubule, and microfilament networks. Our results indicate that the balance among these different components is vital for normal early cell cycles and for embryonic development. Our observations also indicate that microtubules and cortical microfilaments antagonize each other during the preblastoderm stage. PMID:12454065

  8. The phytochemical and genetic survey of common and dwarf juniper (Juniperus communis and Juniperus nana) identifies chemical races and close taxonomic identity of the species.

    PubMed

    Filipowicz, Natalia; Piotrowski, Arkadiusz; Ochocka, J Renata; Asztemborska, Monika

    2006-07-01

    Juniperus communis L. (= J. communis var. communis) and Juniperus nana Willd. (= J. communis var. SAXATILIS) are subspecies of juniper. J. communis grows widely in both hemispheres, primarily in lower elevations while J. nana is mainly observed in high mountains. Although they can be distinguished by morphological features, it is not known whether they are genetically and phytochemically distinct entities. We aimed to check whether it is possible to distinguish these two plants (i) by pharmaceutically important chemical traits and (ii) on the basis of intraspecifically highly polymorphic fragment of chloroplast DNA. We used GC with achiral as well as with enantioselective stationary phase columns to identify the main monoterpenes of the essential oil. Sequence analysis of the TRNL (UAA)- TRNF (GAA) intergenic spacer of the chloroplast genome was used as a genetic marker of taxonomic identity between these two subspecies. The chromatographic analysis showed the existence of three chemical races - the alpha-pinene type, the sabinene type and one with intermediate contents of these terpenes among both J. communis and J. nana. Surprisingly, sequence analysis of TRNL (UAA)- TRNF (GAA) revealed 100 % similarity between the common and the dwarf juniper. Thus, the monoterpene pattern is related to geographical origin, and not to the species identity. We suggest that the three chemical races identified in the present study should be considered as separate sources of pharmaceutical raw material. Our results demonstrate that the contents of alpha-pinene and sabinene may be applied as a quick diagnostic test for preliminary evaluation of plant material. PMID:16783703

  9. DNA Polymerase ? Subunit Residues and Interactions Required for Efficient Initiation Complex Formation Identified by a Genetic Selection.

    PubMed

    Lindow, Janet C; Dohrmann, Paul R; McHenry, Charles S

    2015-07-01

    Biophysical and structural studies have defined many of the interactions that occur between individual components or subassemblies of the bacterial replicase, DNA polymerase III holoenzyme (Pol III HE). Here, we extended our knowledge of residues and interactions that are important for the first step of the replicase reaction: the ATP-dependent formation of an initiation complex between the Pol III HE and primed DNA. We exploited a genetic selection using a dominant negative variant of the polymerase catalytic subunit that can effectively compete with wild-type Pol III ? and form initiation complexes, but cannot elongate. Suppression of the dominant negative phenotype was achieved by secondary mutations that were ineffective in initiation complex formation. The corresponding proteins were purified and characterized. One class of mutant mapped to the PHP domain of Pol III ?, ablating interaction with the ? proofreading subunit and distorting the polymerase active site in the adjacent polymerase domain. Another class of mutation, found near the C terminus, interfered with ? binding. A third class mapped within the known ?-binding domain, decreasing interaction with the ?2 processivity factor. Surprisingly, mutations within the ? binding domain also ablated interaction with ?, suggesting a larger ? binding site than previously recognized. PMID:25987558

  10. High-throughput, luciferase-based reverse genetics systems for identifying inhibitors of Marburg and Ebola viruses.

    PubMed

    Uebelhoer, Luke S; Albariño, César G; McMullan, Laura K; Chakrabarti, Ayan K; Vincent, Joel P; Nichol, Stuart T; Towner, Jonathan S

    2014-06-01

    Marburg virus (MARV) and Ebola virus (EBOV), members of the family Filoviridae, represent a significant challenge to global public health. Currently, no licensed therapies exist to treat filovirus infections, which cause up to 90% mortality in human cases. To facilitate development of antivirals against these viruses, we established two distinct screening platforms based on MARV and EBOV reverse genetics systems that express secreted Gaussia luciferase (gLuc). The first platform is a mini-genome replicon to screen viral replication inhibitors using gLuc quantification in a BSL-2 setting. The second platform is complementary to the first and expresses gLuc as a reporter gene product encoded in recombinant infectious MARV and EBOV, thereby allowing for rapid quantification of viral growth during treatment with antiviral compounds. We characterized these viruses by comparing luciferase activity to virus production, and validated luciferase activity as an authentic real-time measure of viral growth. As proof of concept, we adapt both mini-genome and infectious virus platforms to high-throughput formats, and demonstrate efficacy of several antiviral compounds. We anticipate that both approaches will prove highly useful in the development of anti-filovirus therapies, as well as in basic research on the filovirus life cycle. PMID:24713118

  11. Genetic determinism of phenological traits highly affected by climate change in Prunus avium: flowering date dissected into chilling and heat requirements.

    PubMed

    Castède, Sophie; Campoy, José Antonio; García, José Quero; Le Dantec, Loïck; Lafargue, Maria; Barreneche, Teresa; Wenden, Bénédicte; Dirlewanger, Elisabeth

    2014-04-01

    The present study investigated the genetic determinism of flowering date (FD), dissected into chilling (CR) and heat (HR) requirements. Elucidation of the genetic determinism of flowering traits is crucial to anticipate the increasing of ecological misalignment of adaptative traits with novel climate conditions in most temperate-fruit species. CR and HR were evaluated over 3 yr and FD over 5 yr in an intraspecific sweet cherry (Prunus avium) F1 progeny, and FD over 6 yr in a different F1 progeny. One quantitative trait locus (QTL) with major effect and high stability between years of evaluation was detected for CR and FD in the same region of linkage group (LG) 4. For HR, no stable QTL was detected. Candidate genes underlying the major QTL on LG4 were investigated and key genes were identified for CR and FD. Phenotypic dissection of FD and year repetitions allowed us to identify CR as the high heritable component of FD and a high genotype × environment interaction for HR. QTLs for CR reported in this study are the first described in this species. Our results provide a foundation for the identification of genes involved in CR and FD in sweet cherry which could be used to develop ideotypes adapted to future climatic conditions. PMID:24417538

  12. Resistance determinants and mobile genetic elements of an NDM-1-encoding Klebsiella pneumoniae strain.

    PubMed

    Hudson, Corey M; Bent, Zachary W; Meagher, Robert J; Williams, Kelly P

    2014-01-01

    Multidrug-resistant Enterobacteriaceae are emerging as a serious infectious disease challenge. These strains can accumulate many antibiotic resistance genes though horizontal transfer of genetic elements, those for ?-lactamases being of particular concern. Some ?-lactamases are active on a broad spectrum of ?-lactams including the last-resort carbapenems. The gene for the broad-spectrum and carbapenem-active metallo-?-lactamase NDM-1 is rapidly spreading. We present the complete genome of Klebsiella pneumoniae ATCC BAA-2146, the first U.S. isolate found to encode NDM-1, and describe its repertoire of antibiotic-resistance genes and mutations, including genes for eight ?-lactamases and 15 additional antibiotic-resistance enzymes. To elucidate the evolution of this rich repertoire, the mobile elements of the genome were characterized, including four plasmids with varying degrees of conservation and mosaicism and eleven chromosomal genomic islands. One island was identified by a novel phylogenomic approach, that further indicated the cps-lps polysaccharide synthesis locus, where operon translocation and fusion was noted. Unique plasmid segments and mosaic junctions were identified. Plasmid-borne blaCTX-M-15 was transposed recently to the chromosome by ISEcp1. None of the eleven full copies of IS26, the most frequent IS element in the genome, had the expected 8-bp direct repeat of the integration target sequence, suggesting that each copy underwent homologous recombination subsequent to its last transposition event. Comparative analysis likewise indicates IS26 as a frequent recombinational junction between plasmid ancestors, and also indicates a resolvase site. In one novel use of high-throughput sequencing, homologously recombinant subpopulations of the bacterial culture were detected. In a second novel use, circular transposition intermediates were detected for the novel insertion sequence ISKpn21 of the ISNCY family, suggesting that it uses the two-step transposition mechanism of IS3. Robust genome-based phylogeny showed that a unified Klebsiella cluster contains Enterobacter aerogenes and Raoultella, suggesting the latter genus should be abandoned. PMID:24905728

  13. Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin

    PubMed Central

    Troggio, Michela; Šurbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

    2013-01-01

    High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the ‘Golden Delicious’ genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies. PMID:23826289

  14. Genome-wide Association Study Identifies Genetic Variation in Neurocan as a Susceptibility Factor for Bipolar Disorder

    PubMed Central

    Cichon, Sven; Mühleisen, Thomas W.; Degenhardt, Franziska A.; Mattheisen, Manuel; Miró, Xavier; Strohmaier, Jana; Steffens, Michael; Meesters, Christian; Herms, Stefan; Weingarten, Moritz; Priebe, Lutz; Haenisch, Britta; Alexander, Michael; Vollmer, Jennifer; Breuer, René; Schmäl, Christine; Tessmann, Peter; Moebus, Susanne; Wichmann, H.-Erich; Schreiber, Stefan; Müller-Myhsok, Bertram; Lucae, Susanne; Jamain, Stéphane; Leboyer, Marion; Bellivier, Frank; Etain, Bruno; Henry, Chantal; Kahn, Jean-Pierre; Heath, Simon; Hamshere, Marian; O'Donovan, Michael C.; Owen, Michael J.; Craddock, Nick; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Reif, Andreas; Sasse, Johanna; Bauer, Michael; Hautzinger, Martin; Wright, Adam; Mitchell, Philip B.; Schofield, Peter R.; Montgomery, Grant W.; Medland, Sarah E.; Gordon, Scott D.; Martin, Nicholas G.; Gustafsson, Omar; Andreassen, Ole; Djurovic, Srdjan; Sigurdsson, Engilbert; Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Kapur-Pojskic, Lejla; Oruc, Liliana; Rivas, Fabio; Mayoral, Fermín; Chuchalin, Alexander; Babadjanova, Gulja; Tiganov, Alexander S.; Pantelejeva, Galina; Abramova, Lilia I.; Grigoroiu-Serbanescu, Maria; Diaconu, Carmen C.; Czerski, Piotr M.; Hauser, Joanna; Zimmer, Andreas; Lathrop, Mark; Schulze, Thomas G.; Wienker, Thomas F.; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Rietschel, Marcella; Nöthen, Markus M.

    2011-01-01

    We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10?8; odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10?4; odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10?9 (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies. PMID:21353194

  15. Genome-wide multi-omics profiling of colorectal cancer identifies immune determinants strongly associated with relapse

    PubMed Central

    Madhavan, Subha; Gusev, Yuriy; Natarajan, Thanemozhi G.; Song, Lei; Bhuvaneshwar, Krithika; Gauba, Robinder; Pandey, Abhishek; Haddad, Bassem R.; Goerlitz, David; Cheema, Amrita K.; Juhl, Hartmut; Kallakury, Bhaskar; Marshall, John L.; Byers, Stephen W.; Weiner, Louis M.

    2013-01-01

    The use and benefit of adjuvant chemotherapy to treat stage II colorectal cancer (CRC) patients is not well understood since the majority of these patients are cured by surgery alone. Identification of biological markers of relapse is a critical challenge to effectively target treatments to the ~20% of patients destined to relapse. We have integrated molecular profiling results of several “omics” data types to determine the most reliable prognostic biomarkers for relapse in CRC using data from 40 stage I and II CRC patients. We identified 31 multi-omics features that highly correlate with relapse. The data types were integrated using multi-step analytical approach with consecutive elimination of redundant molecular features. For each data type a systems biology analysis was performed to identify pathways biological processes and disease categories most affected in relapse. The biomarkers detected in tumors urine and blood of patients indicated a strong association with immune processes including aberrant regulation of T-cell and B-cell activation that could lead to overall differences in lymphocyte recruitment for tumor infiltration and markers indicating likelihood of future relapse. The immune response was the biologically most coherent signature that emerged from our analyses among several other biological processes and corroborates other studies showing a strong immune response in patients less likely to relapse. PMID:24312117

  16. An XX/XY sex microchromosome system in a freshwater turtle, Chelodina longicollis (Testudines: Chelidae) with genetic sex determination

    E-print Network

    Canberra, University of

    An XX/XY sex microchromosome system in a freshwater turtle, Chelodina longicollis (Testudines: Chelidae) with genetic sex determination Tariq Ezaz1*, Nicole Valenzuela2 , Frank Gru¨tzner1 , Ikuo Miura3, microchromosomes, sex chromosomes Abstract Heteromorphic sex chromosomes are rare in turtles, having been described

  17. Copyright 2001 by the Genetics Society of America Sex Determination in the Androdioecious Plant Datisca glomerata and Its

    E-print Network

    Rieseberg, Loren

    plant species Datisca glomerata and its dioecious of androdioecy (and near-androdioecy) haveCopyright 2001 by the Genetics Society of America Sex Determination in the Androdioecious Plant Datisca glomerata and Its Dioecious Sister Species D. cannabina Diana E. Wolf,1 Jessica A. Satkoski,2 Kara

  18. Integrating chemical and genetic silencing strategies to identify host kinase-phosphatase inhibitor networks that control bacterial infection.

    PubMed

    Albers, Harald M H G; Kuijl, Coenraad; Bakker, Jeroen; Hendrickx, Loes; Wekker, Sharida; Farhou, Nadha; Liu, Nora; Blasco-Moreno, Bernat; Scanu, Tiziana; den Hertog, Jeroen; Celie, Patrick; Ovaa, Huib; Neefjes, Jacques

    2014-02-21

    Every year three million people die as a result of bacterial infections, and this number may further increase due to resistance to current antibiotics. These antibiotics target almost all essential bacterial processes, leaving only a few new targets for manipulation. The host proteome has many more potential targets for manipulation in order to control bacterial infection, as exemplified by the observation that inhibiting the host kinase Akt supports the elimination of different intracellular bacteria including Salmonella and M. tuberculosis. If host kinases are involved in the control of bacterial infections, phosphatases could be as well. Here we present an integrated small interference RNA and small molecule screen to identify host phosphatase-inhibitor combinations that control bacterial infection. We define host phosphatases inhibiting intracellular growth of Salmonella and identify corresponding inhibitors for the dual specificity phosphatases DUSP11 and 27. Pathway analysis places many kinases and phosphatases controlling bacterial infection in an integrated pathway centered around Akt. This network controls host cell metabolism, survival, and growth and bacterial survival and reflect a natural host cell response to bacterial infection. Inhibiting two enzyme classes with opposite activities-kinases and phosphatases-may be a new strategy to overcome infections by antibiotic-resistant bacteria. PMID:24274083

  19. Preliminary evidence of genetic determinants of adiponectin response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

    PubMed Central

    Aslibekyan, S; An, P; Frazier-Wood, AC; Kabagambe, EK; Irvin, MR; Straka, RJ; Tiwari, HK; Tsai, MY; Hopkins, PN; Borecki, IB; Ordovas, JM; Arnett, DK

    2012-01-01

    Background and Aims Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. Methods and Results Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant (P=5×10?8) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. Conclusions We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease. PMID:23149075

  20. Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†.

    PubMed

    Kirsten, Holger; Al-Hasani, Hoor; Holdt, Lesca; Gross, Arnd; Beutner, Frank; Krohn, Knut; Horn, Katrin; Ahnert, Peter; Burkhardt, Ralph; Reiche, Kristin; Hackermüller, Jörg; Löffler, Markus; Teupser, Daniel; Thiery, Joachim; Scholz, Markus

    2015-08-15

    Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes. PMID:26019233

  1. Genetic Analysis Using an Isogenic Mating Pair of Aspergillus fumigatus Identifies Azole Resistance Genes and Lack of MAT Locus’s Role in Virulence

    PubMed Central

    Eckhaus, Michael A.; Chang, Yun C.; Mounaud, Stephanie; Figat, Abigail; Joardar, Vinita; Pakala, Suman B.; Pakala, Suchitra; Venepally, Pratap; Fedorova, Natalie; Nierman, William C.; Kwon-Chung, Kyung J.

