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Sample records for exon-based comparative variant

  1. An Exon-Based Comparative Variant Analysis Pipeline to Study the Scale and Role of Frameshift and Nonsense Mutation in the Human-Chimpanzee Divergence

    OpenAIRE

    Yu, GongXin

    2009-01-01

    Chimpanzees and humans are closely related but differ in many deadly human diseases and other characteristics in physiology, anatomy, and pathology. In spite of decades of extensive research, crucial questions about the molecular mechanisms behind the differences are yet to be understood. Here I report ExonVar, a novel computational pipeline for Exon-based human-chimpanzee comparative Variant analysis. The objective is to comparatively analyze mutations specifically those that caused th...

  2. An Exon-Based Comparative Variant Analysis Pipeline to Study the Scale and Role of Frameshift and Nonsense Mutation in the Human-Chimpanzee Divergence

    Directory of Open Access Journals (Sweden)

    GongXin Yu

    2009-01-01

    important biological processes such as T cell lineage development, the pathogenesis of inflammatory diseases, and antigen induced cell death. A “less-is-more” model was previously established to illustrate the role of the gene inactivation and disruptions during human evolution. Here this analysis suggested a different model where the chimpanzee-specific exon-disrupting mutations may act as additional evolutionary force that drove the human-chimpanzee divergence. Finally, the analysis revealed a number of sequencing errors in the chimpanzee and human genome sequences and further illustrated that they could be corrected without resequencing.

  3. Comparing genetic variants detected in the 1000 genomes project ...

    Indian Academy of Sciences (India)

    Single-nucleotide polymorphisms (SNPs) determined based on SNP arrays from the international HapMap consortium (HapMap) and the genetic variants detected in the 1000 genomes project (1KGP) can serve as two references for genomewide association studies (GWAS). We conducted comparative analyses to provide ...

  4. Comparing genetic variants detected in the 1000 genomes project ...

    Indian Academy of Sciences (India)

    2015-12-11

    Dec 11, 2015 ... according to statistics from the National Human Genome. Research Institute's GWAS catalogue (Hindorff et al. 2009). Despite GWAS being widely applied to identify common genetic variants associated with risk across more than 200 diseases and human phenotypic traits, the SNP array-based.

  5. A comparative analysis of VIKOR method and its variants

    Directory of Open Access Journals (Sweden)

    Prasenjit Chatterjee

    2016-09-01

    Full Text Available The VIKOR (Vlse Kriterijumska Optimizacija Kompromisno Resenje which means multi-criteria optimization and compromise solution, in Serbian method has already become a quite popular multi-criteria decision making tool for its computational simplicity and solution accuracy. This method focuses on selecting and ranking from a set of feasible alternatives, and determines compromise solution for a problem with conflicting criteria to help the decision maker in reaching a final course of action. It determines the compromise ranking list based on the particular measure of closeness to the ideal solution. Depending upon the type of decision problem and necessity of the decision maker, apart from VIKOR method, different variants of it, like comprehensive VIKOR, fuzzy VIKOR, regret theory-based VIKOR, modified VIKOR and interval VIKOR methods have also been subsequently developed. In this paper, the ranking performance of original VIKOR method and its five variants is analyzed based on two demonstrative examples. It is observed that interval VIKOR method performs unsatisfactorily and when the information in a decision problem is imprecise, fuzzy VIKOR method should always be preferred. But, for any decision problem, original VIKOR is the best method for solution without unnecessarily complicating the related mathematical computations.

  6. The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer

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    Ofer Nathan Gofrit

    2016-03-01

    Full Text Available Background: High-grade urothelial carcinomas (UC often show foci of variant differentiation. There is limited information in the literature about the response of these variant urothelial tumors to immunotherapy with Bacillus Calmette Guerin (BCG. We compared the response to treatment with BCG of UC containing glandular, squamous, nested and micropapillary types of differentiation to response of conventional non-muscle invasive high-grade urothelial carcinoma. Methods: A total of 100 patients were diagnosed with variant histology urothelial cancer between June 1995 and December 2013. 41 patients with Ta or T1, confirmed by 2nd look biopsies, received immunotherapy with BCG. Fourteen patients in this group were diagnosed with micropapillary differentiation 13 patients with squamous differentiation, in 9 patients glandular differentiation was seen and in 7 patients nested variant. The control group included 140 patients with conventional high-grade UC. Both groups have been treated and followed similarly. Findings: Patients with variant tumors had similar clinical features to patients with conventional disease including: age, males to female ratio, stage, presence of Tis and median follow-up. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade UC including: 5-year recurrence-free survival (63.5% Vs. 71.5%, p=0.05, 5-year progression to≥T2 -free survival (60% Vs. 82.5%, p=0.002, 5-year disease-specific survival (73% Vs. 92.5%, p=0.0004 and overall survival (66% Vs. 89.5%, 0.05. Interpretation: A patient with variant bladder cancer treated with intra-vesical immunotherapy has a 27% chance of dying from this disease within 5-years compared to 7.5% for a patient with conventional high-grade UC.

  7. A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

    Science.gov (United States)

    Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

    2017-12-01

    Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD50) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

  8. Frontal variant of Alzheimer's disease and typical Alzheimer's disease: a comparative study

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    Bernardino Fernández-Calvo

    2013-01-01

    Full Text Available Clinical heterogeneity is one of the characteristics of Alzheimer's disease (AD. Hence, the atypical frontal or dysexecutive presentation is becoming increasingly well-known, although the underlying factors are still unknown. In this study, the neuropsychological performance of two groups of patients with AD (frontal variant--ADfv--and typical--TAD were compared. The ADfv group (n = 13 was selected due to the existence of frontal hypoperfusion on a simple photon emission computer tomography (SPECT. The results revealed that the ADfv group displayed a severe dysexecutive disorder, more severe neuropsychiatric symptomatology (disinhibition and apathy, more functional impairment, and it generated a higher caregiver overload than the TAD group without frontal impairment (n = 47. Despite the facts that the ADfv group's performance was poorer in all the neuropsychological tests, significant group differences were only found in the processing speed and visuoconstruction tasks. Logistic regression analysis revealed that the processing speed and mental flexibility scores significantly predicted a diagnosis of ADfv. The existence of the grasp reflex, anosognosia, and the absence of apolipoprotein E epsilon 4 allele (APOE e4 were also more prevalent in the ADfv group. This group had a predominance of males and it was more likely to have a positive family history of AD. To conclude, the study suggests that ADfv represents a subtype of AD that seems to have different clinical, neuropsychological, and genetic characteristics from TAD.

  9. The comparative effectiveness of serving peak loads in the variants of providing nuclear power plants with a base load

    Science.gov (United States)

    Batenin, V. M.; Aminov, R. Z.; Shkret, A. F.; Garievskii, M. V.

    2012-07-01

    The present paper reports the results of an investigation into the effectiveness of serving peak loads in the variants of providing nuclear power plants with a base load through unloading condensing power plants, combined heat and power (CHP) plants, combined-cycle thermal power plants during night-time off-peak hours, the use of the off-peak electric power for power and heat supply, and water electrolysis with the use of hydrogen and oxygen for production of the peak electric power, as compared with the variant of the development of pumped storage hydropower plants.

  10. Velar morphological variants in oral submucous fibrosis: A comparative digital cephalometric study

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    Bhagyashree Mahadevappa Patil

    2017-01-01

    Full Text Available Context: Soft palate (velar plays a significant role in various important functions in the head and neck region. Its diverse morphology is implicated in a variety of diseases. Knowledge about the varied morphological pattern of soft palate in oral submucous fibrosis (OSMF patients can give us a clear understanding about disease progress in the oropharyngeal region for a proper diagnosis and also help the maxillofacial surgeon in successful structural and functional corrections associated with this disorder. Aim: (1 To evaluate the morphological variations of soft palate in OSMF patients using digital lateral cephalogram. (2 To assess the morphological variations of soft palate with respect to the different clinical stages of OSMF patients. Subjects and Methods: A total number of 300 patients were included in the study (150 participants each in study and control group, evaluated clinically, and subjected for digital lateral cephalogram for evaluating velar morphological variants. Statistical Analysis: The data were statistically evaluated using SPSS 11.5 software with Student's t-test, Chi-square test, and ANOVA. Results: Among Group I, 34 participants had Stage I OSMF, 90 participants had Stage II OSMF, and 26 participants had Stage III OSMF. Type I velar was commonly seen in Stage I OSMF, Type VI velar in Stage II OSMF, and Type III velar in Stage III OSMF. There was statistically highly significant decrease in anterior-posterior (AP length and increase in width of superior-inferior (SI measurement, as compared to the Group II. Conclusion: There was diminution in AP length and increase in SI measurement as the OSMF disease progressed.

  11. Comparative evaluation of Populus variants total sugar release and structural features following pretreatment and digestion by two distinct biological systems.

    Science.gov (United States)

    Thomas, Vanessa A; Kothari, Ninad; Bhagia, Samarthya; Akinosho, Hannah; Li, Mi; Pu, Yunqiao; Yoo, Chang Geun; Pattathil, Sivakumar; Hahn, Michael G; Raguaskas, Arthur J; Wyman, Charles E; Kumar, Rajeev

    2017-01-01

    Populus natural variants have been shown to realize a broad range of sugar yields during saccharification, however, the structural features responsible for higher sugar release from natural variants are not clear. In addition, the sugar release patterns resulting from digestion with two distinct biological systems, fungal enzymes and Clostridium thermocellum, have yet to be evaluated and compared. This study evaluates the effect of structural features of three natural variant Populus lines, which includes the line BESC standard, with respect to the overall process of sugar release for two different biological systems. Populus natural variants, SKWE 24-2 and BESC 876, showed higher sugar release from hydrothermal pretreatment combined with either enzymatic hydrolysis or Clostridium thermocellum fermentation compared to the Populus natural variant, BESC standard. However, C. thermocellum outperformed the fungal cellulases yielding 96.0, 95.5, and 85.9% glucan plus xylan release from SKWE 24-2, BESC 876, and BESC standard, respectively. Among the feedstock properties evaluated, cellulose accessibility and glycome profiling provided insights into factors that govern differences in sugar release between the low recalcitrant lines and the BESC standard line. However, because this distinction was more apparent in the solids after pretreatment than in the untreated biomass, pretreatment was necessary to differentiate recalcitrance among Populus lines. Glycome profiling analysis showed that SKWE 24-2 contained the most loosely bound cell wall glycans, followed by BESC 876, and BESC standard. Additionally, lower molecular weight lignin may be favorable for effective hydrolysis, since C. thermocellum reduced lignin molecular weight more than fungal enzymes across all Populus lines. Low recalcitrant Populus natural variants, SKWE 24-2 and BESC 876, showed higher sugar yields than BESC standard when hydrothermal pretreatment was combined with biological digestion. However

  12. Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

    Energy Technology Data Exchange (ETDEWEB)

    Peters, Diane E. [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA (United States); Hoover, Benjamin [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Cloud, Loretta Grey [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Liu, Shihui [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Molinolo, Alfredo A. [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Leppla, Stephen H. [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Bugge, Thomas H., E-mail: thomas.bugge@nih.go [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

    2014-09-01

    We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti

  13. Evaluation of Partially Overlapping 3D Point Cloud's Registration by using ICP variant and CloudCompare.

    Science.gov (United States)

    Rajendra, Y. D.; Mehrotra, S. C.; Kale, K. V.; Manza, R. R.; Dhumal, R. K.; Nagne, A. D.; Vibhute, A. D.

    2014-11-01

    Terrestrial Laser Scanners (TLS) are used to get dense point samples of large object's surface. TLS is new and efficient method to digitize large object or scene. The collected point samples come into different formats and coordinates. Different scans are required to scan large object such as heritage site. Point cloud registration is considered as important task to bring different scans into whole 3D model in one coordinate system. Point clouds can be registered by using one of the three ways or combination of them, Target based, feature extraction, point cloud based. For the present study we have gone through Point Cloud Based registration approach. We have collected partially overlapped 3D Point Cloud data of Department of Computer Science & IT (DCSIT) building located in Dr. Babasaheb Ambedkar Marathwada University, Aurangabad. To get the complete point cloud information of the building we have taken 12 scans, 4 scans for exterior and 8 scans for interior façade data collection. There are various algorithms available in literature, but Iterative Closest Point (ICP) is most dominant algorithms. The various researchers have developed variants of ICP for better registration process. The ICP point cloud registration algorithm is based on the search of pairs of nearest points in a two adjacent scans and calculates the transformation parameters between them, it provides advantage that no artificial target is required for registration process. We studied and implemented three variants Brute Force, KDTree, Partial Matching of ICP algorithm in MATLAB. The result shows that the implemented version of ICP algorithm with its variants gives better result with speed and accuracy of registration as compared with CloudCompare Open Source software.

  14. Comparative Assessment of Mediterranean Gorgonian-Associated Microbial Communities Reveals Conserved Core and Locally Variant Bacteria

    KAUST Repository

    van de Water, Jeroen A J M

    2016-10-10

    Gorgonians are key habitat-forming species of Mediterranean benthic communities, but their populations have suffered from mass mortality events linked to high summer seawater temperatures and microbial disease. However, our knowledge on the diversity, dynamics and function of gorgonian-associated microbial communities is limited. Here, we analysed the spatial variability of the microbiomes of five sympatric gorgonian species (Eunicella singularis, Eunicella cavolini, Eunicella verrucosa, Leptogorgia sarmentosa and Paramuricea clavata), collected from the Mediterranean Sea over a scale of ∼1100 km, using next-generation amplicon sequencing of the 16S rRNA gene. The microbiomes of all gorgonian species were generally dominated by members of the genus Endozoicomonas, which were at very low abundance in the surrounding seawater. Although the composition of the core microbiome (operational taxonomic units consistently present in a species) was found to be unique for each host species, significant overlap was observed. These spatially consistent associations between gorgonians and their core bacteria suggest intricate symbiotic relationships and regulation of the microbiome composition by the host. At the same time, local variations in microbiome composition were observed. Functional predictive profiling indicated that these differences could be attributed to seawater pollution. Taken together, our data indicate that gorgonian-associated microbiomes are composed of spatially conserved bacteria (core microbiome members) and locally variant members, and that local pollution may influence these local associations, potentially impacting gorgonian health.

  15. Comparative study of feature selection with ensemble learning using SOM variants

    Science.gov (United States)

    Filali, Ameni; Jlassi, Chiraz; Arous, Najet

    2017-03-01

    Ensemble learning has succeeded in the growth of stability and clustering accuracy, but their runtime prohibits them from scaling up to real-world applications. This study deals the problem of selecting a subset of the most pertinent features for every cluster from a dataset. The proposed method is another extension of the Random Forests approach using self-organizing maps (SOM) variants to unlabeled data that estimates the out-of-bag feature importance from a set of partitions. Every partition is created using a various bootstrap sample and a random subset of the features. Then, we show that the process internal estimates are used to measure variable pertinence in Random Forests are also applicable to feature selection in unsupervised learning. This approach aims to the dimensionality reduction, visualization and cluster characterization at the same time. Hence, we provide empirical results on nineteen benchmark data sets indicating that RFS can lead to significant improvement in terms of clustering accuracy, over several state-of-the-art unsupervised methods, with a very limited subset of features. The approach proves promise to treat with very broad domains.

  16. Hydrogen Exchange Mass Spectrometry of Related Proteins with Divergent Sequences: A Comparative Study of HIV-1 Nef Allelic Variants

    Science.gov (United States)

    Wales, Thomas E.; Poe, Jerrod A.; Emert-Sedlak, Lori; Morgan, Christopher R.; Smithgall, Thomas E.; Engen, John R.

    2016-06-01

    Hydrogen exchange mass spectrometry can be used to compare the conformation and dynamics of proteins that are similar in tertiary structure. If relative deuterium levels are measured, differences in sequence, deuterium forward- and back-exchange, peptide retention time, and protease digestion patterns all complicate the data analysis. We illustrate what can be learned from such data sets by analyzing five variants (Consensus G2E, SF2, NL4-3, ELI, and LTNP4) of the HIV-1 Nef protein, both alone and when bound to the human Hck SH3 domain. Regions with similar sequence could be compared between variants. Although much of the hydrogen exchange features were preserved across the five proteins, the kinetics of Nef binding to Hck SH3 were not the same. These observations may be related to biological function, particularly for ELI Nef where we also observed an impaired ability to downregulate CD4 surface presentation. The data illustrate some of the caveats that must be considered for comparison experiments and provide a framework for investigations of other protein relatives, families, and superfamilies with HX MS.

  17. Comparing genetic variants detected in the 1000 genomes project with SNPs determined by the International HapMap Consortium.

    Science.gov (United States)

    Zhang, Wenqian; Ng, Hui Wen; Shu, Mao; Luo, Heng; Su, ZhenQiang; Ge, Weigong; Perkins, Roger; Tong, Weida; Hong, Huixiao

    2015-12-01

    Single-nucleotide polymorphisms (SNPs) determined based on SNP arrays from the international HapMap consortium (HapMap) and the genetic variants detected in the 1000 genomes project (1KGP) can serve as two references for genomewide association studies (GWAS). We conducted comparative analyses to provide a means for assessing concerns regarding SNP array-based GWAS findings as well as for realistically bounding expectations for next generation sequencing (NGS)-based GWAS. We calculated and compared base composition, transitions to transversions ratio, minor allele frequency and heterozygous rate for SNPs from HapMap and 1KGP for the 622 common individuals. We analysed the genotype discordance between HapMap and 1KGP to assess consistency in the SNPs from the two references. In 1KGP, 90.58% of 36,817,799 SNPs detected were not measured in HapMap. More SNPs with minor allele frequencies less than 0.01 were found in 1KGP than HapMap. The two references have low disc ordance (generally smaller than 0.02) in genotypes of common SNPs, with most discordance from heterozygous SNPs. Our study demonstrated that SNP array-based GWAS findings were reliable and useful, although only a small portion of genetic variances were explained. NGS can detect not only common but also rare variants, supporting the expectation that NGS-based GWAS will be able to incorporate a much larger portion of genetic variance than SNP arrays-based GWAS.

  18. Genomic organization, transcript variants and comparative analysis of the human nucleoporin 155 (NUP155) gene

    DEFF Research Database (Denmark)

    Zhang, Xiuqing; Yang, Huanming; Yu, Jun

    2002-01-01

    Nucleoporin 155 (Nup155) is a major component of the nuclear pore complex (NPC) involved in cellular nucleo-cytoplasmic transport. We have acquired the complete sequence and interpreted the genomic organization of the Nup155 orthologos from human (Homo sapiens) and pufferfish (Fugu rubripes), which...... complementary to RNAs of the Nup155 orthologs from Fugu and mouse. Comparative analysis of the Nup155 orthologs in many species, including H. sapiens, Mus musculus, Rattus norvegicus, F. rubripes, Arabidopsis thaliana, Drosophila melanogaster, and Saccharomyces cerevisiae, has revealed two paralogs in S...