    2015-01-01

    Invasive aspergillosis (IA) due to Aspergillus fumigatus is a major cause of mortality in immunocompromised patients. The discovery of highly fertile strains of A. fumigatus opened the possibility to merge classical and contemporary genetics to address key questions about this pathogen. The merger involves sexual recombination, selection of desired traits, and genomics to identify any associated loci. We constructed a highly fertile isogenic pair of A. fumigatus strains with opposite mating types and used them to investigate whether mating type is associated with virulence and to find the genetic loci involved in azole resistance. The pair was made isogenic by 9 successive backcross cycles of the foundational strain AFB62 (MAT1-1) with a highly fertile (MAT1-2) progeny. Genome sequencing showed that the F9 MAT1-2 progeny was essentially identical to the AFB62. The survival curves of animals infected with either strain in three different animal models showed no significant difference, suggesting that virulence in A. fumigatus was not associated with mating type. We then employed a relatively inexpensive, yet highly powerful strategy to identify genomic loci associated with azole resistance. We used traditional in vitro drug selection accompanied by classical sexual crosses of azole-sensitive with resistant isogenic strains. The offspring were plated under varying drug concentrations and pools of resulting colonies were analyzed by whole genome sequencing. We found that variants in 5 genes contributed to azole resistance, including mutations in erg11A (cyp51A), as well as multi-drug transporters, erg25, and in HMG-CoA reductase. The results demonstrated that with minimal investment into the sequencing of three pools from a cross of interest, the variation(s) that contribute any phenotype can be identified with nucleotide resolution. This approach can be applied to multiple areas of interest in A. fumigatus or other heterothallic pathogens, especially for virulence associated traits. PMID:25909486

  2. Heterogeneity and Seroprevalence of a Newly Identified Avian Hepatitis E Virus from Chickens in the United States

    Microsoft Academic Search

    F. F. Huang; G. Haqshenas; H. L. Shivaprasad; D. K. Guenette; P. R. Woolcock; C. T. Larsen; F. W. Pierson; F. Elvinger; T. E. Toth; X. J. Meng

    2002-01-01

    We recently identified and characterized a novel virus, designated avian hepatitis E virus (avian HEV), from chickens with hepatitis-splenomegaly syndrome (HS syndrome) in the United States. Avian HEV is genetically related to but distinct from human and swine HEVs. To determine the extent of genetic variation and the seroprevalence of avian HEV infection in chicken flocks, we genetically identified and

  3. Genetic Differences between Blight-Causing Erwinia Species with Differing Host Specificities, Identified by Suppression Subtractive Hybridization?

    PubMed Central

    Triplett, Lindsay R.; Zhao, Youfu; Sundin, George W.

    2006-01-01

    PCR-based subtractive hybridization was used to isolate sequences from Erwinia amylovora strain Ea110, which is pathogenic on apples and pears, that were not present in three closely related strains with differing host specificities: E. amylovora MR1, which is pathogenic only on Rubus spp.; Erwinia pyrifoliae Ep1/96, the causal agent of shoot blight of Asian pears; and Erwinia sp. strain Ejp556, the causal agent of bacterial shoot blight of pear in Japan. In total, six subtractive libraries were constructed and analyzed. Recovered sequences included type III secretion components, hypothetical membrane proteins, and ATP-binding proteins. In addition, we identified an Ea110-specific sequence with homology to a type III secretion apparatus component of the insect endosymbiont Sodalis glossinidius, as well as an Ep1/96-specific sequence with homology to the Yersinia pestis effector protein tyrosine phosphatase YopH. PMID:16963554

  4. A Novel Fluorescence-based Genetic Strategy Identifies Mutants of Saccharomyces cerevisiae Defective for Nuclear Pore Complex Assembly

    PubMed Central

    Bucci, Mirella; Wente, Susan R.

    1998-01-01

    Nuclear pore complexes (NPCs) are large proteinaceous portals for exchanging macromolecules between the nucleus and the cytoplasm. Revealing how this transport apparatus is assembled will be critical for understanding the nuclear transport mechanism. To address this issue and to identify factors that regulate NPC formation and dynamics, a novel fluorescence-based strategy was used. This approach is based on the functional tagging of NPC proteins with the green fluorescent protein (GFP), and the hypothesis that NPC assembly mutants will have distinct GFP-NPC signals as compared with wild-type (wt) cells. By fluorescence-activated cell sorting for cells with low GFP signal from a population of mutagenized cells expressing GFP-Nup49p, three complementation groups were identified: two correspond to mutant nup120 and gle2 alleles that result in clusters of NPCs. Interestingly, a third group was a novel temperature-sensitive allele of nup57. The lowered GFP-Nup49p incorporation in the nup57-E17 cells resulted in a decreased fluorescence level, which was due in part to a sharply diminished interaction between the carboxy-terminal truncated nup57pE17 and wt Nup49p. Interestingly, the nup57-E17 mutant also affected the incorporation of a specific subset of other nucleoporins into the NPC. Decreased levels of NPC-associated Nsp1p and Nup116p were observed. In contrast, the localizations of Nic96p, Nup82p, Nup159p, Nup145p, and Pom152p were not markedly diminished. Coincidentally, nuclear import capacity was inhibited. Taken together, the identification of such mutants with specific perturbations of NPC structure validates this fluorescence-based strategy as a powerful approach for providing insight into the mechanism of NPC biogenesis. PMID:9725905

  5. Tetra-primer ARMS-PCR identifies the novel genetic variations of bovine HNF-4? gene associating with growth traits.

    PubMed

    Wang, Zi-nian; Li, Mi-jie; Lan, Xian-yong; Li, Ming-xun; Lei, Chu-zhao; Chen, Hong

    2014-08-10

    Hepatocyte nuclear factor-4? (HNF-4?), a member of the hepatocyte nuclear factor family, plays an important role in regulating the expression of genes involved in the development, differentiation and normal function of liver and pancreatic ? cells, as well as the maintenance of glucose homeostasis. Tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) is a new method offering fast detection and extreme simplicity at a negligible cost for SNP genotyping. In this paper, we characterize the polymorphisms of the bovine HNF-4? gene in three Chinese indigenous cattle breeds (n=660). Six novel SNPs were identified including 1 mutation in the coding region and others in introns. The statistical analyses indicated that 4 SNPs (g.T53729C, g.A53861G, g.A65188C and g.T65444C) affected growth traits markedly (P<0.05) in Qinchuan cattle (2 years after birth). Besides, haplotypes involving these 4 SNP sites in the bovine HNF-4? gene were identified and their effects on growth traits were also analyzed. The results showed that haplotypes 2, 7, 9 and 11 were predominant and accounted for 73.2%, 59.6%, and 67.1% in Qinchuan, Nanyang and Jiaxian cattle breeds, respectively. Hap9 (TAAT) was extremely predominant in all test populations, which suggested that individuals with Hap9 were more adapted to the environment. Furthermore, 4 combined haplotypes were constructed to guarantee the reliability of analysis results in Qinchuan cattle. There were also significant differences in body length (P<0.05). These findings will benefit for the application of DNA marker related to the growth traits on marker-assisted selection (MAS), and improve the performance of beef cattle. PMID:24914496

  6. A Genetic Screen for Dominant Modifiers of a cyclin E Hypomorphic Mutation Identifies Novel Regulators of S-Phase Entry in Drosophila

    PubMed Central

    Brumby, Anthony; Secombe, Julie; Horsfield, Julie; Coombe, Michelle; Amin, Nancy; Coates, Deborah; Saint, Robert; Richardson, Helena

    2004-01-01

    Cyclin E together with its kinase partner Cdk2 is a critical regulator of entry into S phase. To identify novel genes that regulate the G1- to S-phase transition within a whole animal we made use of a hypomorphic cyclin E mutation, DmcycEJP, which results in a rough eye phenotype. We screened the X and third chromosome deficiencies, tested candidate genes, and carried out a genetic screen of 55,000 EMS or X-ray-mutagenized flies for second or third chromosome mutations that dominantly modified the DmcycEJP rough eye phenotype. We have focused on the DmcycEJP suppressors, S(DmcycEJP), to identify novel negative regulators of S-phase entry. There are 18 suppressor gene groups with more than one allele and several genes that are represented by only a single allele. All S(DmcycEJP) tested suppress the DmcycEJP rough eye phenotype by increasing the number of S phases in the postmorphogenetic furrow S-phase band. By testing candidates we have identified several modifier genes from the mutagenic screen as well as from the deficiency screen. DmcycEJP suppressor genes fall into the classes of: (1) chromatin remodeling or transcription factors; (2) signaling pathways; and (3) cytoskeletal, (4) cell adhesion, and (5) cytoarchitectural tumor suppressors. The cytoarchitectural tumor suppressors include scribble, lethal-2-giant-larvae (lgl), and discs-large (dlg), loss of function of which leads to neoplastic tumors and disruption of apical-basal cell polarity. We further explored the genetic interactions of scribble with S(DmcycEJP) genes and show that hypomorphic scribble mutants exhibit genetic interactions with lgl, scab (?PS3-integrin—cell adhesion), phyllopod (signaling), dEB1 (microtubule-binding protein—cytoskeletal), and moira (chromatin remodeling). These interactions of the cytoarchitectural suppressor gene, scribble, with cell adhesion, signaling, cytoskeletal, and chromatin remodeling genes, suggest that these genes may act in a common pathway to negatively regulate cyclin E or S-phase entry. PMID:15454540

  7. A genetic screen for dominant modifiers of a cyclin E hypomorphic mutation identifies novel regulators of S-phase entry in Drosophila.

    PubMed

    Brumby, Anthony; Secombe, Julie; Horsfield, Julie; Coombe, Michelle; Amin, Nancy; Coates, Deborah; Saint, Robert; Richardson, Helena

    2004-09-01

    Cyclin E together with its kinase partner Cdk2 is a critical regulator of entry into S phase. To identify novel genes that regulate the G1- to S-phase transition within a whole animal we made use of a hypomorphic cyclin E mutation, DmcycEJP, which results in a rough eye phenotype. We screened the X and third chromosome deficiencies, tested candidate genes, and carried out a genetic screen of 55,000 EMS or X-ray-mutagenized flies for second or third chromosome mutations that dominantly modified the DmcycEJP rough eye phenotype. We have focused on the DmcycEJP suppressors, S(DmcycEJP), to identify novel negative regulators of S-phase entry. There are 18 suppressor gene groups with more than one allele and several genes that are represented by only a single allele. All S(DmcycEJP) tested suppress the DmcycEJP rough eye phenotype by increasing the number of S phases in the postmorphogenetic furrow S-phase band. By testing candidates we have identified several modifier genes from the mutagenic screen as well as from the deficiency screen. DmcycEJP suppressor genes fall into the classes of: (1) chromatin remodeling or transcription factors; (2) signaling pathways; and (3) cytoskeletal, (4) cell adhesion, and (5) cytoarchitectural tumor suppressors. The cytoarchitectural tumor suppressors include scribble, lethal-2-giant-larvae (lgl), and discs-large (dlg), loss of function of which leads to neoplastic tumors and disruption of apical-basal cell polarity. We further explored the genetic interactions of scribble with S(DmcycEJP) genes and show that hypomorphic scribble mutants exhibit genetic interactions with lgl, scab (alphaPS3-integrin--cell adhesion), phyllopod (signaling), dEB1 (microtubule-binding protein--cytoskeletal), and moira (chromatin remodeling). These interactions of the cytoarchitectural suppressor gene, scribble, with cell adhesion, signaling, cytoskeletal, and chromatin remodeling genes, suggest that these genes may act in a common pathway to negatively regulate cyclin E or S-phase entry. PMID:15454540

  8. Determination of optimum allocation and pricing of distributed generation using genetic algorithm methodology

    NASA Astrophysics Data System (ADS)

    Mwakabuta, Ndaga Stanslaus

    Electric power distribution systems play a significant role in providing continuous and "quality" electrical energy to different classes of customers. In the context of the present restrictions on transmission system expansions and the new paradigm of "open and shared" infrastructure, new approaches to distribution system analyses, economic and operational decision-making need investigation. This dissertation includes three layers of distribution system investigations. In the basic level, improved linear models are shown to offer significant advantages over previous models for advanced analysis. In the intermediate level, the improved model is applied to solve the traditional problem of operating cost minimization using capacitors and voltage regulators. In the advanced level, an artificial intelligence technique is applied to minimize cost under Distributed Generation injection from private vendors. Soft computing techniques are finding increasing applications in solving optimization problems in large and complex practical systems. The dissertation focuses on Genetic Algorithm for investigating the economic aspects of distributed generation penetration without compromising the operational security of the distribution system. The work presents a methodology for determining the optimal pricing of distributed generation that would help utilities make a decision on how to operate their system economically. This would enable modular and flexible investments that have real benefits to the electric distribution system. Improved reliability for both customers and the distribution system in general, reduced environmental impacts, increased efficiency of energy use, and reduced costs of energy services are some advantages.

  9. Transcription closed and open complex dynamics studies reveal balance between genetic determinants and co-factors

    NASA Astrophysics Data System (ADS)

    Sala, Adrien; Shoaib, Muhammad; Anufrieva, Olga; Mutharasu, Gnanavel; Jahan Hoque, Rawnak; Yli-Harja, Olli; Kandhavelu, Meenakshisundaram

    2015-05-01

    In E. coli, promoter closed and open complexes are key steps in transcription initiation, where magnesium-dependent RNA polymerase catalyzes RNA synthesis. However, the exact mechanism of initiation remains to be fully elucidated. Here, using single mRNA detection and dual reporter studies, we show that increased intracellular magnesium concentration affects Plac initiation complex formation resulting in a highly dynamic process over the cell growth phases. Mg2+ regulates transcription transition, which modulates bimodality of mRNA distribution in the exponential phase. We reveal that Mg2+ regulates the size and frequency of the mRNA burst by changing the open complex duration. Moreover, increasing magnesium concentration leads to higher intrinsic and extrinsic noise in the exponential phase. RNAP-Mg2+ interaction simulation reveals critical movements creating a shorter contact distance between aspartic acid residues and Nucleotide Triphosphate residues and increasing electrostatic charges in the active site. Our findings provide unique biophysical insights into the balanced mechanism of genetic determinants and magnesium ion in transcription initiation regulation during cell growth.

  10. An image segmentation based on a genetic algorithm for determining soil coverage by crop residues.

    PubMed

    Ribeiro, Angela; Ranz, Juan; Burgos-Artizzu, Xavier P; Pajares, Gonzalo; del Arco, Maria J Sanchez; Navarrete, Luis

    2011-01-01

    Determination of the soil coverage by crop residues after ploughing is a fundamental element of Conservation Agriculture. This paper presents the application of genetic algorithms employed during the fine tuning of the segmentation process of a digital image with the aim of automatically quantifying the residue coverage. In other words, the objective is to achieve a segmentation that would permit the discrimination of the texture of the residue so that the output of the segmentation process is a binary image in which residue zones are isolated from the rest. The RGB images used come from a sample of images in which sections of terrain were photographed with a conventional camera positioned in zenith orientation atop a tripod. The images were taken outdoors under uncontrolled lighting conditions. Up to 92% similarity was achieved between the images obtained by the segmentation process proposed in this paper and the templates made by an elaborate manual tracing process. In addition to the proposed segmentation procedure and the fine tuning procedure that was developed, a global quantification of the soil coverage by residues for the sampled area was achieved that differed by only 0.85% from the quantification obtained using template images. Moreover, the proposed method does not depend on the type of residue present in the image. The study was conducted at the experimental farm "El Encín" in Alcalá de Henares (Madrid, Spain). PMID:22163966

  11. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry

    PubMed Central

    Horowitz, Amir; Strauss-Albee, Dara M.; Leipold, Michael; Kubo, Jessica; Nemat-Gorgani, Neda; Dogan, Ozge C.; Dekker, Cornelia L.; Mackey, Sally; Maecker, Holden; Swan, Gary E.; Davis, Mark M.; Norman, Paul J.; Guethlein, Lisbeth A.; Desai, Manisha; Parham, Peter; Blish, Catherine A.