  19. Variants of the Morris water maze task to comparatively assess human and rodent place navigation.

    Science.gov (United States)

    Schoenfeld, Robby; Schiffelholz, Thomas; Beyer, Christian; Leplow, Bernd; Foreman, Nigel

    2017-03-01

    Performance in the Morris water maze has been widely used in routine behavioural studies of rodents. Since the advent of computer-based virtual environments, adaptations of the water maze have become available for human research. Despite decades of comparative neuroscience, formal comparisons of human and animal place navigation performance are rare. We studied 36 subjects, 18 young male mice in a Morris water maze and 18 male students in a virtual version. Quantitative measures (escape latencies, distances and platform crossings) indicated no discernable differences between human and rodent performance, reinforcing the task's general validity and its implied cross-species comparability. However, we extracted, using an a priori free classification method, qualitatively different movement patterns for mice and humans, patterns that reflect the probable strategy that individuals might have been using to solve the task. Our results indicated young male students to have most likely solved the maze by means of spatial strategies whereas mice were observed more often to have adopted non-spatial strategies. These differences could be attributed to differences in our maze setups (spatial cues, task instruction, training protocol, motivation) and gave further hints that maze learning depends on many factors. In summary performance on both spatial tasks was equivalent in humans and mice but the kind of maze learning that was used to achieve maximum performance was different. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Comparative analysis of the construction solution variants for flat arch coverings of buildings

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    Ibragimov Aleksandr Mayorovich

    2014-03-01

    Full Text Available Arch structures of long span buildings’ coverings are more beneficial in respect to material expenses, than beam and frame systems. Constructive schemes of roof frameworks of arch coverings are diverse, which means their operation under loading differs much. The authors offer a number of construction solutions for flat arch coverings of long span buildings. The comparative analysis of these construction solutions is presented. The operation of radial link arch is observed. The arch consists of discontinuous top chord and radial bowstring under the single load (uniformly distributed and concentrated in nods with different spans and rises. The problem of radial link arch optimization is solved in dependence with arising forces and rise. The optimal camber of arch was found. In further works the authors plan to analyze spans more than 36 meters and solve the problem in case of asymmetrical loadings.

  1. A comparative study of variant turbulence modeling in the physical behaviors of diesel spray combustion

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    Amini Behnaz

    2011-01-01

    Full Text Available In this research, the performance of non-linear k-ε turbulence model in resolving the time delay between mean flow changes and its proportionate turbulent dissipation rate adjustment was investigated. For this purpose, the ability of Launder-Spalding linear, Suga non-linear, Yakhot RNG and Rietz modified RNG k-ε models are compared in the estimation of axial mean velocity profile and turbulent integral length scale evolution during engine compression stroke. Computed results showed that even though all the models can predict the acceptable results for velocity profile, for turbulent integral length scale curve, non-linear model is in a good agreement with modified RNG model prediction that depicts correspondence with experimental reported data, while other models show a different unrealistic behaviors. Also after combustion starts and piston is expanding, non-linear model can predicts actual manner for integral length scale while linear one cannot. It is concluded that, physical behavior of turbulence models characteristics should be ascertained before being successfully applied to simulate complex flow fields like internal combustion engines.

  2. Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

    Science.gov (United States)

    Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

    2016-05-01

    Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.

  3. Genotypic distribution of common variants of endosomal toll like receptors in healthy Spanish women. A comparative study with other populations.

    Science.gov (United States)

    Martínez-Robles, Elena; Yebra-Bango, Miguel; Mellor-Pita, Susana; Tutor-Ureta, Pablo; Vargas, Juan A; Citores, Maria J

    2016-03-01

    Genetic variants of endosomal toll like receptors (TLR) have been associated with many infectious, autoimmune and inflammatory diseases, but few studies have been reported in the Spanish population. The aim of this study was to describe the allelic and genotypic distributions of some common nucleotide substitutions of endosomal TLRs in healthy Spanish women and to compare them with those already published in other population groups. Nine substitutions were analysed in 150 DNA samples from 150 Spanish, non-related healthy females: TLR3 rs3775291 and rs5743305; TLR7 rs179008 and rs5743781; TLR8 rs3764880 and TLR9 rs187084, rs5743836, rs352139 and rs352140. Genotyping was carried out by real time PCR and melting curve analysis in a LightCycler 480. A systematic review was performed in order to compare the genotypic distributions in our cohort with those previously published in other population groups. The comparative study was performed with the two tailed Fisher's test or the Yates continuity correction for the Chi-square test when appropriate. No homozygotes for rs5743781 in TLR7 were found, and rs352139 and rs352140 of TLR9 were in strong linkage disequilibrium. Genotype distributions in endosomal TLR are similar to other Spanish series previously reported. As expected, most differences were found when comparing our distributions with Asiatics, but differences were also found with other Caucasian populations. Since there are significant variations in genotypic distributions of TLRs in both interracial groups and within the same ethnic group, to carry out studies of disease susceptibility in more restricted groups is mandatory. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Further Molecular Analysis of G6PD Deficiency Variants in Southern Vietnam and a Novel Variant Designated as G6PD Ho Chi Minh (173 A>G; 58 Asp>Gly): Frequency Distributions of Variants Compared with Those in Other Southeast Asian Countries.

    Science.gov (United States)

    Kawamoto, Fumihiko; Matsuoka, Hiroyuki; Pham, Nghiem Minh; Hayashi, Taeko; Kasahara, Yuichi; Dung, Nguyen The; Kido, Yasutoshi; Kanbe, Toshio; Tantular, Indah S

    2017-08-01

    We conducted a survey of glucose-6-phosphate dehydrogenase (G6PD) deficiency among newborn babies at Tu Du Hospital, Ho Chi Minh, southern Vietnam. A total of 90 deficient babies were detected, including 85 in the Kinh ethnic group, 4 Chinese, and 1 in the K'Ho minority group. In the Kinh ethnic group, G6PD variants such as G6PD Viangchan (n=32), Kaiping (n=11), Canton (n=8), Chinese-5 (n=7), Union (n=5) and Quing Yuan (n=4) were detected. A variant with silent mutations at 1311 C>T and IVS11 nt 93 T>C was also detected in 17 cases. A novel mutation (173 A>G) in exon 4 with a predicted amino acid change of 58 Asp>Gly was also found in a Kinh newborn girl and her father, and it was designated as G6PD Ho Chi Minh. These findings demonstrated that the Kinh ethnic group in southern Vietnam has 8 different G6PD variants, indicating that the members of this group have many ancestors in terms of G6PD variants from Southeast Asia, China, and Oceania. We compared the frequency distribution of G6PD variants in the Kinh population with those of other Southeast Asian populations, and the Kinh population's distribution was quite similar to that in the Thai population, but differed from it by the absence of G6PD Mahidol.

  5. A comparative study of changes across the lifecycle of complex products in a variant and a customised industry

    DEFF Research Database (Denmark)

    Vianello, Giovanna; Ahmed-Kristensen, Saeema

    2012-01-01

    selected and change documentation analysed. The two cases selected were: 1) a variant design product, an aeroengine and 2) a customised product, a drilling equipment for the oil industry. The change requests were analysed to understand their distribution and motivation across the lifecycle of the two...... requests from the later phases of a product’s lifecycle and to support designers to efficiently address the unavoidable change requests. The findings also show that knowledge is transferred implicitly in the customised design case, resulting in very little knowledge of changes transferred to the next...

  6. Comparative genomics and drug resistance of a geographic variant of ST239 methicillin-resistant Staphylococcus aureus emerged in Russia.

    Directory of Open Access Journals (Sweden)

    Tatsuo Yamamoto

    Full Text Available Two distinct classes of methicillin-resistant Staphylococcus aureus (MRSA are spreading in hospitals (as hospital-acquired MRSA, HA-MRSA and in the community (as community-acquired MRSA, CA-MRSA. Multilocus sequence type (ST 239 MRSA, one of the most worldwide-disseminated lineages, has been noted as a representative HA-MRSA. Here, we isolated ST239 MRSA (spa type 3 [t037] and staphylococcal cassette chromosome mec [SCCmec] type III.1.1.1 and its novel variant with ST239/spa351 (t030/SCCmecIII.1.1.4 (SCCmecIII(R not only from hospitals but also from patients with urethritis in the community in Russia. The Russian variant (strain 16K possessed a hybrid genome consisting of CC8 and CC30, similar to the ST239/spa3/SCCmecIII.1.1.1 HA-MRSA (TW20 genome, but with marked diversity. The 16K' CC30 section had SCCmecIII(R carrying the dcs-carrying unit (which corresponded to the SCCmecIVc J3 joining region of ST30 CA-MRSA, lacked SCCmercury, and possessed a novel mobile element structure (MES16K carrying the ccrC-carrying unit (with the recombinase gene ccrC1 allele 3 and drug resistance tranposons. The Russian variant included strains with a high ability to transfer its multiple drug resistance by conjugation; e.g., for strain 16K, the transfer frequency of a chloramphenicol resistance plasmid (p16K-1 with 2.9 kb in size reached 1.4×10(-2, followed by Tn554 conjugative transfer at 3.6×l0(-4. The Russian variant, which has been increasing recently, included divergent strains with different plasmid patterns and pulsed field gel electrophoresis profiles. The data demonstrate the alternative nature of ST239 MRSA as CA-MRSA and also as a drug resistance disseminator, and its micro but dynamic evolution in Russia.

  7. Comparative examinations on the activity and variant selection of twinning during tension and compression of magnesium alloys

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Dejia [College of Materials Science and Engineering, Chongqing University, Chongqing (China); School of Mechatronics Engineering, East China Jiaotong University, Nanchang (China); Xin, Renlong, E-mail: rlxin@cqu.edu.cn [College of Materials Science and Engineering, Chongqing University, Chongqing (China); State Key Laboratory of Mechanical Transmission, Chongqing University, Chongqing (China); Hongni, Yu; Liu, Zhe; Zheng, Xuan [College of Materials Science and Engineering, Chongqing University, Chongqing (China); Liu, Qing, E-mail: qingliu@cqu.edu.cn [College of Materials Science and Engineering, Chongqing University, Chongqing (China)

    2016-03-21

    In the present study, an Mg weld with β-type fiber texture was produced by friction stir welding (FSW) and then was subjected to tension and compression along the transverse direction (TD). The deformed microstructure by 5% strain was examined in various regions of the Mg weld by electron backscatter diffraction (EBSD) technique. It was found that profuse twinning was activated in stir zone (SZ) -side after tension and in SZ-center and crown zone (CZ) -center after compression due to the presence of relatively large Schmid factor (SF). However, a few twins (2–3%) were also observed in SZ-center after tension and in SZ-side after compression. In this case, the twins have very small and even negative SF. For the twins with large SF, they were likely connected at grain boundaries forming twin pairs, while for those with small or negative SF, they were mostly confined within grains. For connected twins, most of the active variants have favorable SF and geometric compatibility factor (m′). However, the distributions of SF and m′ are different between the twins formed in compression and tension. For isolated twins, the adjacent grains connected with the twins were generally in favorable orientation for basal slip, and the selection of twin variants was likely affected by m′ between the most favorable basal slip and the twins.

  8. Combined DOG1 and Mammaglobin Immunohistochemistry Is Comparable to ETV6-breakapart Analysis for Differentiating Between Papillary Cystic Variants of Acinic Cell Carcinoma and Mammary Analogue Secretory Carcinoma.

    Science.gov (United States)

    Said-Al-Naief, Nasser; Carlos, Roman; Vance, Gail H; Miller, Caroline; Edwards, Paul C

    2017-04-01

    We investigated the reliability of combined DOG1 and mammaglobin immunohistochemistry compared with ETV6 fluorescence in situ hybridization (FISH) in the assessment of salivary tumors previously diagnosed as acinic cell carcinoma (ACC). Ultrastructural features of cases reclassified as mammary analogue secretory carcinoma (MASC) were assessed by transmission electron microscopy (TEM). Immunohistochemical (IHC) reactivity to DOG1 and mammaglobin was validated against FISH targeting the ETV6 gene in all 14 cases. Three cases with papillary cystic histomorphology previously diagnosed as ACC were revised to MASC. TEM features of the ETV6 rearrangement-positive MASC cases showed large numbers of secretory granules with extrusion into the intercellular spaces, well-developed endoplasmic reticulum, lipid-laden vacuoles, well-formed microvilli, and large lining cystic spaces. Combined DOG1 and mammaglobin immunohistochemistry is comparable to ETV6 -breakapart analysis for differentiating between papillary cystic variants of ACC and MASC.

  9. Comparative analysis between the SPIF and DPIF variants for die-less forming process for an automotive workpiece

    Directory of Open Access Journals (Sweden)

    Adrian José Benitez Lozano

    2015-07-01

    Full Text Available Over time the process of incremental deformation Die-less has been developed in many ways to meet the needs of flexible production with no investment in tooling and low production costs. Two of their configurations are the SPIF (Single point incremental forming and DPIF (Double point Incremental forming technique. The aim of this study is to compare both techniques with the purpose of exposing their advantages and disadvantages in the production of industrial parts, as well as to inform about Die-less as an alternative manufacturing process. Experiments with the exhaust pipe cover of a vehicle are performed, the main process parameters are described, and formed workpieces without evidence of defects are achieved. Significant differences between the two techniques in terms of production times and accuracy to the original model are also detected. Finally, it is suggested when is more convenient to use each of these.

  10. Comparative analysis of cytokeratin 15, TDAG51, cytokeratin 20 and androgen receptor in sclerosing adnexal neoplasms and variants of basal cell carcinoma.

    Science.gov (United States)

    Evangelista, Mara Therese P; North, Jeffrey P

    2015-11-01

    Desmoplastic trichoepithelioma (DTE), morpheaform basal cell carcinoma (BCC) and microcystic adnexal carcinoma (MAC) are sclerosing adnexal neoplasms with overlapping histopathologic features. We compared cytokeratin 15, (CK15), T-cell death-associated gene 51 (TDAG51), cytokeratin 20 (CK20) and androgen receptor (AR) in differentiating these tumors and assessed their expression in BCC subtypes. Fifteen DTE, 15 infundibulocystic BCC, 18 micronodular BCC, 18 morpheaform BCC and 6 MAC were assessed for CK15, TDAG51, CK20 and AR expression. Quantitative CK15 staining was higher in DTE compared with BCC (p < 0.0001) and MAC (p = 0.02). Quantitative TDAG51 staining was higher in DTE than BCC (p < 0.0001). The CK20+AR- immunophenotype was 100% sensitive and specific in diagnosing DTE. The CK20-AR+ immunophenotype was 95.24% specific and 83.33% sensitive for BCC. The CK20-AR- immunophenotype was 83.33% sensitive and 90.91% specific for MAC. CK15, CK20 and AR were positive in 87, 53 and 67% of infundibulocystic BCC cases, respectively. Combination of CK20 and AR best differentiated these sclerosing adnexal neoplasms. Greater positivity for CK15 and TDAG51 generally favors benign lesions. Infundibulocystic BCC has higher CK20 and lower AR immunopositivity than other BCC variants and a high degree of CK15 and TDAG51 positivity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Laboratory testing of hemolytic properties of materials that come in contact with blood: Comparative application testing method’s two variants according to the standard ASTM F756 in accordance with ISO 10993-4

    Directory of Open Access Journals (Sweden)

    Pavlović Katarina B.

    2010-01-01

    Full Text Available The presence of hemolytic material in contact with blood may produce increased levels of blood cell lysis and increased levels of plasma hemoglobin. This may induce toxic effects or other effects which may stress the kidneys or other organs. In this paper two variants of in vitro method and obtained results’ comparison were presented for testing of hemolytic properties of six raw materials (Polipropylene Moplen EP 540 P, Policarbonate colorless 164 R-112, Policarbonate brown 164 R-51918, Polietylene NG 3026 K, Polietylene NG - Purell GB 7250, Polietylene VG - Hiplex 5502 for medical device manufacturing and one raw material (Polietylen NG granulate used for infusion solutions’s plastic bottles manufacturing. One of method’s variants relies on raw material direct contact with swine blood and the other on extract of the material contact with swine blood. Both method’s variants imply reading of the absorbance of the supernatant after tubes were incubated and centrifuged. According to values obtained and using the standard curve free hemoglobin concentration is determined and based on this percentage hemolysis of raw material. Positive and negative controls were used in both variants where water for injection (WFI was used as positive control in which partial or complete hemolysis of erythrocytes occurs due to osmotic shock and phosphate buffer saline was used as negative control with no hemolytic property. In this paper comparison of results obtained by both method’s variants for testing of seven raw materials was presented, while these conclusions can not be used neither for all materials, nor for all applications without preliminary testing using both variants and then choosing more sensitive and more reliable one. It was shown and stated in the paper as well that incubation time being 3, 15 or 24 h, had no impact on the variant’s with direct contact sensitivity. This comparative approach was used for drawing conclusions in terms of

  12. Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion

    DEFF Research Database (Denmark)

    Conn, Erin M; Bøtkjær, Kenneth Alrø; Kupriyanova, Tatyana A

    2009-01-01

    To analyze the process of tumor cell intravasation, we used the human tumor-chick embryo spontaneous metastasis model to select in vivo high (PC-hi/diss) and low (PC-lo/diss) disseminating variants from the human PC-3 prostate carcinoma cell line. These variants dramatically differed in their int...... variants points to key roles for the uPA-plasmin system in PC-hi/diss intravasation, possibly via (1) promoting tumor cell matrix invasion and (2) facilitating development of VEGF-dependent angiogenic blood vessels......To analyze the process of tumor cell intravasation, we used the human tumor-chick embryo spontaneous metastasis model to select in vivo high (PC-hi/diss) and low (PC-lo/diss) disseminating variants from the human PC-3 prostate carcinoma cell line. These variants dramatically differed...... of vascular endothelial growth factor (VEGF), since treating developing tumors with a function-blocking anti-VEGF antibody simultaneously inhibited both processes without affecting primary tumor growth. PC-hi/diss cells were also more migratory and invasive, suggestive of heightened ability to escape from...

  13. Comparative analysis of CE-SSCP to standard RFLP-CE-FLA method in quantification of known viral variants within an RNA virus quasispecies.

    Science.gov (United States)

    Gulija, Tanja Košutić; Ivancic-Jelecki, Jelena; Santak, Maja; Forcic, Dubravko

    2011-07-01

    RNA viruses display the highest replication error rate in our biosphere, leading to highly diverse viral populations termed quasispecies. The gold standard method for detection and quantification of variants in a quasispecies is cloning and sequencing, but it is expensive, laborious and time consuming. Therefore, other mutation detection approaches, including SSCP, are often used. In this study, we demonstrate development and the usage of a CE-SSCP method for quantification of two nearly identical viral variants in heterogenic population of a mumps virus strain and its comparison to RFLP-CE-fragment length analysis (RFLP-CE-FLA). Analyzed PCR fragments were of the same size (245 bp) with one difference in their nucleotide sequence. The limit of detection of both methods was at 5% of the minor variant. When PCR amplicons of the two variants were pooled, methods' results were very similar. On the contrary, the quantification results of samples in which variants were mixed prior to PCR showed substantial difference between the two methods. Our results indicate that although both methods can be used for detection and monitoring of a specific mutation within a viral population, caution should be taken when quantitative analysis of complex samples is based solely on results of one method. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Comparative analysis of the folding dynamics and kinetics of an engineered knotted protein and its variants derived from HP0242 of Helicobacter pylori

    Science.gov (United States)

    Wang, Liang-Wei; Liu, Yu-Nan; Lyu, Ping-Chiang; Jackson, Sophie E.; Hsu, Shang-Te Danny

    2015-09-01

    Understanding the mechanism by which a polypeptide chain thread itself spontaneously to attain a knotted conformation has been a major challenge in the field of protein folding. HP0242 is a homodimeric protein from Helicobacter pylori with intertwined helices to form a unique pseudo-knotted folding topology. A tandem HP0242 repeat has been constructed to become the first engineered trefoil-knotted protein. Its small size renders it a model system for computational analyses to examine its folding and knotting pathways. Here we report a multi-parametric study on the folding stability and kinetics of a library of HP0242 variants, including the trefoil-knotted tandem HP0242 repeat, using far-UV circular dichroism and fluorescence spectroscopy. Equilibrium chemical denaturation of HP0242 variants shows the presence of highly populated dimeric and structurally heterogeneous folding intermediates. Such equilibrium folding intermediates retain significant amount of helical structures except those at the N- and C-terminal regions in the native structure. Stopped-flow fluorescence measurements of HP0242 variants show that spontaneous refolding into knotted structures can be achieved within seconds, which is several orders of magnitude faster than previously observed for other knotted proteins. Nevertheless, the complex chevron plots indicate that HP0242 variants are prone to misfold into kinetic traps, leading to severely rolled-over refolding arms. The experimental observations are in general agreement with the previously reported molecular dynamics simulations. Based on our results, kinetic folding pathways are proposed to qualitatively describe the complex folding processes of HP0242 variants.