    2013-01-01

    Natural Killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 35 parameters, including 28 NK cell receptors, on peripheral blood NK cells from five sets of monozygotic twins and twelve unrelated donors of defined HLA and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6,000-30,000 phenotypic populations within an individual and >100,000 phenotypes in this population. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors, while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation. PMID:24154599

  12. Genetic and physical maps around the sex-determining M-locus of the dioecious plant asparagus.

    PubMed

    Telgmann-Rauber, Alexa; Jamsari, Ari; Kinney, Michael S; Pires, J Chris; Jung, Christian

    2007-09-01

    Asparagus officinalis L. is a dioecious plant. A region called the M-locus located on a pair of homomorphic sex chromosomes controls the sexual dimorphism in asparagus. The aim of this work was to clone the region determining sex in asparagus from its position in the genome. The structure of the region encompassing M should be investigated and compared to the sex-determining regions in other dioecious model species. To establish an improved basis for physical mapping, a high-resolution genetic map was enriched with AFLP markers closely linked to the target locus by carrying out a bulked segregant analysis. By screening a BAC library with AFLP- and STS-markers followed by chromosome walking, a physical map with eight contigs could be established. However, the gaps between the contigs could not be closed due to a plethora of repetitive elements. Surprisingly, two of the contigs on one side of the M-locus did not overlap although they have been established with two markers, which mapped in a distance as low as 0.25 cM flanking the sex locus. Thus, the clustering of the markers indicates a reduced recombination frequency within the M-region. On the opposite side of the M-locus, a contig was mapped in a distance of 0.38 cM. Four closely linked BAC clones were partially sequenced and 64 putative ORFs were identified. Interestingly, only 25% of the ORFs showed sequence similarity to known proteins and ESTs. In addition, an accumulation of repetitive sequences and a low gene density was revealed in the sex-determining region of asparagus. Molecular cytogenetic and sequence analysis of BACs flanking the M-locus indicate that the BACs contain highly repetitive sequences that localize to centromeric and pericentromeric locations on all asparagus chromosomes, which hindered the localization of the M-locus to the single pair of sex chromosomes. We speculate that dioecious Silene, papaya and Asparagus species may represent three stages in the evolution of XX, XY sex determination systems. Given that asparagus still rarely produces hermaphroditic flowers and has homomorphic sex chromosomes, this species may be an ideal system to further investigates early sex chromosome evolution and the origins of dioecy. PMID:17609979

  13. Determination of the linkage relationships and the gene-centromere genetic distances for endopeptidase structural genes in hexaploid wheat 

    E-print Network

    McMillin, David Edwin

    1977-01-01

    DETERNINATION OF THE 3' INKAGE RELATIONSHIPS AND THE GENE-CENTBQYZRZ GENETIC DISTANCES FOR ENDOPEPTIDASE STRUCTU~& GENES IN HEXAPLOID WHEAT A Thesis by DAVID EDWIN NcNILLIN Submitted to the Graduate College of Texas A6K University iri... partial fulfillrr~ent of the requirement for the degree of :PASTER OF SCIE'ACR Nay 1977 Hajor Sub-je" t: Gea, ties DETERMINATION OF THE LD'KACE kEM'). '. ~'OBBHZPS AND THi?: GENE-CENTF''ONEM GENETIC DIS'L&NCES FOR ENDOPEPTIDASE STRUCTURAL GENES IN H...

  14. Molecular genetics of addiction and related heritable phenotypes: genome wide association approaches identify “connectivity constellation” and drug target genes with pleiotropic effects

    PubMed Central

    Uhl, George R; Drgon, Tomas; Johnson, Catherine; Li, Chuan-Yun; Contoreggi, Carlo; Hess, Judith; Naiman, Daniel; Liu, Qing-Rong

    2013-01-01

    Genome wide association (GWA) can elucidate molecular genetic bases for human individual differences in “complex” phenotypes that include vulnerability to addiction. Here, we review: a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; b) technical and ethical aspects of importance for understanding genome wide association data: genotyping in individual samples vs DNA pools, analytic approaches, power estimation and ethical issues in genotyping individuals with illegal behaviors; c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; d) overlaps between GWA datasets for dependence on different substances; e) overlaps between GWA data for addictions vs other heritable, brain-based phenotypes that include: i) bipolar disorder, ii) cognitive ability, iii) frontal lobe brain volume, iv) ability to successfully quit smoking, v) neuroticism and vi) Alzheimer’s disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A “connectivity constellation” of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes. PMID:18991966

  15. Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance*

    PubMed Central

    Warmoes, Marc; Jaspers, Janneke E.; Xu, Guotai; Sampadi, Bharath K.; Pham, Thang V.; Knol, Jaco C.; Piersma, Sander R.; Boven, Epie; Jonkers, Jos; Rottenberg, Sven; Jimenez, Connie R.

    2013-01-01

    In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin. PMID:23397111

  16. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes.

    PubMed

    Xue, Ruidan; Lynes, Matthew D; Dreyfuss, Jonathan M; Shamsi, Farnaz; Schulz, Tim J; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S; White, Andrew P; Lynes, Maureen S; Rubin, Lee L; Goodyear, Laurie J; Cypess, Aaron M; Tseng, Yu-Hua

    2015-07-01

    Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes. PMID:26076036

  17. Analysis of Genetic Diversity in Rough Bluegrass Determined by RAPD Markers

    Microsoft Academic Search

    Shanmugam Rajasekar; Shui-hang Fei; Nick E. Christians

    2006-01-01

    Information on genetic variation in rough bluegrass (Poa trivialis L.), a cool-season grass that is grown for sports fields and lawns, is needed. The objective of this study was to assess genetic variation in 27 accessions of rough bluegrass obtained from the National Plant Germplasm System (NPGS) by random amplified polymorphic DNA (RAPD) markers. Fifteen of the 80 primers screened

  18. Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans

    Microsoft Academic Search

    Yang Li; Olga Alda Alvarez; Evert W. Gutteling; Marcel Tijsterman; Jingyuan Fu; Joost A. G. Riksen; Esther Hazendonk; Pjotr Prins; Ronald H. A. Plasterk; Ritsert C. Jansen; Rainer Breitling; Jan E. Kammenga

    2005-01-01

    Recent genetical genomics studies have provided intimate views on gene regulatory networks. Gene expression variations between genetically different individuals have been mapped to the causal regulatory regions, termed expression quantitative trait loci. Whether the environment-induced plastic response of gene expression also shows heritable difference has not yet been studied. Here we show that differential expression induced by temperatures of 16

  19. Genetic diversity of fringed brome ( Bromus ciliatus ) as determined by amplified fragment length polymorphism

    Microsoft Academic Search

    Yong-Bi Fu; Bruce E. Coulman; Yasas S. N. Ferdinandez; Jacques Cayouette; Paul M. Peterson

    2005-01-01

    Fringed brome (Bromus ciliatus L.) is found in native stands throughout a large area of North America. Little is known about the genetic diversity of this species. The amplified fragment length polymorphism (AFLP) technique was applied to assess the genetic diversity of 16 fringed brome populations sampled in Canada from the provinces of Alberta, British Columbia, Quebec, and Saskatchewan. Four

  20. Determination of the framework of homogeneous magnetic sources through regularized Genetic Algorithm

    NASA Astrophysics Data System (ADS)

    Bijani, R.; Ponte-Neto, C. F.

    2013-05-01

    We present a method for inverting total-field anomaly for determining the framework of 3D magnetic sources such as: batholiths, dikes, sills, geological contacts, kimberlite and lamproite pipes. We use genetic algorithm to obtain magnetic sources' frameworks and their magnetic features simultaneously. Specifically, we estimate the magnetization direction (inclination and declination), the total dipole moment intensity, and the horizontal and vertical positions, in Cartesian coordinates, of a finite set of elementary magnetic dipoles. The spatial distribution of these magnetic dipoles makes up the skeletal outlines of 3D geologic sources. As we already know, the majority of inverse problems are ill-posed, which means that we need to introduce a priori information to stabilize the inverse problem. In our methodology, we use the minimum tree principle, which is solved by Kruskal algorithm. In addition, we impose that thenearest-neighbor nodes are equidistant. We want to estimate a compact and homogeneous distribution of dipoles that better represent a compact and homogeneous 3D magnetic source. As primary results, we apply our methodology to a synthetic data set produced by a vertical prism, with dimensions 4 x 4 x 2 km3, with -17° magnetic inclination and -20° magnetic declination. Figure 1A presents the spatial estimates of the dipoles using the Genetic Algorithm without the minimum tree regularization. We can see that the three deeper dipoles did not get concentrated. In Figure 1B, we check the result by plotting the observed data and the predicted data together. We then repeat the same test presented in Figure 1A with the minimum tree regularization. In Figure 2A, the dipoles became more compact. In Figure 2B, we again plot the observed data and the predicted data to verify the result. Later on, we will test this promising methodology to other synthetic cases. After that, we will be able to apply our methodology to real data sets.; (A) Spatial estimates of dipoles (red circles) without minimum tree regularization. The prism is the true homogeneous magnetic source. (B) Observed data (black dashed lines) and predicted data (red dashed lines) ; (A) Spatial estimates of dipoles (red circles) with minimum tree regularization. The prism is the true homogeneous magnetic source. (B) Observed data (black dashed lines) and predicted data (red dashed lines)

  1. Different genetic components in the Ethiopian population, identified by mtDNA and Y-chromosome polymorphisms.

    PubMed Central

    Passarino, G; Semino, O; Quintana-Murci, L; Excoffier, L; Hammer, M; Santachiara-Benerecetti, A S

    1998-01-01

    Seventy-seven Ethiopians were investigated for mtDNA and Y chromosome-specific variations, in order to (1) define the different maternal and paternal components of the Ethiopian gene pool, (2) infer the origins of these maternal and paternal lineages and estimate their relative contributions, and (3) obtain information about ancient populations living in Ethiopia. The mtDNA was studied for the RFLPs relative to the six classical enzymes (HpaI, BamHI, HaeII, MspI, AvaII, and HincII) that identify the African haplogroup L and the Caucasoid haplogroups I and T. The sample was also examined at restriction sites that define the other Caucasoid haplogroups (H, U, V, W, X, J, and K) and for the simultaneous presence of the DdeI10394 and AluI10397 sites, which defines the Asian haplogroup M. Four polymorphic systems were examined on the Y chromosome: the TaqI/12f2 and the 49a,f RFLPs, the Y Alu polymorphic element (DYS287), and the sY81-A/G (DYS271) polymorphism. For comparison, the last two Y polymorphisms were also examined in 87 Senegalese previously classified for the two TaqI RFLPs. Results from these markers led to the hypothesis that the Ethiopian population (1) experienced Caucasoid gene flow mainly through males, (2) contains African components ascribable to Bantu migrations and to an in situ differentiation process from an ancestral African gene pool, and (3) exhibits some Y-chromosome affinities with the Tsumkwe San (a very ancient African group). Our finding of a high (20%) frequency of the "Asian" DdeI10394AluI10397 (++) mtDNA haplotype in Ethiopia is discussed in terms of the "out of Africa" model. PMID:9463310

  2. A multicopy suppressor screening approach as a means to identify antibiotic resistance determinant candidates in Yersinia pestis

    PubMed Central

    Stirrett, Karen L; Ferreras, Julian A; Rossi, Sebastian M; Moy, Richard L; Fonseca, Fabio V; Quadri, Luis EN

    2008-01-01

    Background Yersinia pestis is the causative agent of plague and a potential agent of bioterrorism and biowarfare. The plague biothreat and the emergence of multidrug-resistant plague underscore the need to increase our understanding of the intrinsic potential of Y. pestis for developing antimicrobial resistance and to anticipate the mechanisms of resistance that may emerge in Y. pestis. Identification of Y. pestis genes that, when overexpressed, are capable of reducing antibiotic susceptibility is a useful strategy to expose genes that this pathogen may rely upon to evolve antibiotic resistance via a vertical modality. In this study, we explored the use of a multicopy suppressor, Escherichia coli host-based screening approach as a means to expose antibiotic resistance determinant candidates in Y. pestis. Results We constructed a multicopy plasmid-based, Y. pestis genome-wide expression library of nearly 16,000 clones in E. coli and screened the library for suppressors of the antimicrobial activity of ofloxacin, a fluoroquinolone antibiotic. The screen permitted the identification of a transcriptional regulator-encoding gene (robAYp) that increased the MIC99 of ofloxacin by 23-fold when overexpressed from a multicopy plasmid in Y. pestis. Additionally, we found that robAYp overexpression in Y. pestis conferred low-level resistance to many other antibiotics and increased organic solvent tolerance. Overexpression of robAYp also upregulated the expression of several efflux pumps in Y. pestis. Conclusion Our study provides proof of principle for the use of multicopy suppressor screening based on the tractable and easy-to-manipulate E. coli host as a means to identify antibiotic resistance determinant candidates of Y. pestis. PMID:18644132

  3. Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

    PubMed Central

    Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Bianco, Luciana Lo; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

    2010-01-01

    Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. PMID:20179754

  4. Genetic diversity and differentiation of Juniperus thurifera in Spain and Morocco as determined by SSR.

    PubMed

    Teixeira, Helena; Rodríguez-Echeverría, Susana; Nabais, Cristina

    2014-01-01

    Juniperus thurifera L. is an important tree endemic to the western Mediterranean basin that it is able to grow in semi-arid climates. It nowadays exhibits a disjunct distribution pattern, occurring in North Africa, Spain, France and the Italian Alps. The Strait of Gibraltar has acted as an efficient barrier against gene flow between African and European populations, which are considered different subspecies by some authors. We aimed at describing the intraspecific genetic diversity of J. thurifera in populations from the Iberian Peninsula and Morocco and the phylogeographical relationships among these populations. The ploidy level of J. thurifera was examined and eleven nuclear microsatellites (nSSRs) developed for J. thurifera were assessed for genotyping this species. Six nSSRs were polymorphic and subsequently used to assess the genetic diversity and structure of the studied populations. Genotyping of the tetraploid J. thurifera using nuclear microsatellites supports the separation of Moroccan and Spanish populations into two genetically differentiated groups that correspond to the proposed subspecies africana and thurifera. High values of within population genetic diversity were found, that accounted for 90% of the total genetic variance, while population structure was weak. The estimators of genetic diversity were higher in populations of Spain than in populations of Morocco pointing for a possible loss of genetic diversity during the spread of this species to Africa from Europe. PMID:24533164

  5. Genetic Diversity and Differentiation of Juniperus thurifera in Spain and Morocco as Determined by SSR

    PubMed Central

    Teixeira, Helena; Rodríguez-Echeverría, Susana; Nabais, Cristina

    2014-01-01

    Juniperus thurifera L. is an important tree endemic to the western Mediterranean basin that it is able to grow in semi-arid climates. It nowadays exhibits a disjunct distribution pattern, occurring in North Africa, Spain, France and the Italian Alps. The Strait of Gibraltar has acted as an efficient barrier against gene flow between African and European populations, which are considered different subspecies by some authors. We aimed at describing the intraspecific genetic diversity of J. thurifera in populations from the Iberian Peninsula and Morocco and the phylogeographical relationships among these populations. The ploidy level of J. thurifera was examined and eleven nuclear microsatellites (nSSRs) developed for J. thurifera were assessed for genotyping this species. Six nSSRs were polymorphic and subsequently used to assess the genetic diversity and structure of the studied populations. Genotyping of the tetraploid J. thurifera using nuclear microsatellites supports the separation of Moroccan and Spanish populations into two genetically differentiated groups that correspond to the proposed subspecies africana and thurifera. High values of within population genetic diversity were found, that accounted for 90% of the total genetic variance, while population structure was weak. The estimators of genetic diversity were higher in populations of Spain than in populations of Morocco pointing for a possible loss of genetic diversity during the spread of this species to Africa from Europe. PMID:24533164

  6. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: implications for the genetic engineering of bioenergy crops

    PubMed Central

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S.; Ding, Shi-You; Ciesielski, Peter N.; Yang, Shihui; Tucker, Melvin P.; Himmel, Michael E.

    2015-01-01

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, ?-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/?-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional ?-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (?-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. The implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed. PMID:26029221

  7. Identifying the ionically bound cell wall and intracellular glycoside hydrolases in late growth stage Arabidopsis stems: implications for the genetic engineering of bioenergy crops.

    PubMed

    Wei, Hui; Brunecky, Roman; Donohoe, Bryon S; Ding, Shi-You; Ciesielski, Peter N; Yang, Shihui; Tucker, Melvin P; Himmel, Michael E

    2015-01-01

    Identifying the cell wall-ionically bound glycoside hydrolases (GHs) in Arabidopsis stems is important for understanding the regulation of cell wall integrity. For cell wall proteomics studies, the preparation of clean cell wall fractions is a challenge since cell walls constitute an open compartment, which is more likely to contain a mixture of intracellular and extracellular proteins due to cell leakage at the late growth stage. Here, we utilize a CaCl2-extraction procedure to isolate non-structural proteins from Arabidopsis whole stems, followed by the in-solution and in-gel digestion methods coupled with Nano-LC-MS/MS, bioinformatics and literature analyses. This has led to the identification of 75 proteins identified using the in-solution method and 236 proteins identified by the in-gel method, among which about 10% of proteins predicted to be secreted. Together, eight cell wall proteins, namely AT1G75040, AT5G26000, AT3G57260, AT4G21650, AT3G52960, AT3G49120, AT5G49360, and AT3G14067, were identified by the in-solution method; among them, three were the GHs (AT5G26000, myrosinase 1, GH1; AT3G57260, ?-1,3-glucanase 2, GH17; AT5G49360, bifunctional XYL 1/?-L-arabinofuranosidase, GH3). Moreover, four more GHs: AT4G30270 (xyloglucan endotransferase, GH16), AT1G68560 (bifunctional ?-l-arabinofuranosidase/XYL, GH31), AT1G12240 (invertase, GH32) and AT2G28470 (?-galactosidase 8, GH35), were identified by the in-gel solution method only. Notably, more than half of above identified GHs are xylan- or hemicellulose-modifying enzymes, and will likely have an impact on cellulose accessibility, which is a critical factor for downstream enzymatic hydrolysis of plant tissues for biofuels production. The implications of these cell wall proteins identified at the late growth stage for the genetic engineering of bioenergy crops are discussed. PMID:26029221

  8. Comparative genetic analysis of a wheat seed dormancy QTL with rice and Brachypodium identifies candidate genes for ABA perception and calcium signaling.

    PubMed

    Somyong, Suthasinee; Munkvold, Jesse D; Tanaka, James; Benscher, David; Sorrells, Mark E

    2011-09-01

    Wheat preharvest sprouting (PHS) occurs when seed germinates on the plant before harvest resulting in reduced grain quality. In wheat, PHS susceptibility is correlated with low levels of seed dormancy. A previous mapping of quantitative trait loci (QTL) revealed a major PHS/seed dormancy QTL, QPhs.cnl-2B.1, located on wheat chromosome 2B. A comparative genetic study with the related grass species rice (Oryza sativa L.) and Brachypodium distachyon at the homologous region to the QPhs.cnl-2B.1 interval was used to identify the candidate genes for marker development and subsequent fine mapping. Expressed sequence tags and a comparative mapping were used to design 278 primer pairs, of which 22 produced polymorphic amplicons that mapped to the group 2 chromosomes. Fourteen mapped to chromosome 2B, and ten were located in the QTL interval. A comparative analysis revealed good macrocollinearity between the PHS interval and 3 million base pair (mb) region on rice chromosomes 7 and 3, and a 2.7-mb region on Brachypodium Bd1. The comparative intervals in rice were found to contain three previously identified rice seed dormancy QTL. Further analyses of the interval in rice identified genes that are known to play a role in seed dormancy, including a homologue for the putative Arabidopsis ABA receptor ABAR/GUN5. Additional candidate genes involved in calcium signaling were identified and were placed in a functional protein association network that includes additional proteins critical for ABA signaling and germination. This study provides promising candidate genes for seed dormancy in both wheat and rice as well as excellent molecular markers for further comparative and fine mapping. PMID:21468744

  9. Genetic Profiling to Determine Risk of Relapse Free Survival in High-risk Localized Prostate Cancer

    PubMed Central

    Barnett, Christine M.; Heinrich, Michael C.; Lim, Jeong; Nelson, Dylan; Beadling, Carol; Warrick, Andrea; Neff, Tanaya; Higano, Celestia S.; Garzotto, Mark; Qian, David; Corless, Christopher L.; Thomas, George V.; Beer, Tomasz M.

    2014-01-01

    Purpose The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high risk clinically localized prostate cancer. Experimental Design 48 samples of formalin fixed paraffin embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy based sequencing. In addition, PTEN loss and ERG translocations were examined using immunohistochemistry in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. Results Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse free survival, 19 vs. 106 months (p = .01). Conclusions This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. While point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high risk prostate cancer treated with chemotherapy followed by surgery. PMID:24352642

  10. 76 FR 78232 - Monsanto Co.; Determination of Nonregulated Status for Soybean Genetically Engineered To Have a...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-16

    ...OF AGRICULTURE Animal and Plant Health Inspection Service...Glyphosate AGENCY: Animal and Plant Health Inspection Service...soybeans are likely to pose a plant pest risk, the draft EA...tests, and health effects of genetically modified organisms and...

  11. Behavioral versus genetic determination of lipoproteins andidentical twins discordant for exercise

    SciTech Connect

    Williams, Paul T.; Blanche, Patricia J.; Krauss, Ronald M.

    2004-06-01

    Lipoprotein and weight differences between vigorously active and sedentary MZ twins are used to: (1) estimate the effects of training while controlling for genotype; (2) estimate genetic concordance in the presence of divergent lifestyles.

  12. Determining natal dispersal patterns in a population of North American pikas ( Ochotona princeps ) using direct mark-resight and indirect genetic methods

    Microsoft Academic Search

    Mary M. Peacock

    1997-01-01

    A combination of direct (mark-resight) and indirect genetic methods were tued to investigate natal dispersal patterns and genetic population structure in a population of North American pikas, Ochotona princeps. Pikas are small lagomorphs found in talus habitat of alpine areas throughout western North America. Adult pikas are individually territorial and rarely disperse. I used multilocus DNA fingerprinting to identify the

  13. A case study of “ disorganized development” and its possible relevance to genetic determinants of aging

    Microsoft Academic Search

    Richard F. Walker; Lawrence C. Pakula; Maxine J. Sutcliffe; Patricia A. Kruk; Jesper Graakjaer; Jerry W. Shay

    2009-01-01

    In 1932, Bidder postulated that senescence results from “continued action of a (genetic) regulator (of development) after growth ceases (maturation occurs).” A 16-year-old girl who physically appears to be an infant has not been diagnosed with any known genetic syndrome or chromosomal abnormality. The subject's anthropometric measurements are that of an 11-month-old. Coordinated development of structures for swallowing\\/breathing has not

  14. Demographic Histories, Isolation and Social Factors as Determinants of the Genetic Structure of Alpine Linguistic Groups

    PubMed Central

    Coia, Valentina; Capocasa, Marco; Anagnostou, Paolo; Pascali, Vincenzo; Scarnicci, Francesca; Boschi, Ilaria; Battaggia, Cinzia; Crivellaro, Federica; Ferri, Gianmarco; Alù, Milena; Brisighelli, Francesca; Busby, George B. J.; Capelli, Cristian; Maixner, Frank; Cipollini, Giovanna; Viazzo, Pier Paolo; Zink, Albert; Destro Bisol, Giovanni

    2013-01-01

    Great European mountain ranges have acted as barriers to gene flow for resident populations since prehistory and have offered a place for the settlement of small, and sometimes culturally diverse, communities. Therefore, the human groups that have settled in these areas are worth exploring as an important potential source of diversity in the genetic structure of European populations. In this study, we present new high resolution data concerning Y chromosomal variation in three distinct Alpine ethno-linguistic groups, Italian, Ladin and German. Combining unpublished and literature data on Y chromosome and mitochondrial variation, we were able to detect different genetic patterns. In fact, within and among population diversity values observed vary across linguistic groups, with German and Italian speakers at the two extremes, and seem to reflect their different demographic histories. Using simulations we inferred that the joint effect of continued genetic isolation and reduced founding group size may explain the apportionment of genetic diversity observed in all groups. Extending the analysis to other continental populations, we observed that the genetic differentiation of Ladins and German speakers from Europeans is comparable or even greater to that observed for well known outliers like Sardinian and Basques. Finally, we found that in south Tyroleans, the social practice of Geschlossener Hof, a hereditary norm which might have favored male dispersal, coincides with a significant intra-group diversity for mtDNA but not for Y chromosome, a genetic pattern which is opposite to those expected among patrilocal populations. Together with previous evidence regarding the possible effects of “local ethnicity” on the genetic structure of German speakers that have settled in the eastern Italian Alps, this finding suggests that taking socio-cultural factors into account together with geographical variables and linguistic diversity may help unveil some yet to be understood aspects of the genetic structure of European populations. PMID:24312576

  15. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

    PubMed

    Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; Bouatia-Naji, Nabila; Harris, Tamara B; Berndt, Sonja I; Ingelsson, Erik; Willer, Cristen J; Weedon, Michael N; Luan, Jian'an; Vedantam, Sailaja; Esko, Tõnu; Kilpeläinen, Tuomas O; Kutalik, Zoltán; Li, Shengxu; Monda, Keri L; Dixon, Anna L; Holmes, Christopher C; Kaplan, Lee M; Liang, Liming; Min, Josine L; Moffatt, Miriam F; Molony, Cliona; Nicholson, George; Schadt, Eric E; Zondervan, Krina T; Feitosa, Mary F; Ferreira, Teresa; Lango Allen, Hana; Weyant, Robert J; Wheeler, Eleanor; Wood, Andrew R; Estrada, Karol; Goddard, Michael E; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M; Yang, Jian; McCarroll, Steven A; Nemesh, James; Voight, Benjamin F; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L; Hayward, Caroline; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W; Kraft, Peter; Kraja, Aldi T; Lamina, Claudia; Leitzmann, Michael F; McKnight, Barbara; Morris, Andrew P; Ong, Ken K; Perry, John R B; Peters, Marjolein J; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proença, Christine; Chines, Peter S; Fisher, Eva; Kulzer, Jennifer R; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M; Timpson, Nicholas John; Watanabe, Richard M; Welch, Ryan; Chasman, Daniel I; Cooper, Matthew N; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D; Bennett, Amanda J; Biffar, Reiner; Bonnycastle, Lori L; Bornstein, Stefan R; Buchanan, Thomas A; Campbell, Harry; Day, Ian N M; Dei, Mariano; Dörr, Marcus; Elliott, Paul; Erdos, Michael R; Eriksson, Johan G; Freimer, Nelson B; Fu, Mao; Gaget, Stefan; Geus, Eco J C; Gjesing, Anette P; Grallert, Harald; Grässler, Jürgen; Groves, Christopher J; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S; Herzig, Karl-Heinz; Hicks, Andrew A; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G Mark; Lokki, Marja-Liisa; Luben, Robert N; Ludwig, Barbara; McArdle, Wendy L; McCarthy, Anne; Morken, Mario A; Nelis, Mari; Neville, Matt J; Paré, Guillaume; Parker, Alex N; Peden, John F; Pichler, Irene; Pietiläinen, Kirsi H; Platou, Carl G P; Pouta, Anneli; Ridderstråle, Martin; Samani, Nilesh J; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H; Strawbridge, Rona J; Stringham, Heather M; Swift, Amy J; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B J; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B; Wallaschofski, Henri; Walters, G Bragi; Widen, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Witte, Daniel R; Zgaga, Lina; Zitting, Paavo; Beilby, John P; James, Alan L; Kähönen, Mika; Lehtimäki, Terho; Nieminen, Markku S; Ohlsson, Claes; Palmer, Lyle J; Raitakari, Olli; Ridker, Paul M; Stumvoll, Michael; Tönjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jørgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E H; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T; Wareham, Nicholas J; Arnold, Alice M; Beckmann, Jacques S; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Collins, Francis S; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T; Hofman, Albert; Hu, Frank B; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W H Linda; Kaprio, Jaakko; Launer, Lenore J; Munroe, Patricia B; Oostra, Ben; Penninx, Brenda W; Pramstaller, Peter P; Psaty, Bruce M

    2010-11-01

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?³ to P = 1.2 × 10?¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. PMID:20935629

  16. A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation

    PubMed Central

    Andrysik, Zdenek; Kim, Jihye; Tan, Aik Choon; Espinosa, Joaquín M.

    2013-01-01

    SUMMARY The p53 transcription factor participates in diverse cellular responses to stress including cell cycle arrest, apoptosis, senescence and autophagy. The molecular mechanisms defining the ultimate outcome to p53 activation remain poorly characterized. We performed a genome-wide genetic screen in human cells to identify pathway-specific coregulators of the p53 target genes CDKN1A (p21), an inhibitor of cell cycle progression, versus BBC3 (PUMA), a key mediator of apoptosis. Our screen identified numerous factors whose depletion creates an imbalance in the p21:PUMA ratio upon p53 activation. The transcription factor TCF3/E2A drives p21 expression while repressing PUMA across cancer cell types of multiple origins. Accordingly, TCF3/E2A depletion impairs the cell cycle arrest response and promotes apoptosis upon p53 activation by chemotherapeutic agents. In contrast, TRIAP1 is a specific repressor of p21 whose depletion slows down cell cycle progression. Our results reveal strategies to drive cells toward specific p53-dependent responses. PMID:23684607

  17. Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

    PubMed Central

    Perry, John R. B.; Voight, Benjamin F.; Yengo, Loïc; Amin, Najaf; Dupuis, Josée; Ganser, Martha; Grallert, Harald; Navarro, Pau; Li, Man; Qi, Lu; Steinthorsdottir, Valgerdur; Scott, Robert A.; Almgren, Peter; Arking, Dan E.; Aulchenko, Yurii; Balkau, Beverley; Benediktsson, Rafn; Bergman, Richard N.; Boerwinkle, Eric; Bonnycastle, Lori; Burtt, Noël P.; Campbell, Harry; Charpentier, Guillaume; Collins, Francis S.; Gieger, Christian; Green, Todd; Hadjadj, Samy; Hattersley, Andrew T.; Herder, Christian; Hofman, Albert; Johnson, Andrew D.; Kottgen, Anna; Kraft, Peter; Labrune, Yann; Langenberg, Claudia; Manning, Alisa K.; Mohlke, Karen L.; Morris, Andrew P.; Oostra, Ben; Pankow, James; Petersen, Ann-Kristin; Pramstaller, Peter P.; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, William; Roden, Michael; Rudan, Igor; Rybin, Denis; Scott, Laura J.; Sigurdsson, Gunnar; Sladek, Rob; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vivequin, Sidonie; Weedon, Michael N.; Wright, Alan F.; Hu, Frank B.; Illig, Thomas; Kao, Linda; Meigs, James B.; Wilson, James F.; Stefansson, Kari; van Duijn, Cornelia; Altschuler, David; Morris, Andrew D.; Boehnke, Michael; McCarthy, Mark I.; Froguel, Philippe; Palmer, Colin N. A.; Wareham, Nicholas J.; Groop, Leif

    2012-01-01

    Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI?30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI?30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P?=?8.4×10?9, OR?=?1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P?=?0.04, OR?=?1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P?=?1.3×10?8, OR?=?1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P?=?0.02, OR?=?1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P?=?0.0002). In the lean analysis, we observed a weighted per-risk allele OR?=?1.13 [95% CI 1.10–1.17], P?=?3.2×10?14. This was larger than the same model fitted in the obese analysis where the OR?=?1.06 [95% CI 1.05–1.08], P?=?2.2×10?16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. PMID:22693455

  18. Genetic Diversity of Echinococcus granulosus in Southwest China Determined by the Mitochondrial NADH Dehydrogenase Subunit 2 Gene

    PubMed Central

    Wang, Jiahai; Wang, Ning; Hu, Dandan; Zhong, Xiuqin; Wang, Shuxian; Gu, Xiaobin; Peng, Xuerong; Yang, Guangyou

    2014-01-01

    We evaluated genetic diversity and structure of Echinococcus granulosus by analyzing the complete mitochondrial NADH dehydrogenase subunit 2 (ND2) gene in 51 isolates of E. granulosus sensu stricto metacestodes collected at three locations in this region. We detected 19 haplotypes, which formed a distinct clade with the standard sheep strain (G1). Hence, all 51 isolates were identified as E. granulosus sensu stricto (G1–G3). Genetic relationships among haplotypes were not associated with geographical divisions, and fixation indices (Fst) among sampling localities were low. Hence, regional populations of E. granulosus in the southwest China are not differentiated, as gene flow among them remains high. This information is important for formulating unified region-wide prevention and control measures. We found large negative Fu's Fs and Tajima's D values and a unimodal mismatch distribution, indicating that the population has undergone a demographic expansion. We observed high genetic diversity among the E. granulosus s. s. isolates, indicating that the parasite population in this important bioregion is genetically robust and likely to survive and spread. The data from this study will prove valuable for future studies focusing on improving diagnosis and prevention methods and developing robust control strategies. PMID:24592194

  19. A High-Throughput In Vitro Drug Screen in a Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma Identifies BMS-754807 as a Promising Therapeutic Agent

    PubMed Central

    Halvorson, Kyle G.; Barton, Kelly L.; Schroeder, Kristin; Misuraca, Katherine L.; Hoeman, Christine; Chung, Alex; Crabtree, Donna M.; Cordero, Francisco J.; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren J.