  15. Modified live infectious bursal disease virus (IBDV) vaccine delays infection of neonatal broiler chickens with variant IBDV compared to turkey herpesvirus (HVT)-IBDV vectored vaccine.

    Science.gov (United States)

    Kurukulasuriya, Shanika; Ahmed, Khawaja Ashfaque; Ojkic, Davor; Gunawardana, Thushari; Goonewardene, Kalhari; Gupta, Ashish; Chow-Lockerbie, Betty; Popowich, Shelly; Willson, Philip; Tikoo, Suresh K; Gomis, Susantha

    2017-02-07

    Chickens are commonly processed around 35-45days of age in broiler chicken industry hence; diseases that occur at a young age are of paramount economic importance. Early age infection with infectious bursal disease virus (IBDV) results in long-lasting immunosuppression and profound economic losses. To our knowledge, this is the first study comparing the protection efficacy of modified live (MdLV) IBDV and herpesvirus turkey (HVT)-IBDV vaccines against early age variant IBDV (varIBDV) infection in chicks. Experiments were carried out in IBDV maternal antibody (MtAb) positive chicks (n=330), divided into 6 groups (n=50-60/group), namely Group 1 (saline), Group 2 (saline+varIBDV), Group 3 (HVT-IBDV), Group 4 (HVT-IBDV+varIBDV), Group 5 (MdLV) and Group 6 (MdLV+varIBDV). HVT-IBDV vaccination was given via the in ovo route to 18-day-old embryonated eggs. MdLV was administered via the subcutaneous route in day-old broilers. Group 2, Group 4 and Group 6 were orally challenged with varIBDV (SK-09, 3×10 3 EID 50 ) at day 6 post-hatch. IBDV seroconversion, bursal weight to body weight ratio (BBW) and bursal histopathology were assessed at 19 and 35days of age. Histopathological examination at day 19 revealed that varIBDV-SK09 challenge caused severe bursal atrophy and lower BBW in HVT-IBDV but not in MdLV vaccinated chicks. However by day 35, all challenged groups showed bursal atrophy and seroconversion. Interestingly, RT-qPCR analysis after varIBDV-SK09 challenge demonstrated an early (9days of age) and significantly high viral load (∼5744 folds) in HVT-IBDV vaccinated group vs unvaccinated challenged group (∼2.25 folds). Furthermore, flow cytometry analysis revealed inhibition of cytotoxic CD8 + T-cell response (CD44-downregulation) and decreased splenic lymphocytes counts in chicks after HVT-IBDV vaccination. Overall, our data suggest that MdLV delays varIBDV pathogenesis, whereas, HVT-IBDV vaccine is potentially immunosuppressive, which may increase the risk of

  16. VARIANT project - further progress

    Science.gov (United States)

    Korepanov, V.; Negoda, O.; Alleyne, H.; Balikhin, M.; Fedorov, A.; Juchniewicz, J.; Klimov, S.; Krasnoselskikh, V.; Lefeuvre, F.; Lizunov, G.

    VARIANT is a joint international space experiment which will be performed onboard the Ukrainian remote sensing satellite SICH-1M, that will be launched in 2003 at the polar circular orbit with the altitude 670s30 km. The scientific payload includes three instruments for registration of space current density: split Langmuir probe, Rogovski coil and Faraday cup. The equipment also includes sensors for measurements of electric and magnetic fields in the frequency range from DC to 40 kHz. Main objectives of the VARIANT mission are as follows: u direct comparison of the spectral characteristics of the electric and magnetic fields with the characteristics of the field aligned currents in the polar regions; mapping of the field aligned current distribution; u comparative study of the field aligned current structures with the characteristics of the ionospheric convection observed by the system of radars SuperDARN; u comparative study of technological problems associated with different techniques of current density measurements; and the secondary objectives are: u active experiments with the onboard radar; registration of the signatures of the seismo-active and volcanic phenomena; investigation of the man-made impact upon the ionosphere (anthropogenichazards, pollution, etc). Recent space experiments tendency U smaller and cheaper U stimulated the new approach to the functions division between scientific instruments and DPU. The peculiarities of such approach and the practical example of onboard DPU for VARIANT experiment to be launched next year are reported. Flight model of the VARIANT instrument is already installed onboard the satellite and successfully tested. The methodological questions of the spatial current density direct measurement in space plasma are constantly studied and recent advances in this branch, as well as the experimental tests results are discussed. This work was partially supported by NSAU contract 1221 and INTAS grant 2000-465.

  17. Cryptanalysis of SIMON Variants with Connections

    DEFF Research Database (Denmark)

    Alizadeh, Javad; Alkhzaimi, Hoda A.; Aref, Mohammad Reza

    2014-01-01

    attacks extend to all variants of SIMON covering more rounds compared to any known results using linear cryptanalysis. We present a key recovery attack against SIMON128/256 which covers 35 out of 72 rounds with data complexity 2123. We have implemented our attacks for small scale variants of SIMON and our...

  18. Comparative study on the immunogenicity between an HLA-A24-restricted cytotoxic T-cell epitope derived from survivin and that from its splice variant survivin-2B in oral cancer patients

    Directory of Open Access Journals (Sweden)

    Yamaguchi Akira

    2009-01-01

    Full Text Available Abstract Background We previously reported an HLA-A24-restricted cytotoxic T-cell epitope, Survivin-2B80-88, derived from a splice variant of survivin, survivin-2B. In this report, we show a novel HLA-A24-restricted T-cell epitope, Survivin-C58, derived from a wild type survivin, and compared their immunogenicity in oral cancer patients. Methods By stimulating peripheral blood lymphocytes of HLA-A24-positive cancer patients with Survivin-C58 peptide in vitro, the peptide-specific CTLs were induced. In order to compare the immunogenic potential between C58 peptide and 2B80-88 peptide, peripheral blood T-cells from thirteen HLA-A24-positive oral cancer patients were stimulated with either or both of these two peptides. Results Survivin-2B80-88 peptide-specific CTLs were induced from four patients, and C58 peptide-specific CTLs were induced from three out of eight patients with over stage II progression. The CTLs exerted cytotoxicity against HLA-A24-positive tumor cells. In contrast, CTL induction failed from a healthy volunteer and all four patients with cancer stage I. Conclusion It was indicated that a splicing variant-derived peptide and wild type survivin-derived peptide might have a comparable potency of CTL induction, and survivin targeting immunotherapy using survivin-2B80-88 and C58 peptide cocktail should be suitable for HLA-A24+ oral cancer patients.

  19. Rare variant density across the genome and across populations

    OpenAIRE

    Raska Paola; Zhu Xiaofeng

    2011-01-01

    Abstract Next-generation sequencing allows for a new focus on rare variant density for conducting analyses of association to disease and for narrowing down the genomic regions that show evidence of functionality. In this study we use the 1000 Genomes Project pilot data as distributed by Genetic Analysis Workshop 17 to compare rare variant densities across seven populations. We made the comparisons using regressions of rare variants on total variant counts per gene for each population and Taji...

  20. Desmoplastic variant of ameloblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Jeong Ick; Kim, Dong Youn; Choi, Karp Shik [Dept. of Dental Radiology, College of Dentistry, Kyungpook National University, Daegu (Korea, Republic of)

    1995-02-15

    Desmoplastic variant of ameloblastoma is new and unusual variant of ameloblastoma with extensive stromal desmoplastic proliferation. The authors experienced a case of desmoplastic variant of amleloblastoma with moderate-defined radiolucency on the right maxillary anterior area in 62-year-old female. As a result of careful analysis of clinical, radiological examinations, we diagnosed it as desmoplastic variant of ameloblastoma. The following results were obtained; 1. Main clinical symptoms were nontender bony swelling with normal intact overlying mucosa on the right maxillary anterior area. 2. Radiographically, moderate-defined, multilocular radioluceney on the right maxillary anterior area were shown, and severe cortical bony thinning and expansion to labial and palatal sides were also observed. And this lesion was shown to be extended to the right nasal cavity. 3. Histopathologically, follicle-like epithelial islands with densely abundant collagenous stroma were morphologically compressed.

  1. Reverse or inverted takotsubo cardiomyopathy (reverse left ventricular apical ballooning syndrome) presents at a younger age compared with the mid or apical variant and is always associated with triggering stress.

    Science.gov (United States)

    Ramaraj, Radhakrishnan; Movahed, Mohammad Reza

    2010-01-01

    Takotsubo cardiomyopathy is usually caused by triggering stress. It has 4 different subtypes. There has been no consensus to differentiate various types with regard to characteristics of the patient population. The goal of this study was to evaluate any clinical differences between the reverse type in comparison to common apical and mid-cavitary types using case series of reported cases. The authors searched published articles in PubMed and Medline on takotsubo or stress-induced cardiomyopathy. They included only cases that reported different types of takotsubo cardiomyopathy with baseline clinical characteristics. They identified 60 patients for the final analysis. The types of takotsubo cardiomyopathy seen in this study are classified as classic (66.7%), mid-cavitary (10%), or reverse (inverted) (23.3%). Patients with reverse-type takotsubo cardiomyopathy were significantly younger compared with those with other types (mean age, 36 for reverse vs 62 for other types; Pcardiomyopathy, the reverse or inverted variant presents at a younger age and is always associated with a triggering of emotional or physical stress. © 2010 Wiley Periodicals, Inc.

  2. Frequency of thermostability variants: estimation of total rare variant frequency in human populations

    Energy Technology Data Exchange (ETDEWEB)

    Mohrenweiser, H.W.; Neel, J.V.

    1981-09-01

    Eight erythrocyte enzymes were examine for thermostability in an unselected sample of 100 newborn infants. Three thermolabile variants, one each of lactate dehydrogenase, glucosephosphate isomerase, and glucose-6-phosphate dehydrogenase, were identified, none of which was detectable as a variant by standard electrophoretic techniques. All were inherited. This frequency of 3.8 heritable thermostability variants per 1000 determinations is to be compared with a frequency of electrophoretically detectable variants of 1.1 per 1000 determinations, a frequency of 2.4 enzyme-deficiency variants per 1000 determinations, and a frequency of individuals with rare enzyme deficiency or electrophoretic or thermostability (or both) variants at these loci is 8.4 per 1000 determinations. A similar distribution and frequency is seen when the comparison is limited to the seven loci studied by all techniques. it is clear that not all of the electrophoretic and thermostability variants present in the population are detected by the techniques used in this study. Accordingly, it is estimated that the true frequency of carriers of a rare variant for each of these enzyme-coding loci averages greater than 10/1000. Some implications of these frequencies for human disease are discussed.

  3. Human immunodeficiency virus type 1 Brazilian subtype B variant showed an increasing avidity of the anti-V3 antibodies over time compared to the subtype B US/European strain in São Paulo, Brazil

    Directory of Open Access Journals (Sweden)

    Casseb Jorge

    2004-01-01

    Full Text Available The Brazilian variant of human immunodeficiency virus type 1 (HIV-1 subtype B, (serotype B"-GWGR, has a tryptophan replacing the proline in position 328 the HIV-1 envelope. A longer median time period from infection to acquired immunodeficiency syndrome (AIDS for serotype B (B"-GWGR infected subjects compared to the B-GPGR US/European strain was reported. In a cohort study, in São Paulo city, 10 B"-GWGR patients had a statistically significant increased avidity of the anti-V3 antibodies, from 79% ± 33% to 85% ± 75%, versus from 48% ± 59% to 32% ± 17% for the 10 B-GPGR subjects (p = 0.02. The T CD4+ cells showed a mean increase of + 0.45 cells/month for the B-GPGR subjects and for B"-GWGR the slope was + 1.24 cells/month (p = 0.06, for 62 and 55 months of follow up, respectively. RNA plasma viral load decreased from 3.98 ± 1.75 to 2.16 ± 1.54 log10 in the B"-GWGR group while B-GPGR patients showed one log10 reduction in viral load from 4.09 ± 0.38 to 3.17 ± 1.47 log10 over time (p = 0.23, with a decreasing slope of 0.0042 ± log10,/month and 0.0080 ± log10/month, for B-GPGR and B"-GWGR patients, respectively (p = 0.53. Neither group presented any AIDS defining events during the study, according to Center for Diseases Control criteria. Although the sample size is small, these results may indicate that differences in the pathogenicity of the 2 HIV-1 B serotypes which co-circulate in Brazil may be correlated to the avidity of anti-V3 antibodies.

  4. Hemoglobin Variants in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Popp, Raymond A.

    1965-04-22

    Variability among mammalian hemoglobins was observed many years ago (35). The chemical basis for differences among hemoglobins from different species of mammals has been studied by several investigators (5, 11, 18, 48). As well as interspecies differences, hemoglobin variants are frequently found within a species of mammals (2, 3, 7, 16) The inheritance of these intraspecies variants can be studied, and pedigrees indicate that the type of hemoglobin synthesized in an individual is genetically controlled (20). Several of the variant human hemoglobins are f'unctionally deficient (7, 16). Such hemoglobin anomalies are of basic interest to man because of the vital role of hemoglobin for transporting oxygen to all tissues of the body.

  5. Hemoglobin Variant Profiles among Brazilian Quilombola Communities.

    Science.gov (United States)

    Santiago, Rayra P; Oliveira, Rodrigo M; Soares, Leonardo F; Figueiredo, Camylla V B; Silva, Denise Oliveira; Hurtado-Guerrero, Ana F; Fiuza, Luciana M; Guarda, Caroline C; Adorno, Elisângela V; Barbosa, Cynara G; Gonçalves, Marilda S

    2017-03-01

    Brazilian Quilombolas are communities composed of African-derived populations that have their territories guaranteed by the Brazilian Constitution. The present study investigated the hemoglobin (Hb) variants among these population groups. This study was conducted in a total of 2843 individuals of Brazilian Quilombola communities of the Bahia, Pará, and Piauí states. All the participants had their Hb profiles evaluated. The Hb S (HBB: c.20A>T) variant was described in all the studied localities. However, the individuals in Bahia State had the highest frequency of the Hb C (HBB: c.19G>A) variant; individuals from Piauí State had a higher frequency of the Hb D-Punjab (HBB: c.364G>C) variant compared to the other states, and individuals from Pará State only carried the Hb S variant. The present study revealed a specific distribution of Hb variants that could represent different waves of African influence in these Brazilian populations.

  6. Gardner's Minichess Variant is solved

    OpenAIRE

    Mhalla, Mehdi; Prost, Frederic

    2013-01-01

    A 5x5 board is the smallest board on which one can set up all kind of chess pieces as a start position. We consider Gardner's minichess variant in which all pieces are set as in a standard chessboard (from Rook to King). This game has roughly 9x10^{18} legal positions and is comparable in this respect with checkers. We weakly solve this game, that is we prove its game-theoretic value and give a strategy to draw against best play for White and Black sides. Our approach requires surprisingly sm...

  7. [Histone variants and histone exchange].

    Science.gov (United States)

    Wu, Nan; Gui, Jian-Fang

    2006-04-01

    Histones, as the basic components of nucleosome, are essential to chromatin structure and function. To adapt to various states of chromatin, corresponding histone variants are incorporated in nucleosome, and certain modifications also occur on the variants' tails. These variants change the conformation and stability of nucleosome to facilitate transcriptional activation or deactivation, DNA repairing, heterochromatin formation, and others. During histone exchange, chromatin remodeling complex facilitates histone variant deposition into nucleosome, and different variants have diverse deposition pathways. Recently, research on histone variants is not only a new hotspot in epigenetics, but also a new annotation of "histone code". In addition, histone exchange reveals new changing mechanism of DNA-histone interaction.

  8. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group

    NARCIS (Netherlands)

    Tallman, Martin S.; Kim, Haesook T.; Montesinos, Pau; Appelbaum, Frederick R.; de la Serna, Javier; Bennett, John M.; Deben, Guillermo; Bloomfield, Clara D.; Gonzalez, Jose; Feusner, James H.; Gonzalez, Marcos; Gallagher, Robert; Gonzalez-San Miguel, Jose D.; Larson, Richard A.; Milone, Gustavo; Paietta, Elisabeth; Rayon, Chelo; Rowe, Jacob M.; Rivas, Concha; Schiffer, Charles A.; Vellenga, Edo; Shepherd, Lois; Slack, James L.; Wiernik, Peter H.; Willman, Cheryl L.; Sanz, Miguel A.

    2010-01-01

    Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-transretinoic acid-based therapy on 3 clinical trials, North American

  9. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  10. Laboratory testing of hemolytic properties of materials that come in contact with blood: Comparative application testing method’s two variants according to the standard ASTM F756 in accordance with ISO 10993-4

    OpenAIRE

    Pavlović Katarina B.; Božanić Vojislav N.; Stanojević Jasna V.; Milićević Vesna K.; Ilić Bojan J.

    2010-01-01

    The presence of hemolytic material in contact with blood may produce increased levels of blood cell lysis and increased levels of plasma hemoglobin. This may induce toxic effects or other effects which may stress the kidneys or other organs. In this paper two variants of in vitro method and obtained results’ comparison were presented for testing of hemolytic properties of six raw materials (Polipropylene Moplen EP 540 P, Policarbonate colorless 164 R-112, Policarbonate brown 164 R-51918, Poli...

  11. Variants of glycoside hydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Teter, Sarah; Ward, Connie; Cherry, Joel; Jones, Aubrey; Harris, Paul; Yi, Jung

    2017-07-11

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  12. Word Variant Identification in Old French

    Directory of Open Access Journals (Sweden)

    Peter Willett

    1997-01-01

    Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

  13. Identification of HPV variants.

    Science.gov (United States)

    Cason, John; Bible, Jon; Mant, Christine

    2005-01-01

    The vast majority of anogenital carcinomas are caused by high-risk human papillomaviruses (HPVs), and among Western nations HPV-16 is usually the most predominant cancer-associated type. As a DNA virus, HPV type 16 has a relatively stable genome that is believed to have co-evolved with its host over the millennia. Nevertheless, among the "wild" populations of HPV-16 that are circulating, a large number of variants have been identified, and these may have considerably different pathogenic potentials. In this chapter, methods for screening and characterizing HPV-16 sequence variants are described. In particular, we describe methods for the identification of variation within the HPV-16 E5 open reading frame and for the detection of the nt 131 A-->G mutation of the E6 ORF, using restriction fragment length polymorphism assays. In addition, we describe approaches for DNA sequencing and analysis. Such methods are likely to be of particular interest to those involved in epidemiological investigations of virus transmission and pathogenicity studies.

  14. Distribution of human papillomavirus type 16 variants in Lithuanian women with cervical cancer

    Directory of Open Access Journals (Sweden)

    Živilė Gudlevičienė

    2015-01-01

    Conclusions: The European HPV 16 L83V variant is usually associated with high risk of cervical cancer among women. However, statistically significant difference was not achieved when comparing difference of L83V variants between investigated groups and in HPV 16 L83V variant and prototype distribution in CIN3/Ca in situ and cancer.

  15. Variants of windmill nystagmus.

    Science.gov (United States)

    Choi, Kwang-Dong; Shin, Hae Kyung; Kim, Ji-Soo; Kim, Sung-Hee; Choi, Jae-Hwan; Kim, Hyo-Jung; Zee, David S

    2016-07-01

    Windmill nystagmus is characterized by a clock-like rotation of the beating direction of a jerk nystagmus suggesting separate horizontal and vertical oscillators, usually 90° out of phase. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. Two patients showed a clock-like pattern, while in the third, the nystagmus was largely diagonal (in phase or 180° out of phase) but also periodically changed direction by 180°. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind." It emerges when the central structures, including the cerebellum, that normally keep eye movements calibrated and gaze steady can no longer perform their task, because they are deprived of the retinal image motion that signals a need for adaptive recalibration.

  16. Detecting rare variants in case-parents association studies.

    Directory of Open Access Journals (Sweden)

    Kuang-Fu Cheng

    Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

  17. Incorporating Non-Coding Annotations into Rare Variant Analysis.

    Directory of Open Access Journals (Sweden)

    Tom G Richardson

    Full Text Available The success of collapsing methods which investigate the combined effect of rare variants on complex traits has so far been limited. The manner in which variants within a gene are selected prior to analysis has a crucial impact on this success, which has resulted in analyses conventionally filtering variants according to their consequence. This study investigates whether an alternative approach to filtering, using annotations from recently developed bioinformatics tools, can aid these types of analyses in comparison to conventional approaches.We conducted a candidate gene analysis using the UK10K sequence and lipids data, filtering according to functional annotations using the resource CADD (Combined Annotation-Dependent Depletion and contrasting results with 'nonsynonymous' and 'loss of function' consequence analyses. Using CADD allowed the inclusion of potentially deleterious intronic variants, which was not possible when filtering by consequence. Overall, different filtering approaches provided similar evidence of association, although filtering according to CADD identified evidence of association between ANGPTL4 and High Density Lipoproteins (P = 0.02, N = 3,210 which was not observed in the other analyses. We also undertook genome-wide analyses to determine how filtering in this manner compared to conventional approaches for gene regions. Results suggested that filtering by annotations according to CADD, as well as other tools known as FATHMM-MKL and DANN, identified association signals not detected when filtering by variant consequence and vice versa.Incorporating variant annotations from non-coding bioinformatics tools should prove to be a valuable asset for rare variant analyses in the future. Filtering by variant consequence is only possible in coding regions of the genome, whereas utilising non-coding bioinformatics annotations provides an opportunity to discover unknown causal variants in non-coding regions as well. This should allow

  18. Variants of beta-glucosidase

    Energy Technology Data Exchange (ETDEWEB)

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2015-07-14

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  19. Variants of beta-glucosidases

    Energy Technology Data Exchange (ETDEWEB)

    Fidantsef, Ana; Lamsa, Michael; Gorre-Clancy, Brian

    2014-10-07

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  20. Variants of beta-glucosidase

    Science.gov (United States)

    Fidantsef, Ana [Davis, CA; Lamsa, Michael [Davis, CA; Gorre-Clancy, Brian [Elk Grove, CA

    2009-12-29

    The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions 142, 183, 266, and 703 of amino acids 1 to 842 of SEQ ID NO: 2 or corresponding to positions 142, 183, 266, and 705 of amino acids 1 to 844 of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  1. Product Variant Master as a Means to Handle Variant Design

    DEFF Research Database (Denmark)

    Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

    1996-01-01

    be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules......, assemblies, and parts. Implementation in an industrial company shows that considerable rationalisation effects can be achieved...

  2. Variant view: visualizing sequence variants in their gene context.

    Science.gov (United States)

    Ferstay, Joel A; Nielsen, Cydney B; Munzner, Tamara

    2013-12-01

    Scientists use DNA sequence differences between an individual's genome and a standard reference genome to study the genetic basis of disease. Such differences are called sequence variants, and determining their impact in the cell is difficult because it requires reasoning about both the type and location of the variant across several levels of biological context. In this design study, we worked with four analysts to design a visualization tool supporting variant impact assessment for three different tasks. We contribute data and task abstractions for the problem of variant impact assessment, and the carefully justified design and implementation of the Variant View tool. Variant View features an information-dense visual encoding that provides maximal information at the overview level, in contrast to the extensive navigation required by currently-prevalent genome browsers. We provide initial evidence that the tool simplified and accelerated workflows for these three tasks through three case studies. Finally, we reflect on the lessons learned in creating and refining data and task abstractions that allow for concise overviews of sprawling information spaces that can reduce or remove the need for the memory-intensive use of navigation.

  3. Impact of Pathogen Population Heterogeneity and Stress-Resistant Variants on Food Safety.

    Science.gov (United States)

    Abee, T; Koomen, J; Metselaar, K I; Zwietering, M H; den Besten, H M W

    2016-01-01

    This review elucidates the state-of-the-art knowledge about pathogen population heterogeneity and describes the genotypic and phenotypic analyses of persister subpopulations and stress-resistant variants. The molecular mechanisms underlying the generation of persister phenotypes and genetic variants are identified. Zooming in on Listeria monocytogenes, a comparative whole-genome sequence analysis of wild types and variants that enabled the identification of mutations in variants obtained after a single exposure to lethal food-relevant stresses is described. Genotypic and phenotypic features are compared to those for persistent strains isolated from food processing environments. Inactivation kinetics, models used for fitting, and the concept of kinetic modeling-based schemes for detection of variants are presented. Furthermore, robustness and fitness parameters of L. monocytogenes wild type and variants are used to model their performance in food chains. Finally, the impact of stress-resistant variants and persistence in food processing environments on food safety is discussed.

  4. Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP.

    Directory of Open Access Journals (Sweden)

    Sanjay Sonney

    2017-12-01

    Full Text Available Novel or rare variants in mitochondrial tRNA sequences may be observed after mitochondrial DNA analysis. Determining whether these variants are pathogenic is critical, but confirmation of the effect of a variant on mitochondrial function can be challenging. We have used available databases of benign and pathogenic variants, alignment between diverse tRNAs, structural information and comparative genomics to predict the impact of all possible single-base variants and deletions. The Mitochondrial tRNA Informatics Predictor (MitoTIP is available through MITOMAP at www.mitomap.org. The source code for MitoTIP is available at www.github.com/sonneysa/MitoTIP.

  5. Gene Variants Reduce Opioid Risks

    Science.gov (United States)

    ... common variant (A). Text Description of Graphic Genetic Markers for Individualized Treatments Dr. Jamie Biswas, Chief of ... other health and disease indications—such as cancer, heart disease, and opportunistic infections.” The studies were supported by ...

  6. Functional characterization of 21 allelic variants of dihydropyrimidinase.

    Science.gov (United States)

    Hishinuma, Eiji; Akai, Fumika; Narita, Yoko; Maekawa, Masamitsu; Yamaguchi, Hiroaki; Mano, Nariyasu; Oda, Akifumi; Hirasawa, Noriyasu; Hiratsuka, Masahiro

    2017-11-01

    Dihydropyrimidinase (DHP, EC 3.5.2.2), encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, Km, Vmax, and intrinsic clearance (Vmax/Km), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Robust and Powerful Affected Sibpair Test for Rare Variant Association.

    Science.gov (United States)

    Lin, Keng-Han; Zöllner, Sebastian

    2015-07-01

    Advances in DNA sequencing technology facilitate investigating the impact of rare variants on complex diseases. However, using a conventional case-control design, large samples are needed to capture enough rare variants to achieve sufficient power for testing the association between suspected loci and complex diseases. In such large samples, population stratification may easily cause spurious signals. One approach to overcome stratification is to use a family-based design. For rare variants, this strategy is especially appropriate, as power can be increased considerably by analyzing cases with affected relatives. We propose a novel framework for association testing in affected sibpairs by comparing the allele count of rare variants on chromosome regions shared identical by descent to the allele count of rare variants on nonshared chromosome regions, referred to as test for rare variant association with family-based internal control (TRAFIC). This design is generally robust to population stratification as cases and controls are matched within each sibpair. We evaluate the power analytically using general model for effect size of rare variants. For the same number of genotyped people, TRAFIC shows superior power over the conventional case-control study for variants with summed risk allele frequency f < 0.05; this power advantage is even more substantial when considering allelic heterogeneity. For complex models of gene-gene interaction, this power advantage depends on the direction of interaction and overall heritability. In sum, we introduce a new method for analyzing rare variants in affected sibpairs that is robust to population stratification, and provide freely available software. © 2015 WILEY PERIODICALS, INC.

  8. Hemoglobin Variants in Northern Thailand: Prevalence, Heterogeneity and Molecular Characteristics.

    Science.gov (United States)

    Panyasai, Sitthichai; Fucharoen, Goonnapa; Fucharoen, Supan

    2016-01-01

    There are limited data on hemoglobin (Hb) variants among peoples of northern Thailand. Hence, we determined the prevalence of Hb variants among a large cohort from this region. A study was done on 23,914 subjects recruited from eight provinces during June 2012-January 2014. Hb was analyzed by high performance liquid chromatography (HPLC) and capillary electrophoresis, and corresponding mutations were identified by polymerase chain reaction. Among 23,914 subjects examined, 211 (0.88%) were found to carry 14 different Hb variants. Five α-globin chain variants were identified: Hb Q-Thailand (n = 40; 19.0%), Hb Hekinan (n = 8, 3.8%), Hb Siam (n = 2, 0.9%), Hb Beijing (n = 1, 0.5%), and Hb Kawachi (n = 1, 0.5%), not previously described in the Thai population. Seven β-globin variants, including Hb Hope, Hb Tak, Hb S, Hb J-Bangkok, Hb G-Makassar, Hb C, and Hb Korle-Bu, were found in 115 (54.5%), 30 (14.2%), 3 (1.4%), 3 (1.4%), 1 (0.5%), 1 (0.5%), and 1 (0.5%) subjects, respectively. The remaining five subjects (2.4%) were carriers of two different δ-globin chain variants. A different spectrum and frequencies of Hb variants were noted compared to other geographical areas. Haplotype analysis demonstrated multiple origins for Hbs Hope and Tak and confirmed a non-African origin of Hb C. Several genetic interactions between these variants with other hemoglobinopathies were encountered. Associated hematological phenotypes and novel Hb derivatives formed were presented. The prevalence and molecular heterogeneities of the Hb variants found in this large cohort of the northern Thai people's should prove useful in developing a screening program, and for the performance of additional population genetics studies of hemoglobinopathy in the region.

  9. Variants of glycerol dehydrogenase having D-lactate dehydrogenase activity and uses thereof

    Science.gov (United States)

    Wang, Qingzhao; Shanmugam, Keelnatham T.; Ingram, Lonnie O'Neal

    2017-08-29

    The present invention provides methods of designing and generating glycerol dehydrogenase (GlyDH) variants that have altered function as compared to a parent polypeptide. The present invention further provides nucleic acids encoding GlyDH polypeptide variants having altered function as compared to the parent polypeptide. Host cells comprising polynucleotides encoding GlyDH variants and methods of producing lactic acids are also provided in various aspects of the invention.

  10. Structure of chymotrypsin variant B from Atlantic cod, Gadus morhua

    DEFF Research Database (Denmark)

    Leth-Larsen, Rikke; Asgeirsson, B; Thórólfsson, M

    1996-01-01

    The amino-acid sequence of chymotrypsin variant B isolated from the pyloric caeca of Atlantic cod has been elucidated. The characterization of the primary structure is based on N-terminal Edman degradation and mass spectrometry of the native protein and enzymatically derived peptides. Chymotrypsin...... variant B showed 72% sequence identity with the A-variant and 64% and 62%, respectively, with the bovine counterparts A and B, all consisting of 245 amino acids. This new sequence contains a higher proportion of charged residues compared with bovine chymotrypsin but fewer polar hydrogen-bond forming...... side-chains may contribute to the maintenance of flexibility at low temperatures. Several amino-acid sequence differences adjacent to the catalytic site are observed in the two cod chymotrypsin variants which also differ in kinetic properties. Unlike the mammalian chymotrypsins, which contain several...

  11. Disease-associated variants in different categories of disease located in distinct regulatory elements.

    Science.gov (United States)

    Ma, Meng; Ru, Ying; Chuang, Ling-Shiang; Hsu, Nai-Yun; Shi, Li-Song; Hakenberg, Jörg; Cheng, Wei-Yi; Uzilov, Andrew; Ding, Wei; Glicksberg, Benjamin S; Chen, Rong

    2015-01-01

    The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (qdisease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively. Disease-associated variants in different disease categories are preferentially located in particular regulatory

  12. Comparison of Motor Inhibition in Variants of the Instructed-Delay Choice Reaction Time Task.

    Science.gov (United States)

    Quoilin, Caroline; Lambert, Julien; Jacob, Benvenuto; Klein, Pierre-Alexandre; Duque, Julie

    2016-01-01

    Using instructed-delay choice reaction time (RT) paradigms, many previous studies have shown that the motor system is transiently inhibited during response preparation: motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex are typically suppressed during the delay period. This effect has been observed in both selected and non-selected effectors, although MEP changes in selected effectors have been more inconsistent across task versions. Here, we compared changes in MEP amplitudes in three different variants of an instructed-delay choice RT task. All variants required participants to choose between left and right index finger movements but the responses were either provided "in the air" (Variant 1), on a regular keyboard (Variant 2), or on a response device designed to control from premature responses (Variant 3). The task variants also differed according to the visual layout (more concrete in Variant 3) and depending on whether participants received a feedback of their performance (absent in Variant 1). Behavior was globally comparable between the three variants of the task although the propensity to respond prematurely was highest in Variant 2 and lowest in Variant 3. MEPs elicited in a non-selected hand were similarly suppressed in the three variants of the task. However, significant differences emerged when considering MEPs elicited in the selected hand: these MEPs were suppressed in Variants 1 and 3 whereas they were often facilitated in Variant 2, especially in the right dominant hand. In conclusion, MEPs elicited in selected muscles seem to be more sensitive to small variations to the task design than those recorded in non-selected effectors, probably because they reflect a complex combination of inhibitory and facilitatory influences on the motor output system. Finally, the use of a standard keyboard seems to be particularly inappropriate because it encourages participants to respond promptly with no

  13. Data-variant kernel analysis

    CERN Document Server

    Motai, Yuichi

    2015-01-01

    Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

  14. Performance comparison of various time variant filters

    Energy Technology Data Exchange (ETDEWEB)

    Kuwata, M. [JEOL Engineering Co. Ltd., Akishima, Tokyo (Japan); Husimi, K.

    1996-07-01

    This paper describes the advantage of the trapezoidal filter used in semiconductor detector system comparing with the other time variant filters. The trapezoidal filter is the compose of a rectangular pre-filter and a gated integrator. We indicate that the best performance is obtained by the differential-integral summing type rectangular pre-filter. This filter is not only superior in performance, but also has the useful feature that the rising edge of the output waveform is linear. We introduce an example of this feature used in a high-energy experiment. (author)

  15. Prevalence of Titin Truncating Variants in General Population.

    Directory of Open Access Journals (Sweden)

    Oyediran Akinrinade

    Full Text Available Truncating titin (TTN mutations, especially in A-band region, represent the most common cause of dilated cardiomyopathy (DCM. Clinical interpretation of these variants can be challenging, as these variants are also present in reference populations. We carried out systematic analyses of TTN truncating variants (TTNtv in publicly available reference populations, including, for the first time, data from Exome Aggregation Consortium (ExAC. The goal was to establish more accurate estimate of prevalence of different TTNtv to allow better clinical interpretation of these findings.Using data from 1000 Genomes Project, Exome Sequencing Project (ESP and ExAC, we estimated the prevalence of TTNtv in the population. In the three population datasets, 52-54% of TTNtv were not affecting all TTN transcripts. The frequency of truncations affecting all transcripts in ExAC was 0.36% (0.32% - 0.41%, 95% CI and 0.19% (0.16% - 0.23%, 95% CI for those affecting the A-band. In the A-band region, the prevalences of frameshift, nonsense and essential splice site variants were 0.057%, 0.090%, and 0.047% respectively. Cga/Tga (arginine/nonsense-R/* transitional change at CpG mutation hotspots was the most frequent type of TTN nonsense mutation accounting for 91.3% (21/23 of arginine residue nonsense mutation (R/* at TTN A-band region. Non-essential splice-site variants had significantly lower proportion of private variants and higher proportion of low-frequency variants compared to essential splice-site variants (P = 0.01; P = 5.1 X 10-4, respectively.A-band TTNtv are more rare in the general population than previously reported. Based on this analysis, one in 500 carries a truncation in TTN A-band suggesting the penetrance of these potentially harmful variants is still poorly understood, and some of these variants do not manifest as autosomal dominant DCM. This calls for caution when interpreting TTNtv in individuals and families with no history of DCM. Considering the

  16. Certain variants of multipermutohedron ideals

    Indian Academy of Sciences (India)

    016-0313-4. Certain variants of multipermutohedron ideals. AJAY KUMAR1,2 and CHANCHAL KUMAR1,∗. 1Indian Institute of ... 2010 Mathematics Subject Classification. 05E40 .... eral questions and conjectures from [10] and [5]. In particular ...

  17. Likelihood ratio tests in rare variant detection for continuous phenotypes.

    Science.gov (United States)

    Zeng, Ping; Zhao, Yang; Liu, Jin; Liu, Liya; Zhang, Liwei; Wang, Ting; Huang, Shuiping; Chen, Feng

    2014-09-01

    It is believed that rare variants play an important role in human phenotypes; however, the detection of rare variants is extremely challenging due to their very low minor allele frequency. In this paper, the likelihood ratio test (LRT) and restricted likelihood ratio test (ReLRT) are proposed to test the association of rare variants based on the linear mixed effects model, where a group of rare variants are treated as random effects. Like the sequence kernel association test (SKAT), a state-of-the-art method for rare variant detection, LRT and ReLRT can effectively overcome the problem of directionality of effect inherent in the burden test in practice. By taking full advantage of the spectral decomposition, exact finite sample null distributions for LRT and ReLRT are obtained by simulation. We perform extensive numerical studies to evaluate the performance of LRT and ReLRT, and compare to the burden test, SKAT and SKAT-O. The simulations have shown that LRT and ReLRT can correctly control the type I error, and the controls are robust to the weights chosen and the number of rare variants under study. LRT and ReLRT behave similarly to the burden test when all the causal rare variants share the same direction of effect, and outperform SKAT across various situations. When both positive and negative effects exist, LRT and ReLRT suffer from few power reductions compared to the other two competing methods; under this case, an additional finding from our simulations is that SKAT-O is no longer the optimal test, and its power is even lower than that of SKAT. The exome sequencing SNP data from Genetic Analysis Workshop 17 were employed to illustrate the proposed methods, and interesting results are described. © 2014 John Wiley & Sons Ltd/University College London.

  18. Swine Influenza/Variant Influenza Viruses

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

  19. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

    Science.gov (United States)

    Kasahara, Takaoki; Ishiwata, Mizuho; Kakiuchi, Chihiro; Fuke, Satoshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Minabe, Yoshio; Nakamura, Kazuhiko; Iwata, Yasuhide; Fujii, Kumiko; Kanba, Shigenobu; Ujike, Hiroshi; Kusumi, Ichiro; Kataoka, Muneko; Matoba, Nana; Takata, Atsushi; Iwamoto, Kazuya; Yoshikawa, Takeo; Kato, Tadafumi

    2017-08-01

    Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. © 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

  20. Semantic prioritization of novel causative genomic variants

    OpenAIRE

    Imane Boudellioua; Rozaimi B Mahamad Razali; Maxat Kulmanov; Yasmeen Hashish; Bajic, Vladimir B.; Eva Goncalves-Serra; Nadia Schoenmakers; Gkoutos, Georgios V.; Schofield, Paul N.; Robert Hoehndorf

    2017-01-01

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated rea...