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 ?M, significant inhibition of proliferation at a concentration of 1.5 ?M, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice. PMID:25748921

  20. A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

    PubMed

    Halvorson, Kyle G; Barton, Kelly L; Schroeder, Kristin; Misuraca, Katherine L; Hoeman, Christine; Chung, Alex; Crabtree, Donna M; Cordero, Francisco J; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren J

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 ?M, significant inhibition of proliferation at a concentration of 1.5 ?M, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice. PMID:25748921

  1. What is a population? An empirical evaluation of some genetic methods for identifying the number of gene pools and their degree of connectivity.

    PubMed

    Waples, Robin S; Gaggiotti, Oscar

    2006-05-01

    We review commonly used population definitions under both the ecological paradigm (which emphasizes demographic cohesion) and the evolutionary paradigm (which emphasizes reproductive cohesion) and find that none are truly operational. We suggest several quantitative criteria that might be used to determine when groups of individuals are different enough to be considered 'populations'. Units for these criteria are migration rate (m) for the ecological paradigm and migrants per generation (Nm) for the evolutionary paradigm. These criteria are then evaluated by applying analytical methods to simulated genetic data for a finite island model. Under the standard parameter set that includes L = 20 High mutation (microsatellite-like) loci and samples of S = 50 individuals from each of n = 4 subpopulations, power to detect departures from panmixia was very high ( approximately 100%; P < 0.001) even with high gene flow (Nm = 25). A new method, comparing the number of correct population assignments with the random expectation, performed as well as a multilocus contingency test and warrants further consideration. Use of Low mutation (allozyme-like) markers reduced power more than did halving S or L. Under the standard parameter set, power to detect restricted gene flow below a certain level X (H(0): Nm < X) can also be high, provided that true Nm < or = 0.5X. Developing the appropriate test criterion, however, requires assumptions about several key parameters that are difficult to estimate in most natural populations. Methods that cluster individuals without using a priori sampling information detected the true number of populations only under conditions of moderate or low gene flow (Nm < or = 5), and power dropped sharply with smaller samples of loci and individuals. A simple algorithm based on a multilocus contingency test of allele frequencies in pairs of samples has high power to detect the true number of populations even with Nm = 25 but requires more rigorous statistical evaluation. The ecological paradigm remains challenging for evaluations using genetic markers, because the transition from demographic dependence to independence occurs in a region of high migration where genetic methods have relatively little power. Some recent theoretical developments and continued advances in computational power provide hope that this situation may change in the future. PMID:16629801

  2. Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual.

    PubMed

    Kajimura, Daisuke; Hinoi, Eiichi; Ferron, Mathieu; Kode, Aruna; Riley, Kyle J; Zhou, Bin; Guo, X Edward; Karsenty, Gerard

    2011-04-11

    The sympathetic nervous system, whose activity is regulated by leptin signaling in the brain, is a major regulator of bone mass accrual. To determine the identity of the cell type in which the sympathetic tone signals to inhibit bone mass accrual, we performed a systematic, cell-specific analysis of the function of the ?2 adrenergic receptor (Adr?2) and various genes implicated in the pathway in the mouse. This was followed by leptin intracerebroventricular (ICV) infusion and bone histomorphometric analyses of bone parameters. We show that the sympathetic tone signals in the osteoblasts to inhibit CREB (cAMP-responsive element-binding protein) phosphorylation and thus decrease osteoblast proliferation and to promote ATF4 phosphorylation and thus increase RANKL (receptor activator of NF-?B ligand) expression, which then stimulates osteoclast differentiation. Leptin ICV infusion in various mouse models established that leptin-dependent inhibition of bone mass accrual relies on both transcriptional events taking place in osteoblasts. Thus, this study formally identifies the osteoblast as the major cell type in which the molecular events triggered by the sympathetic regulation of bone mass accrual take place. As such, it suggests that inhibiting sympathetic signaling could be beneficial in the treatment of low bone mass conditions. PMID:21444660

  3. 41 CFR 102-75.775 - Is the disposal agency required to approve a determination by FEMA that identifies surplus...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    41 Public Contracts and Property Management 3 2010-07-01 2010-07-01...identifies surplus property for emergency management response use? 102-75.775 Section...775 Public Contracts and Property Management Federal Property Management...

  4. The Roles of Standing Genetic Variation and Evolutionary History in Determining the Evolvability of Anti-Predator Strategies

    PubMed Central

    Dworkin, Ian; Wagner, Aaron P.

    2014-01-01

    Standing genetic variation and the historical environment in which that variation arises (evolutionary history) are both potentially significant determinants of a population's capacity for evolutionary response to a changing environment. Using the open-ended digital evolution software Avida, we evaluated the relative importance of these two factors in influencing evolutionary trajectories in the face of sudden environmental change. We examined how historical exposure to predation pressures, different levels of genetic variation, and combinations of the two, affected the evolvability of anti-predator strategies and competitive abilities in the presence or absence of threats from new, invasive predator populations. We show that while standing genetic variation plays some role in determining evolutionary responses, evolutionary history has the greater influence on a population's capacity to evolve anti-predator traits, i.e. traits effective against novel predators. This adaptability likely reflects the relative ease of repurposing existing, relevant genes and traits, and the broader potential value of the generation and maintenance of adaptively flexible traits in evolving populations. PMID:24955847

  5. The European Prader-Willi Syndrome Clinical Research Database: An Aid in the Investigation of a Rare Genetically Determined Neurodevelopmental Disorder

    ERIC Educational Resources Information Center

    Holland, A.; Whittington, J.; Cohen, O.; Curfs, L.; Delahaye, F.; Dudley, O.; Horsthemke, B.; Lindgren, A. -C.; Nourissier, C.; Sharma, N.; Vogels, A.

    2009-01-01

    Background: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research…

  6. Genetic Screen of a Library of Chimeric Poxviruses Identifies an Ankyrin Repeat Protein Involved in Resistance to the Avian Type I Interferon Response

    PubMed Central

    Buttigieg, Karen; Laidlaw, Stephen M.; Ross, Craig; Davies, Marc; Goodbourn, Stephen

    2013-01-01

    Viruses must be able to resist host innate responses, especially the type I interferon (IFN) response. They do so by preventing the induction or activity of IFN and/or by resisting the antiviral effectors that it induces. Poxviruses are no exception, with many mechanisms identified whereby mammalian poxviruses, notably, vaccinia virus (VACV), but also cowpox and myxoma viruses, are able to evade host IFN responses. Similar mechanisms have not been described for avian poxviruses (avipoxviruses). Restricted for permissive replication to avian hosts, they have received less attention; moreover, the avian host responses are less well characterized. We show that the prototypic avipoxvirus, fowlpox virus (FWPV), is highly resistant to the antiviral effects of avian IFN. A gain-of-function genetic screen identified fpv014 to contribute to increased resistance to exogenous recombinant chicken alpha IFN (ChIFN1). fpv014 is a member of the large family of poxvirus (especially avipoxvirus) genes that encode proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. By binding the Skp1/cullin-1 complex, the F box in such proteins appears to target ligands bound by the ANKs for ubiquitination. Mass spectrometry and immunoblotting demonstrated that tandem affinity-purified, tagged fpv014 was complexed with chicken cullin-1 and Skp1. Prior infection with an fpv014-knockout mutant of FWPV still blocked transfected poly(I·C)-mediated induction of the beta IFN (ChIFN2) promoter as effectively as parental FWPV, but the mutant was more sensitive to exogenous ChIFN1. Therefore, unlike the related protein fpv012, fpv014 does not contribute to the FWPV block to induction of ChIFN2 but does confer resistance to an established antiviral state. PMID:23427151

  7. Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

    PubMed Central

    Nho, K; Corneveaux, JJ; Kim, S; Lin, H; Risacher, SL; Shen, L; Swaminathan, S; Ramanan, VK; Liu, Y; Foroud, T; Inlow, MH; Siniard, AL; Reiman, RA; Aisen, PS; Petersen, RC; Green, RC; Jack, CR; Weiner, MW; Baldwin, CT; Lunetta, K; Farrer, LA; Furney, SJ; Lovestone, S; Simmons, A; Mecocci, P; Vellas, B; Tsolaki, M; Kloszewska, I; Soininen, H; McDonald, BC; Farlow, MR; Ghetti, B; Huentelman, MJ; Saykin, AJ

    2013-01-01

    Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ?4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ?3 homozygous male Caucasian participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as ‘probably damaging’ missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ?3/?3 group (N =315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ?3/?3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ?3/?3 individuals (N =923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration. PMID:23608917

  8. Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

    PubMed

    Nho, K; Corneveaux, J J; Kim, S; Lin, H; Risacher, S L; Shen, L; Swaminathan, S; Ramanan, V K; Liu, Y; Foroud, T; Inlow, M H; Siniard, A L; Reiman, R A; Aisen, P S; Petersen, R C; Green, R C; Jack, C R; Weiner, M W; Baldwin, C T; Lunetta, K; Farrer, L A; Furney, S J; Lovestone, S; Simmons, A; Mecocci, P; Vellas, B; Tsolaki, M; Kloszewska, I; Soininen, H; McDonald, B C; Farlow, M R; Ghetti, B; Huentelman, M J; Saykin, A J

    2013-07-01

    Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ?4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ?3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ?3/?3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ?3/?3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ?3/?3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration. PMID:23608917

  9. Genetic screen of a library of chimeric poxviruses identifies an ankyrin repeat protein involved in resistance to the avian type I interferon response.

    PubMed

    Buttigieg, Karen; Laidlaw, Stephen M; Ross, Craig; Davies, Marc; Goodbourn, Stephen; Skinner, Michael A

    2013-05-01

    Viruses must be able to resist host innate responses, especially the type I interferon (IFN) response. They do so by preventing the induction or activity of IFN and/or by resisting the antiviral effectors that it induces. Poxviruses are no exception, with many mechanisms identified whereby mammalian poxviruses, notably, vaccinia virus (VACV), but also cowpox and myxoma viruses, are able to evade host IFN responses. Similar mechanisms have not been described for avian poxviruses (avipoxviruses). Restricted for permissive replication to avian hosts, they have received less attention; moreover, the avian host responses are less well characterized. We show that the prototypic avipoxvirus, fowlpox virus (FWPV), is highly resistant to the antiviral effects of avian IFN. A gain-of-function genetic screen identified fpv014 to contribute to increased resistance to exogenous recombinant chicken alpha IFN (ChIFN1). fpv014 is a member of the large family of poxvirus (especially avipoxvirus) genes that encode proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. By binding the Skp1/cullin-1 complex, the F box in such proteins appears to target ligands bound by the ANKs for ubiquitination. Mass spectrometry and immunoblotting demonstrated that tandem affinity-purified, tagged fpv014 was complexed with chicken cullin-1 and Skp1. Prior infection with an fpv014-knockout mutant of FWPV still blocked transfected poly(I·C)-mediated induction of the beta IFN (ChIFN2) promoter as effectively as parental FWPV, but the mutant was more sensitive to exogenous ChIFN1. Therefore, unlike the related protein fpv012, fpv014 does not contribute to the FWPV block to induction of ChIFN2 but does confer resistance to an established antiviral state. PMID:23427151

  10. Genetic determinants of individual differences in avoidance learning: Behavioral and endocrine characteristics

    Microsoft Academic Search

    F. R. Brush; W. Lafayette

    1991-01-01

    Bidirectional genetic selection for good and poor active avoidance learning in a shuttle box has been carried out in three independent laboratories using remarkably similar discrete-trial training procedures. The resulting strains are known as the Roman High and Low Avoidance (RHA and RLA), the Syracuse High and Low Avoidance (SHA and SLA) and the Australian High and Low Avoidance (AHA

  11. Genetic distances and variations of three clupeid species determined by PCR technique.

    PubMed

    Choi, Sang-Hoon; Yoon, Jong-Man

    2014-12-01

    In this study, seven oligonucleotides primers were shown to generate the shared loci, specific loci, unique shared loci to each species and shared loci by the three species which could be obviously calculated. Euclidean genetic distances within- and between-species were also calculated by complete linkage method with the sustenance of the hierarchical dendevrepogram program Systat version 13. The genomic DNA isolated from herring (Clupea pallasii), Korean anchovy (Coilia nasus) and large-eyed herring (Harengula zunashi), respectively, in the Yellow Sea, were amplified several times by PCR reaction. The hierarchical dendevrepogram shows three chief branches: cluster 1 (PALLASII 01, 02, 03, 04, 06 and 07), cluster 2 (NASUS 08, 09, 10, 11, 12, 13 and 14), and cluster 3 (ZUNASHI 15, 16, 17, 18, 19, 20, 21 and PALLASII 05). In three clupeid species, the shortest genetic distance displaying significant molecular difference was between individual PALLASII no. 03 and PALLASII no. 02 (0.018). Individual no. 06 of PALLASII was most distantly related to NASUS no. 11 (genetic distance = 0.318). Individuals from herring (C. pallasii) species (0.920) exhibited higher bandsharing values than did individuals from Korean anchovy (C. nasus) species (0.872) (P<0.05). As a result, this PCR analysis generated on the genetic data displayed that the herring (C. pallasii) species was widely separated from Korean anchovy (C. nasus) species. Reversely, individuals of Korean anchovy (C. nasus) species were a little closely related to those of large-eyed herring (H. zunashi) species. PMID:25949199

  12. Genetic Distances and Variations of Three Clupeid Species Determined by PCR Technique

    PubMed Central

    Choi, Sang-Hoon; Yoon, Jong-Man

    2014-01-01

    In this study, seven oligonucleotides primers were shown to generate the shared loci, specific loci, unique shared loci to each species and shared loci by the three species which could be obviously calculated. Euclidean genetic distances within- and between-species were also calculated by complete linkage method with the sustenance of the hierarchical dendevrepogram program Systat version 13. The genomic DNA isolated from herring (Clupea pallasii), Korean anchovy (Coilia nasus) and large-eyed herring (Harengula zunashi), respectively, in the Yellow Sea, were amplified several times by PCR reaction. The hierarchical dendevrepogram shows three chief branches: cluster 1 (PALLASII 01, 02, 03, 04, 06 and 07), cluster 2 (NASUS 08, 09, 10, 11, 12, 13 and 14), and cluster 3 (ZUNASHI 15, 16, 17, 18, 19, 20, 21 and PALLASII 05). In three clupeid species, the shortest genetic distance displaying significant molecular difference was between individual PALLASII no. 03 and PALLASII no. 02 (0.018). Individual no. 06 of PALLASII was most distantly related to NASUS no. 11 (genetic distance = 0.318). Individuals from herring (C. pallasii) species (0.920) exhibited higher bandsharing values than did individuals from Korean anchovy (C. nasus) species (0.872) (P<0.05). As a result, this PCR analysis generated on the genetic data displayed that the herring (C. pallasii) species was widely separated from Korean anchovy (C. nasus) species. Reversely, individuals of Korean anchovy (C. nasus) species were a little closely related to those of large-eyed herring (H. zunashi) species. PMID:25949199

  13. Determining rice cooking, processing, and sensory quality through the use of genetic markers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rice molecular markers have been developed that are associated with genes which control amylose content, gelatinization temperature, aroma, cooked kernel elongation, and RVA paste viscosity properties. These genetic markers can be used to predict rice cooking, sensory, and processing quality in ric...