  1. DHAD variants and methods of screening

    Energy Technology Data Exchange (ETDEWEB)

    Kelly, Kristen J.; Ye, Rick W.

    2017-02-28

    Methods of screening for dihydroxy-acid dehydratase (DHAD) variants that display increased DHAD activity are disclosed, along with DHAD variants identified by these methods. Such enzymes can result in increased production of compounds from DHAD requiring biosynthetic pathways. Also disclosed are isolated nucleic acids encoding the DHAD variants, recombinant host cells comprising the isolated nucleic acid molecules, and methods of producing butanol.

  2. Variant Humicola grisea CBH1.1

    Energy Technology Data Exchange (ETDEWEB)

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Larenas, Edmund

    2017-05-09

    Disclosed are variants of Humicola grisea CeI7A (CBH1.1), H. jecorina CBH1 variant or S. thermophilium CBH1, nucleic acids encoding the same and methods for producing the same. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

  3. Mendelian randomization analysis with multiple genetic variants using summarized data.

    Science.gov (United States)

    Burgess, Stephen; Butterworth, Adam; Thompson, Simon G

    2013-11-01

    Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10⁻⁵, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed. © 2013 WILEY PERIODICALS, INC.

  4. Cerivastatin, genetic variants, and the risk of rhabdomyolysis.

    Science.gov (United States)

    Marciante, Kristin D; Durda, Jon P; Heckbert, Susan R; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A; Tamraz, Bani; Kroetz, Deanna L; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C; Glazer, Nicole L; Li, Guo; Austin, Thomas R; Taylor, Kent D; Rotter, Jerome I; Jaquish, Cashell E; Kwok, Pui-Yan; Tracy, Russell P; Psaty, Bruce M

    2011-05-01

    The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63). We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.

  5. Coronary artery anatomy and variants.

    Science.gov (United States)

    Malagò, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicolì, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto

    2011-12-01

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions.

  6. Coronary artery anatomy and variants

    Energy Technology Data Exchange (ETDEWEB)

    Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)

    2011-12-15

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

  7. Clinicopathologic Variants of Mycosis Fungoides.

    Science.gov (United States)

    Muñoz-González, H; Molina-Ruiz, A M; Requena, L

    2017-04-01

    Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. The clinical course of the disease is typically characterized by progression from a nonspecific phase of erythematous macules to the appearance of plaques and ultimately, in some patients, tumors. However, numerous clinical and histopathologic variants of MF with specific therapeutic and prognostic implications have been described in recent decades. Clarification of the differential diagnosis can be frustrated by the wide range of clinical manifestations and histopathologic patterns of cutaneous infiltration, particularly in the early phases of the disease. In this paper, we review the main clinical, histopathologic, and immunohistochemical characteristics of the variants of MF described in the literature in order to facilitate early diagnosis of the disease. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy.

    Science.gov (United States)

    Peuchant, Olivia; Thiébaut, Rodolphe; Capdepont, Sophie; Lavignolle-Aurillac, Valérie; Neau, Didier; Morlat, Philippe; Dabis, François; Fleury, Hervé; Masquelier, Bernard

    2008-07-31

    The transmission of drug-resistant HIV-1 can impair the virological response to antiretroviral therapy. Minority-resistant variants have been detected in acute seroconverters. We investigated the clinical relevance of the detection of majority and minority-resistant variants in an observational study in antiretroviral therapy naive, recently infected patients. We included patients infected between 1996 and 2005, with a plasma sample obtained less than 18 months after seroconversion and prior to antiretroviral therapy initiation. Majority-resistant variants were determined by direct population sequencing. Minority-resistant variants were searched by allele-specific PCR for the mutations K103N and M184V in reverse transcriptase and L90M in protease. The association between resistance and viroimmunological response to antiretroviral therapy was estimated by using a piecewise linear mixed model. Majority-resistant variants were detected in 23/172 (13.4%) patients. Patients with majority-resistant variants had a lower mean plasma viral load and higher mean CD4 cell count at baseline compared with those without resistance. The decrease in viral load between 1 and 6 months on antiretroviral therapy was significantly steeper in patients with sensitive viruses compared with those with majority-resistant variants (P = 0.029). Minority-resistant variants were detected in 21/73 (29%) patients with wild-type viruses at sequencing analysis. The presence of minority-resistant variants did not modify baseline viral load and CD4 cell count and did not affect the changes in viral load and CD4 cell count. The transmission of majority-resistant variants, but not minority-resistant variants, influenced the response to antiretroviral therapy in this prospective study. The detection of the transmission of minority-resistant variants warrants further clinical validation.

  9. Microcystic Variant of Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2013-01-01

    Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

  10. A TIMP-1 splice variant transcript

    DEFF Research Database (Denmark)

    Øbro, Nina Friesgård; Lademann, Ulrik Axel; Birkenkamp-Demtroder, Karin

    2008-01-01

    A splice variant of tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA lacking exon 2 (TIMP-1-v2) has been identified in human cancer cells and in colorectal and breast cancer tumors. The purpose of this study was (1) to study the level of full length TIMP-1 and TIMP-1-v2 transcripts in color...... of TIMP-1 pre-mRNA to TIMP-1-v2 mRNA might be involved in regulating TIMP-1 expression.......A splice variant of tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA lacking exon 2 (TIMP-1-v2) has been identified in human cancer cells and in colorectal and breast cancer tumors. The purpose of this study was (1) to study the level of full length TIMP-1 and TIMP-1-v2 transcripts...... in colorectal tumors; (2) to investigate if TIMP-1-v2 is translated to protein. Full length TIMP-1 and TIMP-1-v2 mRNA levels were compared between colorectal tumors and normal mucosa by Q-PCR. Both full length TIMP-1 and TIMP-1-v2 transcripts were upregulated in tumor tissue. However, the level of TIMP-1-v2...

  11. [Specificities of the logopenic variant of primary progressive aphasia].

    Science.gov (United States)

    Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

    2015-01-01

    The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  12. A hierarchical particle swarm optimizer and its adaptive variant.

    Science.gov (United States)

    Janson, Stefan; Middendorf, Martin

    2005-12-01

    A hierarchical version of the particle swarm optimization (PSO) metaheuristic is introduced in this paper. In the new method called H-PSO, the particles are arranged in a dynamic hierarchy that is used to define a neighborhood structure. Depending on the quality of their so-far best-found solution, the particles move up or down the hierarchy. This gives good particles that move up in the hierarchy a larger influence on the swarm. We introduce a variant of H-PSO, in which the shape of the hierarchy is dynamically adapted during the execution of the algorithm. Another variant is to assign different behavior to the individual particles with respect to their level in the hierarchy. H-PSO and its variants are tested on a commonly used set of optimization functions and are compared to PSO using different standard neighborhood schemes.

  13. Detailed comparison of two popular variant calling packages for exome and targeted exon studies

    Directory of Open Access Journals (Sweden)

    Charles D. Warden

    2014-09-01

    Full Text Available The Genome Analysis Toolkit (GATK is commonly used for variant calling of single nucleotide polymorphisms (SNPs and small insertions and deletions (indels from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compare (1 the effects of different pre-processing steps prior to variant calling with both GATK and VarScan, (2 VarScan variants called with increasingly conservative parameters, and (3 filtered and unfiltered GATK variant calls (for both the UnifiedGenotyper and the HaplotypeCaller. Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets, each with approximately a dozen subjects. In most cases, pre-processing steps (e.g., indel realignment and quality score base recalibration using GATK had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. Based upon concordance statistics presented in this study, we recommend GATK users focus on “high-quality” GATK variants by filtering out variants flagged as low-quality. We also found that running VarScan with a conservative set of parameters (referred to as “VarScan-Cons” resulted in a reproducible list of variants, with high concordance (>97% to high-quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84–88% of the high-quality GATK SNPs in the exome datasets. This study also provides limited evidence that VarScan-Cons has a decreased false positive rate among novel variants (relative to high-quality GATK SNPs and that the GATK HaplotypeCaller has an increased false positive rate for indels (relative to VarScan-Cons and high-quality GATK Unified

  14. Detailed comparison of two popular variant calling packages for exome and targeted exon studies

    Science.gov (United States)

    Adamson, Aaron W.; Neuhausen, Susan L.

    2014-01-01

    The Genome Analysis Toolkit (GATK) is commonly used for variant calling of single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compare (1) the effects of different pre-processing steps prior to variant calling with both GATK and VarScan, (2) VarScan variants called with increasingly conservative parameters, and (3) filtered and unfiltered GATK variant calls (for both the UnifiedGenotyper and the HaplotypeCaller). Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets), each with approximately a dozen subjects. In most cases, pre-processing steps (e.g., indel realignment and quality score base recalibration using GATK) had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. Based upon concordance statistics presented in this study, we recommend GATK users focus on “high-quality” GATK variants by filtering out variants flagged as low-quality. We also found that running VarScan with a conservative set of parameters (referred to as “VarScan-Cons”) resulted in a reproducible list of variants, with high concordance (>97%) to high-quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84–88% of the high-quality GATK SNPs in the exome datasets. This study also provides limited evidence that VarScan-Cons has a decreased false positive rate among novel variants (relative to high-quality GATK SNPs) and that the GATK HaplotypeCaller has an increased false positive rate for indels (relative to VarScan-Cons and high-quality GATK UnifiedGenotyper indels

  15. Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans.

    Directory of Open Access Journals (Sweden)

    Jac M M J G Aarts

    Full Text Available Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.

  16. Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans

    Science.gov (United States)

    Alink, Gerrit M.; Scherjon, Fulco; MacDonald, Katharine; Smith, Alison C.; Nijveen, Harm; Roebroeks, Wil

    2016-01-01

    Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions. PMID:27655273

  17. Charge variant analysis of proposed biosimilar to Trastuzumab.

    Science.gov (United States)

    Dakshinamurthy, Pravinkumar; Mukunda, Pavithra; Prasad Kodaganti, Bhargav; Shenoy, Bharath Ravindra; Natarajan, Bairavabalakumar; Maliwalave, Amol; Halan, Vivek; Murugesan, Sathyabalan; Maity, Sunit

    2017-03-01

    Trastuzumab is a humanized monoclonal antibody (mAb) employed for the treatment of HER2 Positive Breast Cancer. A HER2 overexpressing tumor cell binds to Trastuzumab and attracts immune cells which lead to induction of Antibody Dependent Cellular Cytotoxicity (ADCC) by binding to Fc receptors (CD16a or FcγRIIIa) on an effector cell, such as natural killer (NK) cells. The most commonly expressed receptor on NK cell is CD16a which binds to the Fc portion of Trastuzumab. The ligand-independent HER2-HER3 dimerization is the most potent stimulator of downstream pathways for regulation of cell growth and survival. An attempt has been made in this study to understand the impact of charge heterogeneity on the binding kinetics and potency of the monoclonal antibody. Trastuzumab has a pI range of 8.7-8.9 and is composed of mixture of acidic and basic variants beside the main peak. Ion exchange chromatography was used to isolate the acidic, basic, and main peak fractions from in-house proposed biosimilar to Trastuzumab and their activities were compared to the Innovator Trastuzumab Herclon(®). Data from the mass analysis confirmed the potential modifications in both acidic and basic variant. Binding activity studies performed using Surface Plasmon Resonance (SPR) revealed that acidic variants had lesser binding to HER2 in comparison to the basic variants. Both acidic and basic variant showed no significant changes in their binding to soluble CD16a receptors. In vitro assay studies using a breast cancer cell line (BT-474) confirmed the binding potency of acidic variant to be lesser than basic variant, along with reduced anti-proliferative activity for the acidic variant of Trastuzumab. Overall, these data has provided meaningful insights to the impact of antibody charge variants on in vitro potency and CD16 binding affinity of trastuzumab. Copyright © 2016 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  18. Alternatively Spliced Human TREK-1 Variants Alter TREK-1 Channel Function and Localization.

    Science.gov (United States)

    Cowles, Chad L; Wu, Yi-Ying; Barnett, Scott D; Lee, Michael T; Burkin, Heather R; Buxton, Iain L O

    2015-11-01

    TREK-1, an outward-rectifying potassium channel activated by stretch, is found in the myometrium of pregnant women. Decreased expression of TREK-1 near term suggests that TREK-1 may contribute to uterine quiescence during gestation. Five alternatively spliced TREK-1 variants were identified in the myometrium of mothers who delivered spontaneously preterm (TREK-1 variants could interfere with TREK-1 function or expression. To investigate a potential role for these variants, immunofluorescence, cell surface assays, Western blots, and patch clamp were employed to study TREK-1 and TREK-1 variants expressed in HEK293T cells. The results of this study demonstrate that coexpression of TREK-1 with TREK-1 variants alters TREK-1 expression and suppresses channel function. Each variant affected TREK-1 in a disparate manner. In HEK293T cells coexpressing TREK-1 and each variant, TREK-1 membrane expression was diminished with compartmentalization inside the cell. When expressed alone, individual variants displayed channel properties that were significantly decreased compared to full-length TREK-1. In coexpression studies using patch clamp, basal TREK-1 currents were reduced by ∼64% (4.3 vs. 12.0 pA/pF) on average at 0 mV when coexpressed with each variant. TREK-1 currents that were activated by intracellular acidosis were reduced an average of ∼77% (21.4 vs. 94.5 pA/pF) at 0 mV when cells were transfected with TREK-1 and any one of the splice variants. These data correlate the presence of TREK-1 variants to reduced TREK-1 activity, suggesting a pathological role for TREK-1 variants in preterm labor. © 2015 by the Society for the Study of Reproduction, Inc.

  19. Alternatively Spliced Human TREK-1 Variants Alter TREK-1 Channel Function and Localization1

    Science.gov (United States)

    Cowles, Chad L.; Wu, Yi-Ying; Barnett, Scott D.; Lee, Michael T.; Burkin, Heather R.; Buxton, Iain L.O.

    2015-01-01

    TREK-1, an outward-rectifying potassium channel activated by stretch, is found in the myometrium of pregnant women. Decreased expression of TREK-1 near term suggests that TREK-1 may contribute to uterine quiescence during gestation. Five alternatively spliced TREK-1 variants were identified in the myometrium of mothers who delivered spontaneously preterm (TREK-1 variants could interfere with TREK-1 function or expression. To investigate a potential role for these variants, immunofluorescence, cell surface assays, Western blots, and patch clamp were employed to study TREK-1 and TREK-1 variants expressed in HEK293T cells. The results of this study demonstrate that coexpression of TREK-1 with TREK-1 variants alters TREK-1 expression and suppresses channel function. Each variant affected TREK-1 in a disparate manner. In HEK293T cells coexpressing TREK-1 and each variant, TREK-1 membrane expression was diminished with compartmentalization inside the cell. When expressed alone, individual variants displayed channel properties that were significantly decreased compared to full-length TREK-1. In coexpression studies using patch clamp, basal TREK-1 currents were reduced by ∼64% (4.3 vs. 12.0 pA/pF) on average at 0 mV when coexpressed with each variant. TREK-1 currents that were activated by intracellular acidosis were reduced an average of ∼77% (21.4 vs. 94.5 pA/pF) at 0 mV when cells were transfected with TREK-1 and any one of the splice variants. These data correlate the presence of TREK-1 variants to reduced TREK-1 activity, suggesting a pathological role for TREK-1 variants in preterm labor. PMID:26400398

  20. Rare Titin (TTN Variants in Diseases Associated with Sudden Cardiac Death

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    Oscar Campuzano

    2015-10-01

    Full Text Available A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.

  1. Variant Interpretation: Functional Assays to the Rescue.

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    Starita, Lea M; Ahituv, Nadav; Dunham, Maitreya J; Kitzman, Jacob O; Roth, Frederick P; Seelig, Georg; Shendure, Jay; Fowler, Douglas M

    2017-09-07

    Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Estudo comparativo entre vitiligo, nevo halo e lúpus eritematoso vitiligóide por meio de métodos imunológicos, histológicos e imuno-histoquímicos Comparative study of vitiligo, halo nevus, and vitiligoid variant of lupus erythematosus by immunological, histological, and immunohistochemical methods

    Directory of Open Access Journals (Sweden)

    Luiz Gonzaga C. Souza Filho

    2005-04-01

    Full Text Available FUNDAMENTOS: O estudo compara o vitiligo, o nevo halo (NH e lúpus eritematoso vitiligóide (LEV do ponto de vista imunológico, histológico e histoquímico. OBJETIVOS: Avaliar diferenças imuno-histoquímicas entre essas doenças e investigar se a despigmentação do LEV deve-se à destruição pós-inflamatória ou à agressão imunológica aos melanócitos. MÉTODOS: Foram avaliados 20 pacientes com vitiligo, 17 com vitiligo e NH, cinco com NH isolado e 15 com LEV. Detecção de anticorpos: IF direta e indireta com células névicas e de melanoma. Citotoxicidade: atividade NK contra células de melanoma. Estudo anátomo-histoquímico: exame histológico com hematoxilina e eosina, Fontana-Masson, Dopa e Dopa mais prata (D+P e exame histoquímico com proteína S-100. RESULTADOS: Doentes com vitiligo, NH e LEV apresentaram anticorpos antimelanócitos. Tanto no vitiligo e NH, como no LEV, demonstrou-se a presença de fatores de risco favorecedores da citotoxicidade celular. A coloração com D+P foi superior às colorações tradicionais e à proteína S-100 na detecção de melanócitos e melanina nas lesões de vitiligo, NH e LEV. CONCLUSÕES: Demonstrou-se a existência de anticorpos antimelanócitos no vitiligo e NH. É possível que a despigmentação no LEV se deva a fenômenos imunológicos semelhantes aos do vitiligo e NH. A detecção de melanócitos nas lesões de vitiligo sugere mais inibição funcional do que destruição dessas células.BACKGROUND: There are no records of comparative studies on the immunological, histological and immunohistochemical aspects of vitiligo, halo nevus and vitiligoid variant of lupus erythematosus in the literature. The studies available present only descriptive clinical data on leucoderma that accompanies lupus erythematosus in its diverse clinical forms. OBJECTIVES: 1- To evaluate the immunohistochemical differences between vitiligo, halo nevus and vitiligoid variant of lupus erythematosus; 2- To

  3. A look-ahead variant of TFQMR

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    Freund, R.W. [AT& T Bell Labs., Murray Hill, NJ (United States); Nachtigal, N.M. [Oak Ridge National Lab., TN (United States)

    1994-12-31

    Recently, Freund proposed a Krylov subspace iteration, the transpose-free quasi-minimal residual method (TFQMR), for solving general nonsingular non-Hermitian linear systems. The algorithm relies on a version of the squared Lanczos process to generate the basis vectors for the underlying Krylov subspace. It then constructs iterates defined by a quasi-minimization property, which leads to a smooth and nearly monotone convergence behavior. The authors investigate a variant of TFQMR that uses look-ahead to avoid some of the problems associated with breakdowns in the underlying squared Lanczos procedure. They also present some numerical examples that illustrate the properties of the new method, as compared to the original TFQMR algorithm.

  4. Impact of MYH6 variants in hypoplastic left heart syndrome

    Science.gov (United States)

    Stamm, Karl D.; Mahnke, Donna K.; Kim, Min-Su; Hidestrand, Pip M.; Liang, Huan Ling; Goetsch, Mary A.; Hidestrand, Mats; Simpson, Pippa; Pelech, Andrew N.; Tweddell, James S.; Benson, D. Woodrow; Lough, John W.; Mitchell, Michael E.

    2016-01-01

    Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications. PMID:27789736

  5. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

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    Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  6. Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant.

    Science.gov (United States)

    Lee, In-Kyung; Lee, Seoung-Ae; Kim, Hong; Won, You-Sub; Kim, Bum-Joon

    2015-06-14

    To investigate the mechanism of endoplasmic reticulum (ER) stress induction by an occult infection related hepatitis B virus S surface antigen (HBsAg) variant. We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot. Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant up-regulated ER stress-related proteins and induced reactive oxygen species (ROS) compared to the wild-type via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins (HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the up-regulation of caspase proteins (caspase 6, 9 and 12). Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein. Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.

  7. Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders.

    Science.gov (United States)

    Ogaki, Kotaro; Koga, Shunsuke; Heckman, Michael G; Fiesel, Fabienne C; Ando, Maya; Labbé, Catherine; Lorenzo-Betancor, Oswaldo; Moussaud-Lamodière, Elisabeth L; Soto-Ortolaza, Alexandra I; Walton, Ronald L; Strongosky, Audrey J; Uitti, Ryan J; McCarthy, Allan; Lynch, Timothy; Siuda, Joanna; Opala, Grzegorz; Rudzinska, Monika; Krygowska-Wajs, Anna; Barcikowska, Maria; Czyzewski, Krzysztof; Puschmann, Andreas; Nishioka, Kenya; Funayama, Manabu; Hattori, Nobutaka; Parisi, Joseph E; Petersen, Ronald C; Graff-Radford, Neill R; Boeve, Bradley F; Springer, Wolfdieter; Wszolek, Zbigniew K; Dickson, Dennis W; Ross, Owen A

    2015-12-08

    To assess the role of CHCHD2 variants in patients with Parkinson disease (PD) and Lewy body disease (LBD) in Caucasian populations. All exons of the CHCHD2 gene were sequenced in a US Caucasian patient-control series (878 PD, 610 LBD, and 717 controls). Subsequently, exons 1 and 2 were sequenced in an Irish series (355 PD and 365 controls) and a Polish series (394 PD and 350 controls). Immunohistochemistry and immunofluorescence studies were performed on pathologic LBD cases with rare CHCHD2 variants. We identified 9 rare exonic variants of unknown significance. These variants were more frequent in the combined group of PD and LBD patients compared to controls (0.6% vs 0.1%, p = 0.013). In addition, the presence of any rare variant was more common in patients with LBD (2.5% vs 1.0%, p = 0.050) compared to controls. Eight of these 9 variants were located within the gene's mitochondrial targeting sequence. Although the role of variants of the CHCHD2 gene in PD and LBD remains to be further elucidated, the rare variants in the mitochondrial targeting sequence may be a risk factor for Lewy body disorders, which may link CHCHD2 to other genetic forms of parkinsonism with mitochondrial dysfunction. © 2015 American Academy of Neurology.

  8. Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

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    Pfeiffer Ronald F

    2010-04-01

    Full Text Available Abstract Background Mitochondrial function is impaired in Parkinson's disease (PD and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. Methods We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. Results The frequency of affected mothers of the proband with PD (83/167, 49.4% was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4% (Odds Ratio 1.22; 95%CI 0.83 - 1.81. After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. Conclusions These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic m

  9. Histone variants: emerging players in cancer biology

    Science.gov (United States)

    Vardabasso, Chiara; Hasson, Dan; Ratnakumar, Kajan; Chung, Chi-Yeh; Duarte, Luis F.

    2014-01-01

    Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology. PMID:23652611

  10. Nested Variant of Urothelial Carcinoma

    Science.gov (United States)

    Venyo, Anthony Kodzo-Grey

    2014-01-01

    Background. Nested variant of urothelial carcinoma was added to the WHO's classification in 2004. Aims. To review the literature on nested variant of urothelial carcinoma. Results. About 200 cases of the tumour have been reported so far and it has the ensuing morphological features: large numbers of small confluent irregular nests of bland-appearing, closely packed, haphazardly arranged, and poorly defined urothelial cells infiltrating the lamina propria and the muscularis propria. The tumour has a bland histomorphologic appearance, has an aggressive biological behaviour, and has at times been misdiagnosed as a benign lesion which had led to a significant delay in the establishment of the correct diagnosis and contributing to the advanced stage of the disease. Immunohistochemically, the tumour shares some characteristic features with high-risk conventional urothelial carcinomas such as high proliferation index and loss of p27 expression. However, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen. The tumour must be differentiated from a number of proliferative lesions of the urothelium. Conclusions. Correct and early diagnosis of this tumour is essential to provide early curative treatment to avoid diagnosis at an advanced stage. A multicentre trial is required to identify treatment options that would improve the outcome of this tumour. PMID:24587796

  11. Histone variants of the insect Plodia interpunctella during metamorphosis.

    Science.gov (United States)

    Pataryas, T A; Sekeri-Pataryas, K T; Bonner, W M; Marinou, V A

    1984-01-01

    The pattern of histone variants from the meal moth Plodia interpunctella was compared to the mouse histone variant pattern. Plodia contains histones which comigrate on two dimensional gels with H3.2, H3.3, H4 and H2A.Z in mouse. Plodia H2A.1 and H2B.1 migrate somewhat differently from the respective mouse histones. Comparison of the iodinated tryptic peptides of H2A.1 and H2A.Z from mouse and Plodia showed that the H2A.Z proteins have two iodinated peptides that comigrate in the two species and three more that are different. The H2A.1 proteins in the two species have one iodinated peptide which comigrates and two more which migrate very close to each other. The histone variants from three developmental stages, larval, pupal and adult of Plodia interpunctella were also identified and compared. The same histone variant pattern is found through all stages of development. It is concluded that histone gene expression does not change during metamorphosis in Plodia .

  12. Reliably Detecting Clinically Important Variants Requires Both Combined Variant Calls and Optimized Filtering Strategies.

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    Matthew A Field

    Full Text Available A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality 'genome in a bottle' reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality.

  13. Analysis of PAC1 receptor gene variants in Caucasian and African American infants dying of sudden infant death syndrome.

    Science.gov (United States)

    Barrett, Karlene T; Rodikova, Ekaterina; Weese-Mayer, Debra E; Rand, Casey M; Marazita, Mary L; Cooper, Margaret E; Berry-Kravis, Elizabeth M; Bech-Hansen, N Torben; Wilson, Richard J A

    2013-12-01

    Stress peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has been implicated in sudden infant death syndrome (SIDS). The aim of this exploratory study was to determine whether variants in the gene encoding the PACAP-specific receptor, PAC1, are associated with SIDS in Caucasian and African American infants. Polymerase chain reaction and Sanger DNA sequencing was used to compare variants in the 5'-untranslated region, exons and intron-exon boundaries of the PAC1 gene in 96 SIDS cases and 96 race- and gender-matched controls. The intron 3 variant, A/G: rs758995 (variant 'h'), and the intron 6 variant, C/T: rs10081254 (variant 'n'), were significantly associated with SIDS in Caucasians and African Americans, respectively (p < 0.05). Also associated with SIDS were interactions between the variants rs2302475 (variant 'i') in PAC1 and rs8192597 and rs2856966 in PACAP among Caucasians (p < 0.02) and rs2267734 (variant 'q') in PAC1 and rs1893154 in PACAP among African Americans (p < 0.01). However, none of these differences survived post hoc analysis. Overall, this study does not support a strong association between variants in the PAC1 gene and SIDS; however, a number of potential associations between race-specific variants and SIDS were identified that warrant targeted investigations in future studies. ©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  14. Gene variants and binge eating as predictors of comorbidity and outcome of treatment in severe obesity.

    Science.gov (United States)

    Potoczna, Natascha; Branson, Ruth; Kral, John G; Piec, Grazyna; Steffen, Rudolf; Ricklin, Thomas; Hoehe, Margret R; Lentes, Klaus-Ulrich; Horber, Fritz F

    2004-12-01

    Melanocortin-4 receptor gene (MC4R) variants are associated with obesity and binge eating disorder (BED), whereas the more prevalent proopiomelanocortin (POMC) and leptin receptor gene (LEPR) mutations are rarely associated with obesity or BED. The complete coding regions of MC4R, POMC, and leptin-binding domain of LEPR were comparatively sequenced in 300 patients (233 women and 67 men; mean +/- SEM age, 42 +/- 1 years; mean +/- SEM body mass index, 43.5 +/- 0.3 kg/m2) undergoing laparoscopic gastric banding. Eating behavior, esophagogastric pathology, metabolic syndrome prevalence, and postoperative weight loss and complications were retrospectively compared between carriers and noncarriers of gene variants with and without BED during 36 +/- 3-month follow-up. Nineteen patients (6.3%) carried 8 MC4R variants, 144 (48.0%) carried 13 POMC variants, and 247 (82.3%) carried 11 LEPR variants. All MC4R variant carriers had BED, compared with 18.1% of noncarriers (P < 0.001). BED rates were similar among POMC and LEPR variant carriers and noncarriers. Gastroscopy revealed more erosive esophagitis in bingers than in nonbingers before and after banding (P < 0.04), regardless of genotype. MC4R variant carriers lost less weight (P=0.003), showed less improvement in metabolic syndrome (P < 0.001), had dilated esophagi (P < 0.001) and more vomiting (P < 0.05), and had fivefold more gastric complications (P < 0.001) than noncarriers. Overall outcome was poorest in MC4R variant carriers, better in noncarriers with BED (P < 0.05), and best in noncarriers without BED (P < 0.001). MC4R variants influence comorbidities and treatment outcomes in severe obesity.

  15. Mitochondrial DNA variants in obesity.

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    Nadja Knoll

    Full Text Available Heritability estimates for body mass index (BMI variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s in the exclusively maternally inherited mitochondrial DNA (mtDNA might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs were available from genome-wide association study SNP arrays (Affymetrix 6.0. For discovery, we analyzed association in a case-control (CC sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI ≥ 30 kg/m2 and n = 2,373 normal weight and lean controls (BMI<25 kg/m2. SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002 located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039. These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048. Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and

  16. Resistance of Abaca Somaclonal Variant Against Fusarium

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    RULLY DYAH PURWATI

    2007-12-01

    Full Text Available The objectives of this study were (i to evaluate responses against F. oxysporum f.sp. cubense (Foc infection of abaca variants regenerated using four different methods, (ii to determine initial root length and plant height effects on survival of inoculated abaca variants, and (iii to identify Foc resistance abaca variants. In the previous experiment, four abaca variant lines were regenerated from (i embryogenic calli (TC line, (ii ethyl methyl sulphonate (EMS treated embryogenic calli (EMS line, (iii EMS treated embryogenic calli, followed by in vitro selection on Foc culture filtrate (EMS+CF line, and (iv EMS treated embryogenic calli, followed by in vitro selection on fusaric acid (EMS+FA line. All abaca variants were grown in a glasshouse and inoculated with Banyuwangi isolate of Foc (Foc Bw. Initial root length (RL and plant height (PH of the abaca variants were recorded before inoculation, while scores of plant damage (SPD, and their survival were recorded at 60 days after inoculation (DAI. The results showed that the initial RL and PH did not affect survival of the tested abaca variants. Regardless of their initial RL and PH, susceptible abaca variants died before 60 DAI while resistance ones still survived. Abaca variants regenerated from single clump of embryogenic callus showed an array of responses against Foc Bw infection, indicating the existence of a mix cells population. The Foc Bw resistance abaca variants were successfully identified from four tested abaca variant lines, although with different frequencies. However, more Foc Bw resistance abaca plants were identified from EMS+CF line than the others. Using the developed procedures, 8 resistance abaca plants were identified from abaca cv. Tangongon and 12 from abaca cv. Sangihe-1.

  17. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants

    NARCIS (Netherlands)

    Betsalel, Ofir T; Pop, Ana; Rosenberg, Efraim H; Fernandez-Ojeda, Matilde; Jakobs, Cornelis; Salomons, Gajja S; Koning, Klaziena

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine

  18. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants

    NARCIS (Netherlands)

    Betsalel, O.T.; Pop, A.; Rosenberg, E.H.; Fernandez-Ojeda, M.; Jakobs, C.; Salomons, G.S.; Brouwer, A.P. de; Wevers, R.A.; Yntema, H.G.

    2012-01-01

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine

  19. Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins.

    Science.gov (United States)

    Gosselin, R C; Carlin, A C; Dwyre, D M

    2011-04-01

    Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high-pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. © 2010 Blackwell Publishing Ltd.

  20. Comparative Genomics in Homo sapiens.

    Science.gov (United States)

    Oti, Martin; Sammeth, Michael

    2018-01-01

    Genomes can be compared at different levels of divergence, either between species or within species. Within species genomes can be compared between different subpopulations, such as human subpopulations from different continents. Investigating the genomic differences between different human subpopulations is important when studying complex diseases that are affected by many genetic variants, as the variants involved can differ between populations. The 1000 Genomes Project collected genome-scale variation data for 2504 human individuals from 26 different populations, enabling a systematic comparison of variation between human subpopulations. In this chapter, we present step-by-step a basic protocol for the identification of population-specific variants employing the 1000 Genomes data. These variants are subsequently further investigated for those that affect the proteome or RNA splice sites, to investigate potentially biologically relevant differences between the populations.

  1. Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

    Energy Technology Data Exchange (ETDEWEB)

    Jans, L., E-mail: lennartjans@hotmail.com [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Jaremko, J., E-mail: jjaremko@gmail.com [Department of Radiology, University of Alberta Hospital, 8440-112 Street, Edmonton T6G 2B7, Alberta (Canada); Ditchfield, M., E-mail: Michael.ditchfield@southernhealth.org.au [Department of Radiology, Monash University Clayton Campus, Wellington Road, Clayton 3800, VIC (Australia); De Coninck, T., E-mail: Tinekedeconinck@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Huysse, W., E-mail: Wouter.huysse@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Moon, A., E-mail: Anna.moon@rch.org.au [Department of Radiology, Royal Children' s Hospital, Flemington Road, Parkville 3052, VIC (Australia); Verstraete, K., E-mail: Koenraad.verstraete@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium)

    2012-11-15

    Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9-14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9-14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

  2. Two new splice variants in porcine PPARGC1A

    Directory of Open Access Journals (Sweden)

    Peelman Luc J

    2008-12-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A is a coactivator with a vital and central role in fat and energy metabolism. It is considered to be a candidate gene for meat quality in pigs and is involved in the development of obesity and diabetes in humans. How its many functions are regulated, is however still largely unclear. Therefore a transcription profile of PPARGC1A in 32 tissues and 4 embryonic developmental stages in the pig was constructed by screening its cDNA for possible splice variants with exon-spanning primers. Findings This led to the discovery of 2 new splice variants in the pig, which were subsequently also detected in human tissues. In these variants, exon 8 was either completely or partly (the last 66 bp were conserved spliced out, potentially coding for a much shorter protein of respectively 337 and 359 amino acids (aa, of which the first 291 aa would be the same compared to the complete protein (796 aa. Conclusion Considering the functional domains of the PPARGC1A protein, it is very likely these splice variants considerably affect the function of the protein and alternative splicing could be one of the mechanisms by which the diverse functions of PPARGC1A are regulated.

  3. Affective Differences Between Psychopathy Variants and Genders in Adjudicated Youth.

    Science.gov (United States)

    Gill, Andrew D; Stickle, Timothy R

    2016-02-01

    The present study used Model-Based Cluster analysis to identify primary and secondary psychopathy variants in a mixed-gender sample of 150 adjudicated adolescents (60 % male; M = 15.2 years old). Distinct primary and secondary psychopathy groups emerged and were entered into a structural equation path model for the purpose of predicting group differences in emotional experiences reported between youth assigned to each variant. Youth characterized by secondary psychopathy reported experiencing significantly more frequent and more intense negative affect than their primary psychopathy counterparts. Frequency and intensity of affect also mediated the association between psychopathy variants and symptoms of depression, in which the secondary psychopathy group endorsed significantly more symptoms of major depression than the primary psychopathy group. Overall, these results suggest that different causal processes and affective experiences may underlie distinct trajectories to primary and secondary psychopathy variants in adjudicated adolescents. As such, youths comprising the secondary subtype of psychopathy may be more aptly considered "callous and emotional," compared with the primary subtype who present as prototypically callous and unemotional.

  4. Oncogenic potential diverge among human papillomavirus type 16 natural variants

    Energy Technology Data Exchange (ETDEWEB)

    Sichero, Laura, E-mail: lsichero@gmail.com [Molecular Biology Laboratory, Center of Translational Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Sao Paulo 01246-000 (Brazil); Department of Virology, Ludwig Institute for Cancer Research, Sao Paulo 01323-903 (Brazil); Simao Sobrinho, Joao [Molecular Biology Laboratory, Center of Translational Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Sao Paulo 01246-000 (Brazil); Department of Virology, Ludwig Institute for Cancer Research, Sao Paulo 01323-903 (Brazil); Lina Villa, Luisa [Molecular Biology Laboratory, Center of Translational Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Sao Paulo 01246-000 (Brazil); Department of Virology, Ludwig Institute for Cancer Research, Sao Paulo 01323-903 (Brazil); Department of Radiology, School of Medicine, University of Sao Paulo (Brazil)

    2012-10-10

    We compared E6/E7 protein properties of three different HPV-16 variants: AA, E-P and E-350G. Primary human foreskin keratinocytes (PHFK) were transduced with HPV-16 E6 and E7 and evaluated for proliferation and ability to grow in soft agar. E-P infected keratinocytes presented the lowest efficiency in colony formation. AA and E-350G keratinocytes attained higher capacity for in vitro transformation. We observed similar degradation of TP53 among HPV-16 variants. Furthermore, we accessed the expression profile in early (p5) and late passage (p30) transduced cells of 84 genes commonly involved in carcinogenesis. Most differences could be attributed to HPV-16 E6/E7 expression. In particular, we detected different expression of ITGA2 and CHEK2 in keratinocytes infected with AA and AA/E-350G late passage cells, respectively, and higher expression of MAP2K1 in E-350G transduced keratinocytes. Our results indicate differences among HPV-16 variants that could explain, at least in part, differences in oncogenic potential attributed to these variants.

  5. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  6. Beta-glucosidase I variants with improved properties

    Science.gov (United States)

    Bott, Richard R.; Kaper, Thijs; Kelemen, Bradley; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus; Kralj, Slavko; Kruithof, Paulien; Nikolaev, Igor; Van Der Kley, Wilhelmus Antonious Hendricus; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2016-09-20

    The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants, compositions comprising beta-glucosidase variants, methods of using beta-glucosidase variants, and methods of identifying additional useful beta-glucosidase variants.

  7. Characterization of Coconut cadang-cadang viroid variants from oil palm affected by orange spotting disease in Malaysia.

    Science.gov (United States)

    Wu, Y H; Cheong, L C; Meon, S; Lau, W H; Kong, L L; Joseph, H; Vadamalai, G

    2013-06-01

    A 246-nt variant of Coconut cadang-cadang viroid (CCCVd) has been identified and described from oil palms with orange spotting symptoms in Malaysia. Compared with the 246-nt form of CCCVd from coconut, the oil palm variant substituted C(31)→U in the pathogenicity domain and G(70)→C in the central conserved domain. This is the first sequence reported for a 246-nt variant of CCCVd in oil palms expressing orange spotting symptoms.