  14. Genetic variability in spotted seatrout (Cynoscion nebulosus), determined with microsatellite DNA markers

    USGS Publications Warehouse

    Ward, R.; Bowers, K.; Hensley, R.; Mobley, B.; Belouski, E.

    2007-01-01

    Variation in the allele frequencies of five microsatellite loci was surveyed in 1256 individual spotted seatrout (Cynoscion nebulosus) obtained from 12 bays and estuaries from Laguna Madre, Texas, to Charlotte Harbor, Florida, to St. John's River on the Florida Atlantic Coast. Texas and Louisiana collection sites were resampled each year for two to four years (1998-2001). Genetic differentiation was observed. Spotted seatrout from Florida waters were strongly differentiated from spotted seatrout collected in Louisiana and Texas. The greatest genetic discontinuity was observed between Tampa Bay and Charlotte Harbor, and Charlotte Harbor seatrout were most similar to Atlantic Coast spotted seatrout. Texas and Louisiana samples were not strongly structured within the northwestern Gulf of Mexico and there was little evidence of temporal differentiation within bays. These findings are contrary to those of earlier analyses with allozymes and mitochondrial DNA (mtDNA) where evidence of spatial differentiation was found for spotted seatrout resident on the Texas coast. The differences in genetic structure observed among these markers may reflect differences in response to selective pressure, or may be due to differences in underlying genetic processes.

  15. Selection and determination of beam weights based on genetic algorithms for conformal radiotherapy treatment planning

    Microsoft Academic Search

    Xingen Wu; Yunping Zhu; Jianrong Dai; Zunliang Wang

    2000-01-01

    A genetic algorithm has been used to optimize the selection of beam weights for external beam three-dimensional conformal radiotherapy treatment planning. A fitness function is defined, which includes a difference function to achieve a least-square fit to doses at preselected points in a planning target volume, and a penalty item to constrain the maximum allowable doses delivered to critical organs.

  16. A Genetic Screen for Pathogenicity Genes in the Hemibiotrophic Fungus Colletotrichum higginsianum Identifies the Plasma Membrane Proton Pump Pma2 Required for Host Penetration

    PubMed Central

    Dahl, Marlis; Müller, Susanne; Voll, Lars M.; Koch, Christian

    2015-01-01

    We used insertional mutagenesis by Agrobacterium tumefaciens mediated transformation (ATMT) to isolate pathogenicity mutants of Colletotrichum higginsianum. From a collection of 7200 insertion mutants we isolated 75 mutants with reduced symptoms. 19 of these were affected in host penetration, while 17 were affected in later stages of infection, like switching to necrotrophic growth. For 16 mutants the location of T-DNA insertions could be identified by PCR. A potential plasma membrane H+-ATPase Pma2 was targeted in five independent insertion mutants. We genetically inactivated the Ku80 component of the non-homologous end-joining pathway in C. higginsianum to establish an efficient gene knockout protocol. Chpma2 deletion mutants generated by homologous recombination in the ?Chku80 background form fully melanized appressoria but entirely fail to penetrate the host tissue and are non-pathogenic. The ChPMA2 gene is induced upon appressoria formation and infection of A. thaliana. Pma2 activity is not important for vegetative growth of saprophytically growing mycelium, since the mutant shows no growth penalty under these conditions. Colletotrichum higginsianum codes for a closely related gene (ChPMA1), which is highly expressed under most growth conditions. ChPMA1 is more similar to the homologous yeast genes for plasma membrane pumps. We propose that expression of a specific proton pump early during infection may be common to many appressoria forming fungal pathogens as we found ChPMA2 orthologs in several plant pathogenic fungi. PMID:25992547

  17. Differential plague-transmission dynamics determine Yersinia pestis population genetic structure on local, regional, and global scales

    PubMed Central

    Girard, Jessica M.; Wagner, David M.; Vogler, Amy J.; Keys, Christine; Allender, Christopher J.; Drickamer, Lee C.; Keim, Paul

    2004-01-01

    Plague, the disease caused by the bacterium Yersinia pestis, has greatly impacted human civilization. Y. pestis is a successful global pathogen, with active foci on all continents except Australia and Antarctica. Because the Y. pestis genome is highly monomorphic, previous attempts to characterize the population genetic structure within a single focus have been largely unsuccessful. Here we report that highly mutable marker loci allow determination of Y. pestis population genetic structure and tracking of transmission patterns at two spatial scales within a single focus. In addition, we found that in vitro mutation rates for these loci are similar to those observed in vivo, which allowed us to develop a mutation-rate-based model to examine transmission mechanisms. Our model suggests there are two primary components of plague ecology: a rapid expansion phase for population growth and dispersal followed by a slower persistence phase. This pattern seems consistent across local, regional, and even global scales. PMID:15173603

  18. Castra, J., Sarapuu, T., & Clment, P. (2013). Comparison of French and Estonian students' conceptions in genetic determinism of human behaviours. Journal of Biological Education, 47(1), 12-20.

    E-print Network

    Paris-Sud XI, Université de

    2013-01-01

    ' conceptions in genetic determinism of human behaviours. Journal of Biological Education, 47(1), 12-20. (on of French and Estonian students' conceptions in genetic determinism of human behaviours PrePrint Jérémy of French and Estonian students' conceptions in genetic determinism of human behaviours hal-01024531,version

  19. Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents

    PubMed Central

    2010-01-01

    Background Inactivation of the Fanconi anemia (FA) pathway through defects in one of 13 FA genes occurs at low frequency in various solid cancer entities among the general population. As FA pathway inactivation confers a distinct hypersensitivity towards DNA interstrand-crosslinking (ICL)-agents, FA defects represent rational targets for individualized therapeutic strategies. Except for pancreatic cancer, however, the prevalence of FA defects in gastrointestinal (GI) tumors has not yet been systematically explored. Results A panel of GI cancer cell lines was screened for FA pathway inactivation applying FANCD2 monoubiquitination and FANCD2/RAD51 nuclear focus formation and a newly identified FA pathway-deficient cell line was functionally characterized. The hepatocellular carcinoma (HCC) line HuH-7 was defective in FANCD2 monoubiquitination and FANCD2 nuclear focus formation but proficient in RAD51 focus formation. Gene complementation studies revealed that this proximal FA pathway inactivation was attributable to defective FANCC function in HuH-7 cells. Accordingly, a homozygous inactivating FANCC nonsense mutation (c.553C > T, p.R185X) was identified in HuH-7, resulting in partial transcriptional skipping of exon 6 and leading to the classic cellular FA hypersensitivity phenotype; HuH-7 cells exhibited a strongly reduced proliferation rate and a pronounced G2 cell cycle arrest at distinctly lower concentrations of ICL-agents than a panel of non-isogenic, FA pathway-proficient HCC cell lines. Upon retroviral transduction of HuH-7 cells with FANCC cDNA, FA pathway functions were restored and ICL-hypersensitivity abrogated. Analyses of 18 surgical HCC specimens yielded no further examples for genetic or epigenetic inactivation of FANCC, FANCF, or FANCG in HCC, suggesting a low prevalence of proximal FA pathway inactivation in this tumor type. Conclusions As the majority of HCC are chemoresistant, assessment of FA pathway function in HCC could identify small subpopulations of patients expected to predictably benefit from individualized treatment protocols using ICL-agents. PMID:20509860

  20. Genetic screen identifies suppressor of morphogenesis in genitalia-1 (SMG-1) as a modulator of sorafenib resistance in hepatocellular carcinoma cell lines.

    PubMed

    Nam, Soon Woo; Park, Ki Cheol; Yang, Keum Jin; Lee, Byoungchun; Kim, Sung-Woo

    2014-10-01

    Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis and a very complex dysregulated molecular etiology. Furthermore, conventional therapy thus far has had only limited success. A recently developed oral multikinase inhibitor, sorafenib, has been used to improve survival in HCC patients, however, follow?up studies have revealed a high rate of cancer recurrence. Therefore, identification of genes involved in sorafenib resistance is urgently required. RNA interference (RNAi) is a powerful tool for performing loss-of-function genetic screens and can facilitate the identification of components of the cellular signaling pathway. This study describes the results of an unbiased genomic screening using RNAi in an HCC cell line to elucidate genes related to sorafenib non-responsiveness or resistance. A genome-wide in vitro RNA interference screen revealed the role of suppressor of morphogenesis in genitalia-1 (SMG-1) as a determinant of sorafenib resistance. The inhibition of SMG-1 reduced sorafenib sensitivity in the studied HCC cell lines. An immunohistochemical comparison of cancerous and non?cancerous regions showed strong staining in the non?neoplastic hepatocyte regions of HCC. SMG-1 may warrant investigation as an agent to reverse sorafenib resistance. PMID:25017961

  1. Genetic Variability and Determinism of Adaptation of Plants to Soil Waterlogging

    Microsoft Academic Search

    Julien Parelle; Erwin Dreyer; Oliver Brendel

    \\u000a Flooding or waterlogging, and associated soil hypoxia, affect severely the growth and fitness of plant species, from crops\\u000a to forest ecosystems. An improved understanding of the intra-species genetic diversity of traits involved in hypoxia tolerance\\u000a is a prerequisite for crop breeding programmes aimed at increasing the tolerance to waterlogging, as well as for assessing\\u000a the adaptability of natural populations to

  2. Genetic Determinants for Gestational Diabetes Mellitus and Related Metabolic Traits in Mexican Women

    PubMed Central

    Huerta-Chagoya, Alicia; Vázquez-Cárdenas, Paola; Moreno-Macías, Hortensia; Tapia-Maruri, Leonardo; Rodríguez-Guillén, Rosario; López-Vite, Erika; García-Escalante, Guadalupe; Escobedo-Aguirre, Fernando; Parra-Covarrubias, Adalberto; Cordero-Brieño, Roberto; Manzo-Carrillo, Lizette; Zacarías-Castillo, Rogelio; Aguilar-Salinas, Carlos; Tusié-Luna, Teresa

    2015-01-01

    Epidemiological and physiological similarities among Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes (T2D) suggest that both diseases, share a common genetic background. T2D risk variants have been associated to GDM susceptibility. However, the genetic architecture of GDM is not yet completely understood. We analyzed 176 SNPs for 115 loci previously associated to T2D, GDM and body mass index (BMI), as well as a set of 118 Ancestry Informative Markers (AIMs), in 750 pregnant Mexican women. Association with GDM was found for two of the most frequently replicated T2D loci: a TCF7L2 haplotype (CTTC: rs7901695, rs4506565, rs7903146, rs12243326; P=2.16x10-06; OR=2.95) and a KCNQ1 haplotype (TTT: rs2237892, rs163184, rs2237897; P=1.98x10-05; OR=0.55). In addition, we found two loci associated to glycemic traits: CENTD2 (60’ OGTT glycemia: rs1552224, P=0.03727) and MTNR1B (HOMA B: rs1387153, P=0.05358). Remarkably, a major susceptibility SLC16A11 locus for T2D in Mexicans was not shown to play a role in GDM risk. The fact that two of the main T2D associated loci also contribute to the risk of developing GDM in Mexicans, confirm that both diseases share a common genetic background. However, lack of association with a Native American contribution T2D risk haplotype, SLC16A11, suggests that other genetic mechanisms may be in play for GDM. PMID:25973943

  3. Impact of Genetic and Environmental Determinants of Taste with Food Preferences in Older Adults

    Microsoft Academic Search

    Alejandra Navarro-Allende; Nora Khataan; Ahmed El-Sohemy

    2008-01-01

    Individual differences in the ability to detect bitter tasting compounds, such as phenylthiocarbamide (PTC) or its derivative, 6-n-propylthiouracil (PROP) has long been recognized as a common genetic trait. This observation has been proposed to explain some of the variability in the dietary habits of a population. Several members of the TAS2R receptor gene family encode taste receptors on the tongue,

  4. PNPLA3 genetic variants determine hepatic steatosis in non-obese chronic hepatitis C patients

    PubMed Central

    Huang, Chung-Feng; Chen, Jyh-Jou; Yeh, Ming-Lun; Huang, Ching-I; Hsieh, Ming-Yen; Yang, Hua-Ling; Dai, Chia-Yen; Huang, Jee-Fu; Lin, Zu-Yau; Chen, Shinn-Cherng; Chuang, Wan-Long; Chen, Yao-Li; Yu, Ming-Lung

    2015-01-01

    The influence of patatin-like phospholipase domain-containing 3 (PNPLA3) genetic variants in the development of liver steatosis in Asian chronic hepatitis C patients remains elusive. A total of 1018 biopsy-proven chronic hepatitis C patients were enrolled for evaluation. The proportions of PNPLA3 rs738409 GG genotype carriage were 7.8% (44/563), 15.8% (58/367) and 19.3% (17/88) in patients with no (liver fat content <5%), mild (5–33%) and moderate/severe (>66%) hepatic steatosis, respectively (trend P?genetic variants had minimal effects on hepatic steatosis among overweight or obese patients. Compared to patients with BMI<24?kg/m2/non-GG genotype, those with BMI>24?kg/m2/GG genotype were more likely to have hepatic steatosis (OR/CI:3.87/2.292–6.524, P?genetic variants and BMI played important roles in hepatic steatosis among Asian chronic hepatitis C patients. However, the genetic effect was mainly restricted to non-obese patients. PMID:26139292

  5. Pharmacogenetics and Pharmacogenomics II: Genetic Determinants of Drug Responses and Adverse Drug Reactions

    Microsoft Academic Search

    Stephane Dalle; Sandra Knowles; Neil H. Shear

    \\u000a The ability to predict efficacy and safety is crucial for drug discovery and development. To date, there are only a few genetic\\u000a biomarkers whose clinical validity in predicting drug response has been clearly established; for example, HER-2\\/neu-positivity\\u000a in breast cancer as a predictor of response to trastuzumab (Herceptin) [1]. Patient variability in response to medications\\u000a can range from failure to

  6. Application of rapd in the determination of genetic fidelity in micropropagated Drosera plantlets

    Microsoft Academic Search

    Anna Kawiak; Ewa ?ojkowska

    2004-01-01

    Summary  Random amplified polymorphic DNA (RAPD) markers were used to verify the clonal fidelity of two micropropagated Drosera species, D. anglica and D. binata, which were regenerated by adventitious budding from leaf explants and shoot tips, respectively. Twenty arbitrary decamers\\u000a were used to screen 15 randomly selected plantlets of each species. No genetic variation was detected among D. binata regenerants, whereas

  7. Genetic diversity of Brucella abortus isolates as determined by amplified fragment length polymorphism (AFLP) analysis

    E-print Network

    Bliss, Katherine Ann

    2013-02-22

    the Bacillus isolates were consistent with geographic distribution and the current theoretical origin of B. anthracis. A study of the molecular diversity of Vibrio cholerae was published in 2000 by Sunny C. Jiang, et al. (7), analyzed sixty-seven V. cholerae.... Molecular evolution and diversity in Bacillus anthracis as detected by amplified fragment length polymorphism markers. Jour of Bacteriol. 179(3): 818-824. 1997. 7. Jiang, Sunny C. , et al. Genetic diversityofclinical and environmental isolates of Vibrio...