  8. Local binary patterns new variants and applications

    CERN Document Server

    Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

    2014-01-01

    This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

  9. Somatic cancer variant curation and harmonization through consensus minimum variant level data

    Directory of Open Access Journals (Sweden)

    Deborah I. Ritter

    2016-11-01

    Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

  10. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

    Science.gov (United States)

    Carss, Keren J; Arno, Gavin; Erwood, Marie; Stephens, Jonathan; Sanchis-Juan, Alba; Hull, Sarah; Megy, Karyn; Grozeva, Detelina; Dewhurst, Eleanor; Malka, Samantha; Plagnol, Vincent; Penkett, Christopher; Stirrups, Kathleen; Rizzo, Roberta; Wright, Genevieve; Josifova, Dragana; Bitner-Glindzicz, Maria; Scott, Richard H; Clement, Emma; Allen, Louise; Armstrong, Ruth; Brady, Angela F; Carmichael, Jenny; Chitre, Manali; Henderson, Robert H H; Hurst, Jane; MacLaren, Robert E; Murphy, Elaine; Paterson, Joan; Rosser, Elisabeth; Thompson, Dorothy A; Wakeling, Emma; Ouwehand, Willem H; Michaelides, Michel; Moore, Anthony T; Webster, Andrew R; Raymond, F Lucy

    2017-01-05

    Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease. Copyright © 2017. Published by Elsevier Inc.

  11. Germline Genetic Variants and Lung Cancer Survival in African Americans.

    Science.gov (United States)

    Jones, Carissa C; Bush, William S; Crawford, Dana C; Wenzlaff, Angela S; Schwartz, Ann G; Wiencke, John K; Wrensch, Margaret R; Blot, William J; Chanock, Stephen J; Grogan, Eric L; Aldrich, Melinda C

    2017-08-01

    Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases. Methods: Incident non-small cell lung cancer cases ( N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies ( N = 316 and 298) were used for replication. Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54-0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71-0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33-0.66). Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene-environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival. Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288-95. ©2017 AACR . ©2017 American Association for Cancer Research.

  12. Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.

    Science.gov (United States)

    Harrison, Steven M; Dolinsky, Jill S; Knight Johnson, Amy E; Pesaran, Tina; Azzariti, Danielle R; Bale, Sherri; Chao, Elizabeth C; Das, Soma; Vincent, Lisa; Rehm, Heidi L

    2017-10-01

    Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants. ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations. At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines. Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.

  13. Utilizing mutual information for detecting rare and common variants associated with a categorical trait

    Directory of Open Access Journals (Sweden)

    Leiming Sun

    2016-06-01

    Full Text Available Background. Genome-wide association studies have succeeded in detecting novel common variants which associate with complex diseases. As a result of the fast changes in next generation sequencing technology, a large number of sequencing data are generated, which offers great opportunities to identify rare variants that could explain a larger proportion of missing heritability. Many effective and powerful methods are proposed, although they are usually limited to continuous, dichotomous or ordinal traits. Notice that traits having nominal categorical features are commonly observed in complex diseases, especially in mental disorders, which motivates the incorporation of the characteristics of the categorical trait into association studies with rare and common variants. Methods. We construct two simple and intuitive nonparametric tests, MIT and aMIT, based on mutual information for detecting association between genetic variants in a gene or region and a categorical trait. MIT and aMIT can gauge the difference among the distributions of rare and common variants across a region given every categorical trait value. If there is little association between variants and a categorical trait, MIT or aMIT approximately equals zero. The larger the difference in distributions, the greater values MIT and aMIT have. Therefore, MIT and aMIT have the potential for detecting functional variants. Results.We checked the validity of proposed statistics and compared them to the existing ones through extensive simulation studies with varied combinations of the numbers of variants of rare causal, rare non-causal, common causal, and common non-causal, deleterious and protective, various minor allele frequencies and different levels of linkage disequilibrium. The results show our methods have higher statistical power than conventional ones, including the likelihood based score test, in most cases: (1 there are multiple genetic variants in a gene or region; (2 both

  14. Naturally occurring InlB variants that support intragastric Listeria monocytogenes infection in mice.

    Science.gov (United States)

    Sobyanin, Konstantin; Sysolyatina, Elena; Krivozubov, Mikhail; Chalenko, Yaroslava; Karyagina, Anna; Ermolaeva, Svetlana

    2017-02-01

    Listeria monocytogenes is a causative agent of foodborne infection in humans and animals. The virulence factor InlB interacts with mammalian receptor c-Met via its internalin domain to provide L. monocytogenes invasion in non-professional phagocytes. Naturally occurring InlB internalin domain variants form four subclusters on the maximal likelihood tree. Four variants belonging to distinct subclusters were cloned into the vector carrying 3΄ and 5΄-flanking sequences to restore full length inlB and expressed in the L. monocytogenes strain EGDeΔinlB. The substitutions Val132Ile, Thr117Ala and Ile138Leu, Thr251Met/Ser were specific for variants 13, 14 and 1, respectively, the variant 9 carried Ser73Asn, Ile91Val, Leu164Pro, Met251Ser/Thr substitutions. All InlB variants improved invasion of the parental strain in murine colon carcinoma C26 cells with 4.6-fold difference between the most and least effective variants (variants 14 and 13, respectively, P < 0.05). Bacterial loads in livers of intragastrically infected mice were 258, 149 and 92 times higher for variant 14, 13 and 1 carrying strains, respectively, than for EGDeΔinlB (P < 0.01). In contrast, the variant 9 did not noticeably improve infection comparatively to the parental strain. Overall, obtained results demonstrated that naturally occurred InlB internalin domain variants differed in their ability to support intragastric infection in mice. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. A Protein Domain and Family Based Approach to Rare Variant Association Analysis.

    Science.gov (United States)

    Richardson, Tom G; Shihab, Hashem A; Rivas, Manuel A; McCarthy, Mark I; Campbell, Colin; Timpson, Nicholas J; Gaunt, Tom R

    2016-01-01

    It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT). We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed. We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals.

  16. A Protein Domain and Family Based Approach to Rare Variant Association Analysis

    Science.gov (United States)

    Richardson, Tom G.; Shihab, Hashem A.; Rivas, Manuel A.; McCarthy, Mark I.; Campbell, Colin; Timpson, Nicholas J.; Gaunt, Tom R.

    2016-01-01

    Background It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit. Methods Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1%) together in three different ways 1) variants within single genomic regions which map to individual protein domains 2) variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3) all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families). A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT). Results We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed. Conclusion We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals. PMID:27128313

  17. A Protein Domain and Family Based Approach to Rare Variant Association Analysis.

    Directory of Open Access Journals (Sweden)

    Tom G Richardson

    Full Text Available It has become common practice to analyse large scale sequencing data with statistical approaches based around the aggregation of rare variants within the same gene. We applied a novel approach to rare variant analysis by collapsing variants together using protein domain and family coordinates, regarded to be a more discrete definition of a biologically functional unit.Using Pfam definitions, we collapsed rare variants (Minor Allele Frequency ≤ 1% together in three different ways 1 variants within single genomic regions which map to individual protein domains 2 variants within two individual protein domain regions which are predicted to be responsible for a protein-protein interaction 3 all variants within combined regions from multiple genes responsible for coding the same protein domain (i.e. protein families. A conventional collapsing analysis using gene coordinates was also undertaken for comparison. We used UK10K sequence data and investigated associations between regions of variants and lipid traits using the sequence kernel association test (SKAT.We observed no strong evidence of association between regions of variants based on Pfam domain definitions and lipid traits. Quantile-Quantile plots illustrated that the overall distributions of p-values from the protein domain analyses were comparable to that of a conventional gene-based approach. Deviations from this distribution suggested that collapsing by either protein domain or gene definitions may be favourable depending on the trait analysed.We have collapsed rare variants together using protein domain and family coordinates to present an alternative approach over collapsing across conventionally used gene-based regions. Although no strong evidence of association was detected in these analyses, future studies may still find value in adopting these approaches to detect previously unidentified association signals.

  18. Variability extraction and modeling for product variants.

    Science.gov (United States)

    Linsbauer, Lukas; Lopez-Herrejon, Roberto Erick; Egyed, Alexander

    2017-01-01

    Fast-changing hardware and software technologies in addition to larger and more specialized customer bases demand software tailored to meet very diverse requirements. Software development approaches that aim at capturing this diversity on a single consolidated platform often require large upfront investments, e.g., time or budget. Alternatively, companies resort to developing one variant of a software product at a time by reusing as much as possible from already-existing product variants. However, identifying and extracting the parts to reuse is an error-prone and inefficient task compounded by the typically large number of product variants. Hence, more disciplined and systematic approaches are needed to cope with the complexity of developing and maintaining sets of product variants. Such approaches require detailed information about the product variants, the features they provide and their relations. In this paper, we present an approach to extract such variability information from product variants. It identifies traces from features and feature interactions to their implementation artifacts, and computes their dependencies. This work can be useful in many scenarios ranging from ad hoc development approaches such as clone-and-own to systematic reuse approaches such as software product lines. We applied our variability extraction approach to six case studies and provide a detailed evaluation. The results show that the extracted variability information is consistent with the variability in our six case study systems given by their variability models and available product variants.

  19. Role of common and rare variants in SCN10A

    DEFF Research Database (Denmark)

    Behr, Elijah R.; Savio-Galimberti, Eleonora; Barc, Julien

    2015-01-01

    AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN.......8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN...

  20. INFLUENCE OF DIFFERENT SOIL TILLAGE VARIANTS ON QUALITY OF SEED DISTRIBUTION QUALITY PER SURFACE AND DEPTH

    Directory of Open Access Journals (Sweden)

    Luka Šumanovac

    2000-12-01

    Full Text Available The paper aims to present influence of different soil tillage variants on quality of seed distribution per surface and depth. A sowing experiment was set up in three soil tillage variants: a repeated disking, b conventional tillage, c ploughing + harrowing. Soil levelling, effects of longitudinal and transverzal distribution as well as seed distribution per depth were analyzed by the investigation. The research results indicate the fact that no soil tillage variant is characterized by achieving satisfactory sowing quality . It means that reduced soil tillage application is justifiable in terms of energetic aspect, work productivity increase, sowing performance in optimal agricultural terms etc., compared to conventional soil tillage.

  1. Molecular basis for Duarte and Los Angeles variant galactosemia

    Energy Technology Data Exchange (ETDEWEB)

    Langley, S.D.; Lai, K.; Dembure, P.P. [Emory Univ. School of Medicine, Atlanta, GA (United States)] [and others

    1997-02-01

    Human erythrocytes that are homozygous for the Duarte enzyme variant of galactosemia (D/D) have a characteristic isoform on isoelectric focusing and 50% reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity. The Duarte biochemical phenotype has a molecular genotype of N314D/N314D. The characteristic Duarte isoform is also associated with a variant called the {open_quotes}Los Angeles (LA) phenotype,{close_quotes} which has increased GALT enzyme activity. We evaluated GALT enzyme activity and screened the GALT genes of 145 patients with one or more N314D-containing alleles. We found seven with the LA biochemical phenotype, and all had a 1721C{r_arrow}T transition in exon 7 in cis with the N314D missense mutation. The 1721C{r_arrow}T transition is a neutral polymorphism for leucine at amino acid 218 (L218L). In pedigree analyses, this 1721C{r_arrow}T transition segregated with the LA phenotype of increased GALT activity in three different biochemical phenotypes (LA/N, LA/G, and LA/D). To determine the mechanism for increased activity of the LA variant, we compared GALT mRNA, protein abundance, and enzyme thermal stability in lymphoblast cell lines of D and LA phenotypes with comparable genotypes. GALT protein abundance was increased in LA compared to D alleles, but mRNA was similar among all genotypes. We conclude that the codon change N314D in cis with the base-pair transition 1721C{r_arrow}T produces the LA variant of galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermal lability. A favorable codon bias for the mutated codon with consequently increased translation rates is postulated as the mechanism. 23 refs., 3 figs., 4 tabs.

  2. Ultrasonographic imaging of papillary thyroid carcinoma variants

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

  3. Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.

    Directory of Open Access Journals (Sweden)

    Yoonhee Kim

    Full Text Available Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1 gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13 selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate. Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5% were noted in African Americans compared to European Americans (108 vs. 45. The common intronic GWAS-identified variant (rs12041331 demonstrated the most significant association signal in African Americans (p = 4.020×10(-4; no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331. Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965 supports the results noted in the sequenced discovery sample: p = 3.56×10(-4, 2.27×10(-7, 5.20×10(-5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans

  4. A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring.

    Science.gov (United States)

    Parker, Ellen; Phillips, D I W; Cockington, Richard A; Cull, Carole; Poulton, Jo

    2005-12-01

    A common mitochondrial (mt)DNA variant that is maternally inherited, the 16189 variant, is associated with type 2 diabetes and thinness at birth. To elucidate the association of the variant with thinness, we studied the 16189 variant in a well-characterized Australian cohort (n = 161) who were followed up from birth to age 20 yr. PCR analysis and mtDNA haplotyping was carried out on DNA from 161 offspring from consecutive, normal, singleton pregnancies followed from birth to age 20 yr. The 16189 mtDNA variant was present in 14 of the 161 20 yr olds (8.7%). Both the mothers with the 16189 variant and their 20-yr-old offspring were thinner than those without. Median (interquartile range) BMI was 21.9 kg/m(2) (20.4 to 22.9) in mothers with the variant compared with 23.5 (21.4 to 26.6) in those without (P = 0.013) and 22.2 (21.1 to 23.8) in 20 yr olds with the variant compared with 22.7 (20.8 to 25.6) in those without (P = 0.019). The 16189 variant was also associated with a high placental weight and high placental-to-birth weight ratio (P = 0.051 and P = 0.0024, respectively). Insulin sensitivity was normal in 20 yr olds with the 16189 variant. This contrasts with 20 yr olds who did not have the variant but who had been thin or small at birth and who had normal BMI and normal placental-to-birth weight ratio, but were insulin resistant. This study suggests that the 16189 mtDNA variant is associated with maternally inherited thinness in young adults. This may be mediated by effects on mtDNA replication and, thence, placental function. Further research is required to confirm these hypotheses.

  5. Contribution of rare and low-frequency whole-genome sequence variants to complex traits variation in dairy cattle

    DEFF Research Database (Denmark)

    Zhang, Qianqian; Calus, Mario P L; Guldbrandtsen, Bernt

    2017-01-01

    variants classified according to their MAF compared with the variance explained by the pedigree-based additive genetic relationship matrix for 17 traits in Nordic Holstein dairy cattle. RESULTS: Imputed sequence variants were grouped into seven classes according to their MAF (0.001-0.01, 0.01-0.05, 0......-related traits than for production traits (

  6. High Prevalence of Long QT Syndrome Associated SCN5A Variants in Patients with Early-Onset Lone Atrial Fibrillation

    DEFF Research Database (Denmark)

    Olesen, Morten S; Yuan, Lei; Liang, Bo

    2012-01-01

    genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1...

  7. Hemilaryngeal Microsomia: An Anatomic Variant.

    Science.gov (United States)

    Urban, Matthew J; Mattioni, Jillian; Jaworek, Aaron; Potigailo, Valeria; Sataloff, Robert T

    2017-09-01

    This study aims to describe a congenital laryngeal structural variant, hemilaryngeal microsomia (HLM), and to correlate identification on physical examination with computerized tomography scan (CT) and laryngoscopy findings. The study was conducted at a tertiary care center. Six patients presenting with hoarseness were admitted to a tertiary care otolaryngology office. These patients had asymmetrical thyroid cartilage prominence on palpation during physical examination. A diagnosis of HLM was made. All patients underwent laryngostroboscopy and CT scan. Four control patients with normal thyroid cartilage anatomy on physical examination, CT, and stroboscopy results were included for comparison. Disparities in thyroid cartilage angles correlated with documented physical examination findings for six out of six HLM patients. On CT scan, the average difference in left and right thyroid laminar angles was 30.2° ± 18.3° in HLM patients vs 4.00° ± 1.63° in control patients (P = 0.023). Strobosocopic findings also correlated with HLM. The arytenoid cartilage was anteriorly or medially displaced on the microsomic side in all six HLM patients. Three patients had anterior placement of the vocal process resulting in shortening of the vocal fold on the microsomic side of the larynx. HLM is a congenital structural anomaly of the larynx that may be palpated on physical examination. HLM found on physical examination can be correlated with asymmetries found on CT scan and endoscopy. There is no evidence that the structural features of HLM were causally related to voice symptoms, but the findings on HLM may lead to misdiagnosis. A larger study is indicated to confirm laryngeal structural differences between patients with HLM on physical examination and the general population. Whether or not HLM affects clinical or surgical outcomes remains to be studied. Copyright © 2017. Published by Elsevier Inc.

  8. Antisocial personality disorder and anxiety disorder: a diagnostic variant?

    Science.gov (United States)

    Coid, Jeremy; Ullrich, Simone

    2010-06-01

    Antisocial personality disorder (ASPD) with co-morbid anxiety disorder may be a variant of ASPD with different etiology and treatment requirements. We investigated diagnostic co-morbidity, ASPD criteria, and anxiety/affective symptoms of ASPD/anxiety disorder. Weighted analyses were carried out using survey data from a representative British household sample. ASPD/anxiety disorder demonstrated differing patterns of antisocial criteria, co-morbidity with clinical syndromes, psychotic symptoms, and other personality disorders compared to ASPD alone. ASPD criteria demonstrated specific associations with CIS-R scores of anxiety and affective symptoms. Findings suggest ASPD/anxiety disorder is a variant of ASPD, determined by symptoms of anxiety. Although co-morbid anxiety and affective symptoms are the same as in anxiety disorder alone, associations with psychotic symptoms require further investigation. Copyright 2010 Elsevier Ltd. All rights reserved.

  9. HD-CNV: hotspot detector for copy number variants.

    Science.gov (United States)

    Butler, Jenna L; Osborne Locke, Marjorie Elizabeth; Hill, Kathleen A; Daley, Mark

    2013-01-15

    Copy number variants (CNVs) are a major source of genetic variation. Comparing CNVs between samples is important in elucidating their potential effects in a wide variety of biological contexts. HD-CNV (hotspot detector for copy number variants) is a tool for downstream analysis of previously identified CNV regions from multiple samples, and it detects recurrent regions by finding cliques in an interval graph generated from the input. It creates a unique graphical representation of the data, as well as summary spreadsheets and UCSC (University of California, Santa Cruz) Genome Browser track files. The interval graph, when viewed with other software or by automated graph analysis, is useful in identifying genomic regions of interest for further study. HD-CNV is an open source Java code and is freely available, with tutorials and sample data from http://daleylab.org. jcamer7@uwo.ca

  10. Histone variants in plant transcriptional regulation.

    Science.gov (United States)

    Jiang, Danhua; Berger, Frédéric

    2017-01-01

    Chromatin based organization of eukaryotic genome plays a profound role in regulating gene transcription. Nucleosomes form the basic subunits of chromatin by packaging DNA with histone proteins, impeding the access of DNA to transcription factors and RNA polymerases. Exchange of histone variants in nucleosomes alters the properties of nucleosomes and thus modulates DNA exposure during transcriptional regulation. Growing evidence indicates the important function of histone variants in programming transcription during developmental transitions and stress response. Here we review how histone variants and their deposition machineries regulate the nucleosome stability and dynamics, and discuss the link between histone variants and transcriptional regulation in plants. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Variant (Swine Origin) Influenza Viruses in Humans

    Science.gov (United States)

    ... at Commercial Swine Farms Fair Organizers & Exhibitors In Humans Key Facts about Human Infections with Variant Viruses Interim Guidance for Clinicians on Human Infections Background, Risk Assessment & Reporting Reported Infections with ...