  8. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study

    E-print Network

    Zhang, Chenan; Doherty, Jennifer A.; Burgess, Stephen; Hung, Rayjean J.; Lindström, Sara; Kraft, Peter; Gong, Jian; Amos, Christopher; Sellers, Thomas A.; Monteiro, Alvaro N.A.; Chenevix-Trench, Georgia; Bickeböller, Heike; Risch, Angela; Brennan, Paul; McKay, James; Houlston, Richard; Landi, Maria Teresa; Timofeeva, Maria; Wang, Yufei; Heinrich, Joachim; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Muir, Ken; Wiklund, Fredrik; Grönberg, Henrik; Berndt, Sonja I.; Chanock, Stephen J.; Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.; Amin Al Olama, Ali; Andrulis, Irene L.; Hopper, John L.; Chang-Claude, Jenny; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Ursin, Giske; Whittemore, Alice S.; Hunter, David J.; Gruber, Stephen B.; Knight, Julia A.; Hou, Lifang; Le Marchand, Loic; Newcomb, Polly A.; Hudson, Thomas J.; Chan, Andrew T.; Li, Li; Woods, Michael O.; Ahsan, Habibul; Pierce, Brandon L.

    2015-07-02

    was included in the analysis. Although the estimates for these 9 SNPs were obtained from three different studies using two different methods (quantitative PCR and Southern blot of the terminal restriction fragment), we scaled the estimates to the same units... of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA 23Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 24Molecular...

  9. Genetic determinants for gestational diabetes mellitus and related metabolic traits in mexican women.

    PubMed

    Huerta-Chagoya, Alicia; Vázquez-Cárdenas, Paola; Moreno-Macías, Hortensia; Tapia-Maruri, Leonardo; Rodríguez-Guillén, Rosario; López-Vite, Erika; García-Escalante, Guadalupe; Escobedo-Aguirre, Fernando; Parra-Covarrubias, Adalberto; Cordero-Brieño, Roberto; Manzo-Carrillo, Lizette; Zacarías-Castillo, Rogelio; Vargas-García, Carlos; Aguilar-Salinas, Carlos; Tusié-Luna, Teresa

    2015-01-01

    Epidemiological and physiological similarities among Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes (T2D) suggest that both diseases, share a common genetic background. T2D risk variants have been associated to GDM susceptibility. However, the genetic architecture of GDM is not yet completely understood. We analyzed 176 SNPs for 115 loci previously associated to T2D, GDM and body mass index (BMI), as well as a set of 118 Ancestry Informative Markers (AIMs), in 750 pregnant Mexican women. Association with GDM was found for two of the most frequently replicated T2D loci: a TCF7L2 haplotype (CTTC: rs7901695, rs4506565, rs7903146, rs12243326; P=2.16x10-06; OR=2.95) and a KCNQ1 haplotype (TTT: rs2237892, rs163184, rs2237897; P=1.98x10-05; OR=0.55). In addition, we found two loci associated to glycemic traits: CENTD2 (60' OGTT glycemia: rs1552224, P=0.03727) and MTNR1B (HOMA B: rs1387153, P=0.05358). Remarkably, a major susceptibility SLC16A11 locus for T2D in Mexicans was not shown to play a role in GDM risk. The fact that two of the main T2D associated loci also contribute to the risk of developing GDM in Mexicans, confirm that both diseases share a common genetic background. However, lack of association with a Native American contribution T2D risk haplotype, SLC16A11, suggests that other genetic mechanisms may be in play for GDM. PMID:25973943

  10. Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

    PubMed Central

    Casadémont, Isabelle; Peerapittayamonkol, Chayanon; Rogier, Christophe; Tortevoye, Patricia; Tall, Adama; Paul, Richard; Turbpaiboon, Chairat; Phimpraphi, Waraphon; Trape, Jean-Francois; Spiegel, André; Heath, Simon; Mercereau-Puijalon, Odile; Dieye, Alioune; Julier, Cécile

    2008-01-01

    Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD?=?2.26, empirical p?=?0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD?=?2.57, empirical p?=?0.001, Dielmo) and 13q13 (LOD?=?2.37, empirical p?=?0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD?=?3.1, empirical p<10?4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved. PMID:18431485

  11. Male dominance and genetically determined reproductive success in the mandrill ( Mandrillus sphinx )

    Microsoft Academic Search

    A. F. Dixson; T. Bossi; E. J. Wickings

    1993-01-01

    Darwin referred to the adult male mandrill (Mandrillus sphinx) as the most brightly coloured of all mammals, citing the brilliant red and blue pigmentation of the face, rump, and genitalia\\u000a as extreme examples of evolution by sexual selection. Considerable controversy exists concerning possible effects of sexually\\u000a selected phenotypes via intermale competition on reproductive success. Behavioural and genetic studies of a

  12. Determination of the genetic diversity of vegetable soybean [Glycine max (L.) Merr.] using EST-SSR markers*

    PubMed Central

    Zhang, Gu-wen; Xu, Sheng-chun; Mao, Wei-hua; Hu, Qi-zan; Gong, Ya-ming

    2013-01-01

    The development of expressed sequence tag-derived simple sequence repeats (EST-SSRs) provided a useful tool for investigating plant genetic diversity. In the present study, 22 polymorphic EST-SSRs from grain soybean were identified and used to assess the genetic diversity in 48 vegetable soybean accessions. Among the 22 EST-SSR loci, tri-nucleotides were the most abundant repeats, accounting for 50.00% of the total motifs. GAA was the most common motif among tri-nucleotide repeats, with a frequency of 18.18%. Polymorphic analysis identified a total of 71 alleles, with an average of 3.23 per locus. The polymorphism information content (PIC) values ranged from 0.144 to 0.630, with a mean of 0.386. Observed heterozygosity (H o) values varied from 0.0196 to 1.0000, with an average of 0.6092, while the expected heterozygosity (H e) values ranged from 0.1502 to 0.6840, with a mean value of 0.4616. Principal coordinate analysis and phylogenetic tree analysis indicated that the accessions could be assigned to different groups based to a large extent on their geographic distribution, and most accessions from China were clustered into the same groups. These results suggest that Chinese vegetable soybean accessions have a narrow genetic base. The results of this study indicate that EST-SSRs from grain soybean have high transferability to vegetable soybean, and that these new markers would be helpful in taxonomy, molecular breeding, and comparative mapping studies of vegetable soybean in the future. PMID:23549845

  13. Genetic Architecture of Aluminum Tolerance in Rice (Oryza sativa) Determined through Genome-Wide Association Analysis and QTL Mapping

    PubMed Central

    Famoso, Adam N.; Zhao, Keyan; Clark, Randy T.; Tung, Chih-Wei; Wright, Mark H.; Bustamante, Carlos; Kochian, Leon V.; McCouch, Susan R.

    2011-01-01

    Aluminum (Al) toxicity is a primary limitation to crop productivity on acid soils, and rice has been demonstrated to be significantly more Al tolerant than other cereal crops. However, the mechanisms of rice Al tolerance are largely unknown, and no genes underlying natural variation have been reported. We screened 383 diverse rice accessions, conducted a genome-wide association (GWA) study, and conducted QTL mapping in two bi-parental populations using three estimates of Al tolerance based on root growth. Subpopulation structure explained 57% of the phenotypic variation, and the mean Al tolerance in Japonica was twice that of Indica. Forty-eight regions associated with Al tolerance were identified by GWA analysis, most of which were subpopulation-specific. Four of these regions co-localized with a priori candidate genes, and two highly significant regions co-localized with previously identified QTLs. Three regions corresponding to induced Al-sensitive rice mutants (ART1, STAR2, Nrat1) were identified through bi-parental QTL mapping or GWA to be involved in natural variation for Al tolerance. Haplotype analysis around the Nrat1 gene identified susceptible and tolerant haplotypes explaining 40% of the Al tolerance variation within the aus subpopulation, and sequence analysis of Nrat1 identified a trio of non-synonymous mutations predictive of Al sensitivity in our diversity panel. GWA analysis discovered more phenotype–genotype associations and provided higher resolution, but QTL mapping identified critical rare and/or subpopulation-specific alleles not detected by GWA analysis. Mapping using Indica/Japonica populations identified QTLs associated with transgressive variation where alleles from a susceptible aus or indica parent enhanced Al tolerance in a tolerant Japonica background. This work supports the hypothesis that selectively introgressing alleles across subpopulations is an efficient approach for trait enhancement in plant breeding programs and demonstrates the fundamental importance of subpopulation in interpreting and manipulating the genetics of complex traits in rice. PMID:21829395

  14. Identifying Genotype-by-Environment Interactions in the Metabolism of Germinating Arabidopsis Seeds Using Generalized Genetical Genomics 1[C][W][OA

    PubMed Central

    Joosen, Ronny Viktor Louis; Arends, Danny; Li, Yang; Willems, Leo A.J.; Keurentjes, Joost J.B.; Ligterink, Wilco; Jansen, Ritsert C.; Hilhorst, Henk W.M.

    2013-01-01

    A complex phenotype such as seed germination is the result of several genetic and environmental cues and requires the concerted action of many genes. The use of well-structured recombinant inbred lines in combination with “omics” analysis can help to disentangle the genetic basis of such quantitative traits. This so-called genetical genomics approach can effectively capture both genetic and epistatic interactions. However, to understand how the environment interacts with genomic-encoded information, a better understanding of the perception and processing of environmental signals is needed. In a classical genetical genomics setup, this requires replication of the whole experiment in different environmental conditions. A novel generalized setup overcomes this limitation and includes environmental perturbation within a single experimental design. We developed a dedicated quantitative trait loci mapping procedure to implement this approach and used existing phenotypical data to demonstrate its power. In addition, we studied the genetic regulation of primary metabolism in dry and imbibed Arabidopsis (Arabidopsis thaliana) seeds. In the metabolome, many changes were observed that were under both environmental and genetic controls and their interaction. This concept offers unique reduction of experimental load with minimal compromise of statistical power and is of great potential in the field of systems genetics, which requires a broad understanding of both plasticity and dynamic regulation. PMID:23606598

  15. Identifying Genes in Monoamine Nuclei that may Determine Stress Vulnerability and Depressive Behavior in Wistar–Kyoto Rats

    PubMed Central

    Pearson, Kimberly A; Stephen, Alisson; Beck, Sheryl G; Valentino, Rita J

    2010-01-01

    The Wistar–Kyoto (WKY) rat is stress sensitive and exhibits depressive-like behavior. The locus coeruleus (LC)–norepinephrine and dorsal raphe (DR)–serotonin systems mediate certain aspects of the stress response and have been implicated in depression. Microarray technology was used to identify gene expression differences in the LC and DR between WKY vs Sprague–Dawley (SD) rats that might account for the WKY phenotype. RNA was isolated from microdissected LC and DR, amplified, and hybridized to microarrays (1 array/subject, n = 4/group). Significance of microarray (SAM) analysis revealed increased expression of 66 genes in the LC and 19 genes in the DR and decreased expression of 33 genes in the DR of WKY rats. Hierarchical clustering identified differences in gene expression profiles of WKY vs SD rats that generally concurred with SAM. Notably, genes that encoded for enzymes involved in norepinephrine turnover, amino-acid receptors, and certain G-protein-coupled receptors were elevated in the LC of WKY rats. The DR of WKY rats showed decreased expression of genes encoding several potassium channels and neurofilament genes. The chromosomal locations of 15 genes that were differentially expressed in WKY rats were near loci identified as contributing to depressive-like behaviors in the rat. The specific genes revealed by the present analysis as being differentially expressed in WKY rats may contribute to their unique behavioral profile and suggest targets that confer susceptibility to stress-related psychiatric disorders. PMID:16710313

  16. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category.

    PubMed

    Metzeler, Klaus H; Becker, Heiko; Maharry, Kati; Radmacher, Michael D; Kohlschmidt, Jessica; Mrózek, Krzysztof; Nicolet, Deedra; Whitman, Susan P; Wu, Yue-Zhong; Schwind, Sebastian; Powell, Bayard L; Carter, Thomas H; Wetzler, Meir; Moore, Joseph O; Kolitz, Jonathan E; Baer, Maria R; Carroll, Andrew J; Larson, Richard A; Caligiuri, Michael A; Marcucci, Guido; Bloomfield, Clara D

    2011-12-22

    The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (? 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1-mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches. PMID:22031865

  17. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category

    PubMed Central

    Metzeler, Klaus H.; Becker, Heiko; Maharry, Kati; Radmacher, Michael D.; Kohlschmidt, Jessica; Mrózek, Krzysztof; Nicolet, Deedra; Whitman, Susan P.; Wu, Yue-Zhong; Schwind, Sebastian; Powell, Bayard L.; Carter, Thomas H.; Wetzler, Meir; Moore, Joseph O.; Kolitz, Jonathan E.; Baer, Maria R.; Carroll, Andrew J.; Larson, Richard A.; Caligiuri, Michael A.; Marcucci, Guido

    2011-01-01

    The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (? 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall survival (OS; P = .006), and event-free survival (EFS; P = .002). Within the European LeukemiaNet (ELN) genetic categories of older CN-AML, ASXL1 mutations associated with inferior CR rate (P = .02), OS (P < .001), and EFS (P < .001) among ELN Favorable, but not among ELN Intermediate-I patients. Multivariable analyses confirmed associations of ASXL1 mutations with unfavorable CR rate (P = .03), DFS (P < .001), OS (P < .001), and EFS (P < .001) among ELN Favorable patients. We identified an ASXL1 mutation-associated gene-expression signature, but no microRNA-expression signature. This first study of ASXL1 mutations in primary CN-AML demonstrates that ASXL1mutated older patients, particularly within the ELN Favorable group, have unfavorable outcomes and may be candidates for experimental treatment approaches. PMID:22031865

  18. Differential Allelic Expression in the Human Genome: A Robust Approach To Identify Genetic and Epigenetic Cis-Acting Mechanisms Regulating Gene Expression

    PubMed Central

    Serre, David; Gurd, Scott; Ge, Bing; Sladek, Robert; Sinnett, Donna; Harmsen, Eef; Bibikova, Marina; Chudin, Eugene; Barker, David L.; Dickinson, Todd; Fan, Jian-Bing; Hudson, Thomas J.

    2008-01-01

    The recent development of whole genome association studies has lead to the robust identification of several loci involved in different common human diseases. Interestingly, some of the strongest signals of association observed in these studies arise from non-coding regions located in very large introns or far away from any annotated genes, raising the possibility that these regions are involved in the etiology of the disease through some unidentified regulatory mechanisms. These findings highlight the importance of better understanding the mechanisms leading to inter-individual differences in gene expression in humans. Most of the existing approaches developed to identify common regulatory polymorphisms are based on linkage/association mapping of gene expression to genotypes. However, these methods have some limitations, notably their cost and the requirement of extensive genotyping information from all the individuals studied which limits their applications to a specific cohort or tissue. Here we describe a robust and high-throughput method to directly measure differences in allelic expression for a large number of genes using the Illumina Allele-Specific Expression BeadArray platform and quantitative sequencing of RT-PCR products. We show that this approach allows reliable identification of differences in the relative expression of the two alleles larger than 1.5-fold (i.e., deviations of the allelic ratio larger than 60?40) and offers several advantages over the mapping of total gene expression, particularly for studying humans or outbred populations. Our analysis of more than 80 individuals for 2,968 SNPs located in 1,380 genes confirms that differential allelic expression is a widespread phenomenon affecting the expression of 20% of human genes and shows that our method successfully captures expression differences resulting from both genetic and epigenetic cis-acting mechanisms. PMID:18454203

  19. Genetic Interactions between the Yeast RNA Helicase Homolog Prp16 and Spliceosomal Snrnas Identify Candidate Ligands for the Prp16 RNA-Dependent Atpase

    PubMed Central

    Madhani, H. D.; Guthrie, C.

    1994-01-01

    Pre-mRNA splicing occurs in a large and dynamic ribonucleoprotein complex, the spliceosome. Several protein factors involved in splicing are homologous to a family of RNA-dependent ATPases, the so-called DEAD/DEAH proteins. A subset of these factors exhibit RNA helicase activity in vitro. The DEAD/DEAH proteins involved in splicing are thought to mediate RNA conformational rearrangements during spliceosome assembly. However, the RNA ligands for these factors are currently unknown. Here, we present genetic evidence in Saccharomyces cerevisiae for a functional interaction between the DEAH protein Prp16, and the U6 and U2 spliceosomal snRNAs. Using a library of mutagenized U6 snRNA genes, we have identified 14 strong suppressors of the cold-sensitive (cs) allele, prp16-302. Remarkably, each suppressor contains a single nucleotide deletion of 1 of the 6 residues that lie immediately upstream of a sequence in U6 that interacts with the 5' splice site. Analysis of site-directed mutations revealed that nucleotide substitutions in the adjacent U2-U6 helix I structure also suppress prp16-302, albeit more weakly. The U6 suppressors tested also partially reverse the phenotype of two other cs alleles, prp16-1 and prp16-301, but not the four temperature-sensitive alleles tested. Finally, overexpression of each cs allele exacerbates its recessive growth phenotype and confers a dominant negative cs phenotype. We propose that the snRNA suppressors function by destabilizing an interaction between the U2-U6 complex and a hypothetical factor (X), which is trapped by cs mutants of PRP16. The phenotypes of overexpressed prp16 alleles are consistent with the model that this trapped interaction inhibits the dissociation of Prp16 from the spliceosome. We discuss the intriguing possibility that factor X is Prp16 itself. PMID:8088513

  20. Genetic screen of a mutant poxvirus library identifies an ankyrin repeat protein involved in blocking induction of avian type I interferon.

    PubMed

    Laidlaw, Stephen M; Robey, Rebecca; Davies, Marc; Giotis, Efstathios S; Ross, Craig; Buttigieg, Karen; Goodbourn, Stephen; Skinner, Michael A

    2013-05-01

    Mammalian poxviruses, including vaccinia virus (VACV), have evolved multiple mechanisms to evade the host type I interferon (IFN) responses at different levels, with viral proteins targeting IFN induction, signaling, and antiviral effector functions. Avian poxviruses (avipoxviruses), which have been developed as recombinant vaccine vectors for permissive (i.e., poultry) and nonpermissive (i.e., mammals, including humans) species, encode no obvious equivalents of any of these proteins. We show that fowlpox virus (FWPV) fails to induce chicken beta IFN (ChIFN2) and is able to block its induction by transfected poly(I·C), an analog of cytoplasmic double-stranded RNA (dsRNA). A broad-scale loss-of-function genetic screen was used to find FWPV-encoded modulators of poly(I·C)-mediated ChIFN2 induction. It identified fpv012, a member of a family of poxvirus genes highly expanded in the avipoxviruses (31 in FWPV; 51 in canarypox virus [CNPV], representing 15% of the total gene complement), encoding proteins containing N-terminal ankyrin repeats (ANKs) and C-terminal F-box-like motifs. Under ectopic expression, the first ANK of fpv012 is dispensable for inhibitory activity and the CNPV ortholog is also able to inhibit induction of ChIFN2. FWPV defective in fpv012 replicates well in culture and barely induces ChIFN2 during infection, suggesting that other factors are involved in blocking IFN induction and resisting the antiviral effectors. Nevertheless, unlike parental and revertant viruses, the mutants induce moderate levels of expression of interferon-stimulated genes (ISGs), suggesting either that there is sufficient ChIFN2 expression to partially induce the ISGs or the involvement of alternative, IFN-independent pathways that are also normally blocked by fpv012. PMID:23427153

  1. A Large-Scale Genetic Screen in Arabidopsis to Identify Genes Involved in Pollen Exine Production1[C][W][OA

    PubMed Central

    Dobritsa, Anna A.; Geanconteri, Aliza; Shrestha, Jay; Carlson, Ann; Kooyers, Nicholas; Coerper, Daniel; Urbanczyk-Wochniak, Ewa; Bench, Bennie J.; Sumner, Lloyd W.; Swanson, Robert; Preuss, Daphne

    2011-01-01

    Exine, the outer plant pollen wall, has elaborate species-specific patterns, provides a protective barrier for male gametophytes, and serves as a mediator of strong and species-specific pollen-stigma adhesion. Exine is made of sporopollenin, a material remarkable for its strength, elasticity, and chemical durability. The chemical nature of sporopollenin, as well as the developmental mechanisms that govern its assembly into diverse patterns in different species, are poorly understood. Here, we describe a simple yet effective genetic screen in Arabidopsis (Arabidopsis thaliana) that was undertaken to advance our understanding of sporopollenin synthesis and exine assembly. This screen led to the recovery of mutants with a variety of defects in exine structure, including multiple mutants with novel phenotypes. Fifty-six mutants were selected for further characterization and are reported here. In 14 cases, we have mapped defects to specific genes, including four with previously demonstrated or suggested roles in exine development (MALE STERILITY2, CYP703A2, ANTHER-SPECIFIC PROTEIN6, TETRAKETIDE ?-PYRONE REDUCTASE/DIHYDROFLAVONOL-4-REDUCTASE-LIKE1), and a number of genes that have not been implicated in exine production prior to this screen (among them, fatty acid ?-hydroxylase CYP704B1, putative glycosyl transferases At1g27600 and At1g33430, 4-coumarate-coenzyme A ligase 4CL3, polygalacturonase QUARTET3, novel gene At5g58100, and nucleotide-sugar transporter At5g65000). Our study illustrates that morphological screens of pollen can be extremely fruitful in identifying previously unknown exine genes and lays the foundation for biochemical, developmental, and evolutionary studies of exine production. PMID:21849515

  2. Determination of genetic stability in long-term somatic embryogenic cultures and derived plantlets of cork oak using microsatellite markers.

    PubMed

    Lopes, Tina; Pinto, Glória; Loureiro, João; Costa, Armando; Santos, Conceição

    2006-09-01

    Microsatellites were used to test genetic stability in somatic embryos (SE) of Quercus suber L. The SE were obtained by a simple somatic embryogenesis protocol: leaf explants from two adult plants (QsG0, QsG5) and from two juvenile plants (QsGM1, QsGM2) were inoculated on Murashige and Skoog (MS) medium with 2,4-dichlorophenoxyacetic acid and zeatin. Calluses with primary embryogenic structures were transferred to MSWH (MS medium without growth regulators) and SE proliferated by secondary somatic embryogenesis. High morphological heterogeneity was found among cotyledonary SE. However, converted plants looked morphologically normal with well-developed rooting systems and shoots. The genetic stability of the plant material during the somatic embryogenesis process was evaluated by using six to eight nuclear microsatellites transferred from Q. myrsinifolia Blume, Q. petraea (Matts.) Liebl. and Q. robur L. Five of eight microsatellites distinguished among the genotypes analyzed, and for QsG0, QsGM1 and QsGM2, uniform microsatellite patterns were generally observed within and between SE and the respective donor genotypes. For genotype QsG5, the same pattern was observed in all samples analyzed except one, where the mutation percentage was 2.5%. We conclude that microsatellite markers can be used to assess genetic stability of clonal materials and to determine genetic stability throughout the process of somatic embryogenesis. The simple somatic embryogenesis protocol described has potential for the commercial propagation of Q. suber because it results in a low percentage of mutations. PMID:16740490

  3. Genetic mechanisms of antimicrobial resistance identified in Salmonella enterica, Escherichia coli, and Enteroccocus spp. isolated from U.S. food animals

    PubMed Central

    Frye, Jonathan G.; Jackson, Charlene R.

    2013-01-01

    The prevalence of antimicrobial resistance (AR) in bacteria isolated from U.S. food animals has increased over the last several decades as have concerns of AR foodborne zoonotic human infections. Resistance mechanisms identified in U.S. animal isolates of Salmonella enterica included resistance to aminoglycosides (e.g., alleles of aacC, aadA, aadB, ant, aphA, and StrAB), ?-lactams (e.g., blaCMY?2, TEM?1, PSE?1), chloramphenicol (e.g., floR, cmlA, cat1, cat2), folate pathway inhibitors (e.g., alleles of sul and dfr), and tetracycline [e.g., alleles of tet(A), (B), (C), (D), (G), and tetR]. In the U.S., multi-drug resistance (MDR) mechanisms in Salmonella animal isolates were associated with integrons, or mobile genetic elements (MGEs) such as IncA/C plasmids which can be transferred among bacteria. It is thought that AR Salmonella originates in food animals and is transmitted through food to humans. However, some AR Salmonella isolated from humans in the U.S. have different AR elements than those isolated from food animals, suggesting a different etiology for some AR human infections. The AR mechanisms identified in isolates from outside the U.S. are also predominantly different. For example the extended spectrum ?-lactamases (ESBLs) are found in human and animal isolates globally; however, in the U.S., ESBLs thus far have only been found in human and not food animal isolates. Commensal bacteria in animals including Escherichia coli and Enterococcus spp. may be reservoirs for AR mechanisms. Many of the AR genes and MGEs found in E. coli isolated from U.S. animals are similar to those found in Salmonella. Enterococcus spp. isolated from animals frequently carry MGEs with AR genes, including resistances to aminoglycosides (e.g., alleles of aac, ant, and aph), macrolides [e.g., erm(A), erm(B), and msrC], and tetracyclines [e.g., tet(K), (L), (M), (O), (S)]. Continuing investigations are required to help understand and mitigate the impact of AR bacteria on human and animal health. PMID:23734150

  4. Modelling foot-and-mouth disease virus dynamics in oral epithelium to help identify the determinants of lysis

    E-print Network

    the determinants of lysis David Schleya, , John Wardb & Zhidong Zhanga a Institute for Animal Health, Pirbright cells and resulting in growing lesions, before eventually being cleared by the immune response the animal has recovered from the disease. Persistence of virus has important implications for disease

  5. Tobacco mosaic virus RNA as genetic determinant: genesis of a discovery.

    PubMed

    Pennazio, S; Roggero, P

    2000-01-01

    It is generally held that the American geneticists Alfred Hershey and Martha Chase were the first to elucidate, in 1952, the genetic functions of phage DNA. The discovery of the genetic functions of RNA in a plant virus (Tobacco mosaic virus, TMV) is commonly attributed to the American plant virologist Heinz Fraenkel-Conrat, and to the Germans Alfred Gierer and Gerhard Schramm, who came to the same conclusion independently in 1956. In reality, the first understandings dated back to about 1940, when several scientists discovered that TMV infectivity was closely related to the presence of undamaged RNA in the virus particles. A very important but underestimated contribution came from the English group of Roy Markham, Kenneth Smith and Richard Matthews in 1948. This group purified and characterized an isometric plant virus, Turnip yellow mosaic virus, and first showed that virus infectivity depended on the presence of the RNA, concluding that nucleic acid was essential for virus multiplication. This finding was confirmed by the same group one year later but it laid neglected. After a five year period, in which several groups attempted to solve the question of the function of TMV RNA, the American electron microscopist Roger Hart offered, in 1955, further direct evidence which correlated RNA to TMV infectivity. One year later, three research groups (Fraenkel-Conrat; Gierer and Schramm; Max Lauffer, David Trkule and Anne Buzzell) obtained evidence that put an end to the question, which was (and is) fundamental to molecular Genetics because it demonstrated that RNA can function independently of DNA. PMID:11256209

  6. Genetics and genomics of melanoma

    PubMed Central

    Ghosh, Papia; Chin, Lynda

    2009-01-01

    The rapidly increasing incidence of melanoma, coupled with its highly aggressive metastatic nature, is of urgent concern. In order to design rational therapies, it is of critical importance to identify the genetic determinants that drive melanoma formation and progression. To date, signaling cascades emanating from the EGF receptor, c-MET and other receptors are known to be altered in melanoma. Important mutations in signaling molecules, such as BRAF and N-RAS, have been identified. In this review, some of the major genetic alterations and signaling pathways involved in melanoma will be discussed. Given the great deal of genetic heterogeneity observed in melanoma, it is likely that many more genetic determinants exist. Through the use of powerful genomic technologies, it is now possible to identify these additional genetic alterations in melanoma. A critical step in this analysis will be culling bystanders from functionally important drivers, as this will highlight genetic elements that will be promising therapeutic targets. Such technologies and the important points to consider in understanding the genetics of melanoma will be reviewed. PMID:20126509

  7. QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains

    Microsoft Academic Search

    H. Wittenburg; M A Lyons; R Li; U Kurtz; X Wang; J Mossner; M C Carey; B Paigen

    2006-01-01

    To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA\\/EiJxI\\/LnJ and PERA\\/EiJxDBA\\/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We

  8. Community landscapes: an integrative approach to determine overlapping network module hierarchy, identify key nodes and predict network dynamics

    Microsoft Academic Search

    Istvan A. Kovacs; Robin Palotai; Mate S. Szalay; Peter Csermely

    2009-01-01

    Background: Network communities help the functional organization and\\u000aevolution of complex networks. However, the development of a method, which is\\u000aboth fast and accurate, provides modular overlaps and partitions of a\\u000aheterogeneous network, has proven to be rather difficult. Methodology\\/Principal\\u000aFindings: Here we introduce the novel concept of ModuLand, an integrative\\u000amethod family determining overlapping network modules as hills of

  9. Genetic susceptibility to Campylobacter infection

    Microsoft Academic Search

    R. Janssen; Jonge R de; B. Hoebee

    2007-01-01

    Genetic factors partially determine the susceptibility of an individual\\u000ato Campylobacter infection. The genes that are specifically responsible\\u000afor this have not been identified but probably do play a role in gastric\\u000aacid production and in the immune response (specific humoral- and\\u000acell-mediated immunity). Genetic studies in humans could very well\\u000aincrease our understanding of an individual's susceptibility to\\u000aCampylobacter

  10. Use of record linkage between a statewide genetics service and a Birth Defects/Congenital Malformations Register to determine use of genetic counselling services.

    PubMed

    Halliday, J; Griffin, O; Bankier, A; Rose, C; Riley, M

    1997-10-01

    The Birth Defects/Congenital Malformations Register of the Victorian Department of Human Services contains detailed, confidential information on over 2,000 babies born with a birth defect each year in Victoria, Australia, representing approximately 3% of the annual number of births. For 1991 and 1993, the type of anomaly was categorised as warranting a high, moderate, or low need of referral for genetic counselling, depending on risk of recurrence and possible genetic cause. The Victorian Clinical Genetics Service at the Murdoch Institute, Melbourne, offers free, centralised genetic counselling services for the entire state. A comparison of case records between the two agencies has shown little difference in overall use of genetic counselling between 1991 (17%) and 1993 (16%). Rate of uptake in the "high need" category improved only slightly during that period, from 40% in 1991 to 43% in 1993. Utilization of genetic counselling services did not vary disproportionately with mother's country of birth, but was higher for older mothers. As was expected, rates were highest when a baby was born at the only hospital that provides on-site genetic counselling services. Even where a statewide genetic counselling service is in place, it is disappointing that over half of those judged at high need for genetic counselling are not making use of this service. This study will provide baseline information to which future studies can be compared. Using the same study methodology, it will be possible to examine whether the uptake rate increases in accordance with increased genetic services. PMID:9295066

  11. Spatio-temporal analysis to identify determinants of Oncomelania hupensis infection with Schistosoma japonicum in Jiangsu province, China

    PubMed Central

    2013-01-01

    Background With the successful implementation of integrated measures for schistosomiasis japonica control, Jiangsu province has reached low-endemicity status. However, infected Oncomelania hupensis snails could still be found in certain locations along the Yangtze river until 2009, and there is concern that they might spread again, resulting in the possible re-emergence of infections among people and domestic animals alike. In order to establish a robust surveillance system that is able to detect the spread of infected snails at an early stage, sensitive and reliable methods to identify risk factors for the establishment of infected snails need to be developed. Methods A total of 107 villages reporting the persistent presence of infected snails were selected. Relevant data on the distribution of infected snails, and human and livestock infection status information for the years 2003 to 2008 were collected. Spatio-temporal pattern analysis including spatial autocorrelation, directional distribution and spatial error models were carried out to explore spatial correlations between infected snails and selected explanatory factors. Results The area where infected snails were found, as well as their density, decreased significantly between 2003 and 2008. Changes in human and livestock prevalences were less pronounced. Three statistically significant spatial autocorrelations for infected snails were identified. (i) The Moran’s I of infected snails increased from 2004 to 2007, with the snail density increasing and the area with infected snails decreasing. (ii) The standard deviations of ellipses around infected snails were decreasing and the central points of the ellipses moved from West to East. (iii) The spatial error models indicated no significant correlation between the density of infected snails and selected risk factors. Conclusions We conclude that the contribution of local infection sources including humans and livestock to the distribution of infected snails might be relatively small and that snail control may limit infected snails to increasingly small areas ecologically most suitable for