  12. Splicing variants of porcine synphilin-1

    DEFF Research Database (Denmark)

    Larsen, Knud Erik; Madsen, Lone Bruhn; Farajzadeh, Leila

    2015-01-01

    %) and to mouse (84%) synphilin-1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing variants and a novel......RNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa) synphilin-1 cDNA (SNCAIP) and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1) of 919 amino acids which shows a high similarity to human (90...... splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation....

  13. Identification of msp1 Gene Variants in Populations of Meloidogyne incognita Using PCR-DGGE

    Science.gov (United States)

    Adam, Mohamed; Hallmann, Johannes; Heuer, Holger

    2014-01-01

    Effectors of root-knot nematodes are essential for parasitism and prone to recognition by adapted variants of the host plants. This selective pressure initiates hypervariability of effector genes. Diversity of the gene variants within nematode populations might correlate with host preferences. In this study we developed a method to compare the distribution of variants of the effector gene msp1 among populations of Meloidogyne incognita. Primers were designed to amplify a 234-bp fragment of msp1. Sequencing of cloned PCR products revealed five msp1 variants from seven populations that were distinguishable in their reproduction on five host plants. A protocol for denaturing gradient gel electrophoresis (DGGE) was developed to separate these msp1 variants. DGGE for replicated pools of juveniles from the seven populations revealed ten variants of msp1. A correlation between the presence of a particular gene variant and the reproductive potential on particular hosts was not evident. Especially race 3 showed substantial variation within the population. DGGE fingerprints of msp1 tended to cluster the populations according to their reproduction rate on pepper. The developed method could be useful for analyzing population heterogeneity and epidemiology of M. incognita. PMID:25276001

  14. A robust GWSS method to simultaneously detect rare and common variants for complex disease.

    Directory of Open Access Journals (Sweden)

    Chung-Feng Kao

    Full Text Available The rapid advances in sequencing technologies and the resulting next-generation sequencing data provide the opportunity to detect disease-associated variants with a better solution, in particular for low-frequency variants. Although both common and rare variants might exert their independent effects on the risk for the trait of interest, previous methods to detect the association effects rarely consider them simultaneously. We proposed a class of test statistics, the generalized weighted-sum statistic (GWSS, to detect disease associations in the presence of common and rare variants with a case-control study design. Information of rare variants was aggregated using a weighted sum method, while signal directions and strength of the variants were considered at the same time. Permutations were performed to obtain the empirical p-values of the test statistics. Our simulation showed that, compared to the existing methods, the GWSS method had better performance in most of the scenarios. The GWSS (in particular VDWSS-t method is particularly robust for opposite association directions, association strength, and varying distributions of minor-allele frequencies. It is therefore promising for detecting disease-associated loci. For empirical data application, we also applied our GWSS method to the Genetic Analysis Workshop 17 data, and the results were consistent with the simulation, suggesting good performance of our method. As re-sequencing studies become more popular to identify putative disease loci, we recommend the use of this newly developed GWSS to detect associations with both common and rare variants.

  15. Identification of copy number variants in horses

    KAUST Repository

    Doan, R.

    2012-03-01

    Copy number variants (CNVs) represent a substantial source of genetic variation in mammals. However, the occurrence of CNVs in horses and their subsequent impact on phenotypic variation is unknown. We performed a study to identify CNVs in 16 horses representing 15 distinct breeds (Equus caballus) and an individual gray donkey (Equus asinus) using a whole-exome tiling array and the array comparative genomic hybridization methodology. We identified 2368 CNVs ranging in size from 197 bp to 3.5 Mb. Merging identical CNVs from each animal yielded 775 CNV regions (CNVRs), involving 1707 protein- and RNA-coding genes. The number of CNVs per animal ranged from 55 to 347, with median and mean sizes of CNVs of 5.3 kb and 99.4 kb, respectively. Approximately 6% of the genes investigated were affected by a CNV. Biological process enrichment analysis indicated CNVs primarily affected genes involved in sensory perception, signal transduction, and metabolism. CNVs also were identified in genes regulating blood group antigens, coat color, fecundity, lactation, keratin formation, neuronal homeostasis, and height in other species. Collectively, these data are the first report of copy number variation in horses and suggest that CNVs are common in the horse genome and may modulate biological processes underlying different traits observed among horses and horse breeds.

  16. Improving bioinformatic pipelines for exome variant calling

    OpenAIRE

    Ji, Hanlee P.

    2012-01-01

    Exome sequencing analysis is a cost-effective approach for identifying variants in coding regions. However, recognizing the relevant single nucleotide variants, small insertions and deletions remains a challenge for many researchers and diagnostic laboratories typically do not have access to the bioinformatic analysis pipelines necessary for clinical application. The Atlas2 suite, recently released by Baylor Genome Center, is designed to be widely accessible, runs on desktop computers but is ...

  17. Rare hemoglobin variants in Tunisian population.

    Science.gov (United States)

    Zorai, A; Moumni, I; Mosbahi, I; Douzi, K; Chaouachi, D; Guemira, F; Abbes, S

    2015-04-01

    During the last 30 years, many studies concerning hemoglobinopathies were realized among Tunisians. More than twenty different thalassemic alleles were detected on the β-globin gene, and less are affecting the α-globin genes. Unusual hemoglobin (Hb) variants other than Hb S, Hb C, and Hb O-arab, which are the most frequent variants in Tunisia, were also detected. Eight Tunisian subjects were studied at phenotypic and molecular levels. Hematological indices and hemoglobin (Hb) pattern were performed by alkaline electrophoresis and isoelectric focusing (IEF),and the Hb fractions were quantitated by cation exchange HPLC. On genomic level, coding regions were amplified by polymerase chain reaction (PCR) followed by a sequencing of the purified PCR products using the dye terminator method. Seven uncommon Hb variants were detected and described for the first time among Tunisians. HbA2-Tunis [δ46(CD5), Gly → Glu, GGG → GAG] is the newly described δ-chain variant in our laboratory, and some other variants (Hb Constant Spring, G San Jose, and Hb J-Bangkok) are very uncommon in the Mediterranean region. We present here an updated review of the Hb variants detected among Tunisians. Twenty-one rare Hb variants were detected affecting the α1-, α2-, δ-, γ-, and β-globin genes, leading in some cases to a severe phenotype especially when the stability is completely altered. The ethnical history of Tunisia could explain this important variability of the observed rare Hb variants. © 2014 John Wiley & Sons Ltd.

  18. Demography and the age of rare variants.

    Science.gov (United States)

    Mathieson, Iain; McVean, Gil

    2014-08-01

    Large whole-genome sequencing projects have provided access to much rare variation in human populations, which is highly informative about population structure and recent demography. Here, we show how the age of rare variants can be estimated from patterns of haplotype sharing and how these ages can be related to historical relationships between populations. We investigate the distribution of the age of variants occurring exactly twice (ƒ(2) variants) in a worldwide sample sequenced by the 1000 Genomes Project, revealing enormous variation across populations. The median age of haplotypes carrying ƒ(2) variants is 50 to 160 generations across populations within Europe or Asia, and 170 to 320 generations within Africa. Haplotypes shared between continents are much older with median ages for haplotypes shared between Europe and Asia ranging from 320 to 670 generations. The distribution of the ages of ƒ(2) haplotypes is informative about their demography, revealing recent bottlenecks, ancient splits, and more modern connections between populations. We see the effect of selection in the observation that functional variants are significantly younger than nonfunctional variants of the same frequency. This approach is relatively insensitive to mutation rate and complements other nonparametric methods for demographic inference.

  19. Detection of variants in SLC6A8 and functional analysis of unclassified missense variants.

    Science.gov (United States)

    Betsalel, Ofir T; Pop, Ana; Rosenberg, Efraim H; Fernandez-Ojeda, Matilde; Jakobs, Cornelis; Salomons, Gajja S

    2012-04-01

    Creatine transporter deficiency is an X-linked disorder caused by mutations in the SLC6A8 gene. Currently, 38 pathogenic, including 15 missense variants, are reported. In this study, we report 33 novel, including 6 missense variants. To classify all known missense variants, we transfected creatine deficient fibroblasts with the SLC6A8 ORF containing one of the unique variants and tested their ability to restore creatine uptake. This resulted in the definitive classification of 2 non-disease associated and 19 pathogenic variants of which 3 have residual activity. Furthermore, we report the development and validation of a novel DHPLC method for the detection of heterozygous SLC6A8 variants. The method was validated by analysis of DNAs that in total contained 67 unique variants of which 66 could be detected. Therefore, this rapid screening method may prove valuable for the analysis of large cohorts of females with mild intellectual disability of unknown etiology, since in this group heterozygous SLC6A8 mutations may be detected. DHPLC proved also to be important for the detection of somatic mosaicism in mothers of patients who have a pathogenic mutation in SLC6A8. All variants reported in the present and previous studies are included in the Leiden Open Source Variant Database (LOVD) of SLC6A8 (www.LOVD.nl/SLC6A8). Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Is radical cystectomy mandatory in every patient with variant histology of bladder cancer

    Directory of Open Access Journals (Sweden)

    Ofer N Gofrit

    2011-04-01

    Full Text Available Urothelial carcinomas have an established propensity for divergent differentiation. Most of these "variant tumors" are muscle invasive but not all. The response of non muscle invasive variant tumors to intravesical immunotherapy with BCG is not established in the literature, and is reported here. Between June 1995 and December 2007, 760 patients (mean age of 67.5 years underwent transurethral resection of first time bladder tumors in our institution. Histologically variant tumors were found in 79 patients (10.4%, 57 patients (72% of them had muscle-invasive disease or extensive non-muscle invasive tumors and 22 patients (28% were treated with BCG immunotherapy. These included 7 patients with squamous differentiation, 4 with glandular, 6 with nested, 4 with micropapillary and 1 patient with sarcomatoid variant. The response of these patients to immunotherapy was compared with that of 144 patients having high-grade conventional urothelial carcinomas. Median follow-up was 46 months. The 2 and 5-year progression (muscle-invasion free survival rates were 92% and 84.24% for patients with conventional carcinoma compared to 81.06% and 63.16% for patients with variant disease (p=0.02. The 2 and 5-year disease specific survival rates were 97% and 91.43% for patients with conventional carcinoma compared to 94.74 % and 82% for patients with variant disease (p=0.33. 5 patients (22.7% of variant group and 13 patients (9.03% of conventional group underwent cystectomy during follow-up (p=0.068. Patients with non-muscle invasive variants of bladder cancers can be managed with intra-vesical immunotherapy if tumor is not bulky (>4cm. Although progression to muscle invasive disease is more common than in conventional group and occurs in about 40% of the patients. Life expectancy is similar to patients with conventional high-grade urothelial carcinomas provided that follow-up is meticulous.

  1. Prevalence of 35delG and Met34Thr GJB2 variants in Portuguese samples.

    Science.gov (United States)

    Dória, Mariana; Neto, Ana Paula; Santos, Ana Cristina; Barros, Henrique; Fernandes, Susana; Moura, Carla Pinto

    2015-12-01

    To estimate the prevalence of 35delG and Met34Thr variants in a Portuguese children's community sample and to compare these frequencies with nonsyndromic hearing-loss patients. 502 children were randomly selected among the 8647 participants of the Portuguese birth cohort Generation XXI, and screened for Met34Thr and 35delG variants in the GJB2 gene. These variants were also studied on 89 index-cases, observed in the Clinic of "Hereditary Hearing-loss" in Saint John's Hospital Center, presenting a mild to profound nonsyndromic hearing-loss. Among the 502 children from Generation XXI, 10 were heterozygous for the 35delG variant (95% Confidence Interval 1.03-3.68) and 1 homozygous (95% Confidence Interval 0.01-1.24). Other 10 children presented heterozygosity for the Met34Thr variant (95% Confidence Interval 1.03-3.68). No homozygous for the Met34Thr or compound heterozygotes (35delG/Met34Thr) were found. In the total of 89 nonsyndromic hearing-loss patients, 5 (95% Confidence Interval 2.11-12.8) were heterozygous and 7 (95% Confidence Interval 3.61-15.6) were homozygous for the 35delG variant. The Met34Thr variant was found in 4 patients, 2 heterozygous (95% Confidence Interval 0.13-8.31) and 2 homozygous (95% Confidence Interval 0.13-8.31). The carrier frequency of 35delG and Met34Thr variants in a Portuguese sample was 1 in 50. Our data suggests that the 35delG mutation has an association with deafness. For the Met34Thr variant, no association was observed. However, Met34Thr seemed to conform to an additive model in hearing-loss. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Distribution and medical impact of loss-of-function variants in the Finnish founder population.

    Directory of Open Access Journals (Sweden)

    Elaine T Lim

    2014-07-01

    Full Text Available Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5% variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸ including splice variants in LPA that lowered plasma lipoprotein(a levels (P = 1.5×10⁻¹¹⁷. Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴, demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health

  3. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia

    Science.gov (United States)

    Yu, Lan; Sawle, Ashley D.; Wynn, Julia; Aspelund, Gudrun; Stolar, Charles J.; Arkovitz, Marc S.; Potoka, Douglas; Azarow, Kenneth S.; Mychaliska, George B.; Shen, Yufeng; Chung, Wendy K.

    2015-01-01

    Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases. PMID:26034137

  4. Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia.

    Science.gov (United States)

    Yu, Lan; Sawle, Ashley D; Wynn, Julia; Aspelund, Gudrun; Stolar, Charles J; Arkovitz, Marc S; Potoka, Douglas; Azarow, Kenneth S; Mychaliska, George B; Shen, Yufeng; Chung, Wendy K

    2015-08-15

    Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. The Use of Variant Maps to Explore Domain-Specific Mutations of FGFR1.

    Science.gov (United States)

    Lansdon, L A; Bernabe, H V; Nidey, N; Standley, J; Schnieders, M J; Murray, J C

    2017-10-01

    Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

  6. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis.

    Science.gov (United States)

    Fargnoli, Maria Concetta; Gandini, Sara; Peris, Ketty; Maisonneuve, Patrick; Raimondi, Sara

    2010-05-01

    We performed a meta-analysis to assess whether MC1R variants increase the risk of melanoma in CDKN2A mutation carriers of melanoma-prone families. Data from 96 CDKN2A-positive melanoma-prone families from seven independent populations of Europe, United States and Australia were included in the analysis. Summary risk estimates were calculated by random-effect models. We explored between-study heterogeneity and publication bias. Association between MC1R variants and age at diagnosis was assessed by the non-parametric Wilcoxon test. CDKN2A mutation carriers with 1 MC1R variant showed a double melanoma risk as compared to CDKN2A mutation carriers without MC1R variants (Summary OR; 95%CI: 2.2; 1.1-4.5). MC1R heterozygous subjects had no significantly higher melanoma risk than wild-type subjects (1.6; 0.5-5.4) while carriers of multiple MC1R variants had a more than four-times higher melanoma risk (4.6; 1.3-16.4). Carriers of red hair colour (RHC) variants showed an increased melanoma risk with a Summary OR of 3.5 (95%CI: 1.3-9.9). CDKN2A mutation carriers with MC1R variants had a statistically significant lower median age at melanoma diagnosis than CDKN2A mutation carriers with no MC1R variants (37years versus 47years, p-valueMC1R variants significantly increase penetrance of CDKN2A mutations in melanoma-prone families, especially with respect to multiple MC1R variants and to RHC variants. A significant anticipation of melanoma diagnosis is observed in CDKN2A mutation carriers with MC1R variants. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  7. [Frequency of chromosome variants in human populations].

    Science.gov (United States)

    Kuleshov, N P; Kulieva, L M

    1979-01-01

    Chromosome variants were analyzed in the course of the population chromosome investigation of 6000 newborns and clinical cytogenetic studies of 403 married couples with recurrent spontaneous abortions, stillbirths or offsprings having congenital malformations or Down's syndrome. The following variants were determined: 1) Igh+, 9gh+, 16gh+ - the enlargement of the secondary constrictions of the size, more than 1/4 of the long arm of the chromosome; 2) Dp+ or Gp+ - the enlargement of the short arms of acrocentrics, their size being more than the short arm of the chromosome 18; 3) Ds+ or Gs - large satellites of the acrocentrics which are equal or more than the thickness of the chromatids of the long arms; 4) Es+ - satellites on the short arms of the chromosomes 17 or 18; 5) Dss of Gss - double satellites; 6) Yq+ - the enlargement of the long arm of Y chromosome, the size of which being more than G chromosome; 7) Yq- - deletion of the long arm of Y chromosome, the size of the long arm being less than chromosomes 21--22. The total frequency of variants in newborns was 12.8/1000 births. The incidence of different types of variants per 1000 births was as follows: Igh+ - 0.33; 9gh+ - 0.17; 16gh+ - 0.50; Ds+ - 2.33; Dp+ - 1.50; Dp- - 0.17; Gs+ - 0.83; Gp+ - 2.17; Yq+ - 6.91/1000 males; Yg- - 0.99/1000 males; double variants - 0.33; other variants - 0.33. 4.0% of married couples with recurrent spontaneous abortions had major chromosome aberrations, 14.6% - extreme variants of chromosomes. Among 113 couples with the history of congenital malformations in their offsprings major chromosome abnormalities were found in 4.4%, chromosome variants - 13.3%. The frequency of chromosome variants among 139 patients with Down's syndrome was 7.2%. In one case Robertsonian translocation t(DqGa) was determined. The most frequent types of variant chromosomes were Ds+, Dp+, Es+, Yq+.

  8. Beta-glucosidase variants and polynucleotides encoding same

    Energy Technology Data Exchange (ETDEWEB)

    Wogulis, Mark; Harris, Paul; Osborn, David

    2017-06-27

    The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

  9. Evidence for impaired CARD15 signalling in Crohn's disease without disease linked variants

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Broom, Oliver Jay; Olsen, Jørgen

    2009-01-01

    BACKGROUND: Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important...... for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS: By mapping...... the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase...

  10. Hb variants in Korea: effect on HbA1c using five routine methods.

    Science.gov (United States)

    Yun, Yeo-Min; Ji, Misuk; Ko, Dae-Hyun; Chun, Sail; Kwon, Gye Cheol; Lee, Kyunghoon; Song, Sang Hoon; Seong, Moon Woo; Park, Sung Sup; Song, Junghan

    2017-07-26

    Quantification of glycated hemoglobin (HbA1c) is a challenge in patients with hemoglobin (Hb) variants. We evaluated the impact of various Hb variants on five routine HbA1c assays by comparing with the IFCC reference measurement procedure (RMP). Whole blood samples showing warning flags or no results on routine HPLC HbA1c assays were confirmed for Hb variants and were submitted to HbA1c quantification using Sebia Capillarys 2 Flex Piercing, Roche Tina-quant HbA1c Gen. 2, Bio-Rad Variant II Turbo 2.0, ADAMS HA-8180, Tosoh G8 standard mode, and IFCC RMP using LC-MS. Among 114 samples, the most common variants were Hb G-Coushatta (n=47), Queens (n=41), Ube-4 (n=11), Chad (n=4), Yamagata (n=4), G-His-Tsou (n=2), G-Taipei (n=1), Fort de France (n=1), Hoshida (n=1), and two novel variants (Hb α-globin, HBA 52 Gly>Cys and Hb β-globin, HBB 146 His>Asn). In terms of control samples, all the result of HbA1c were "acceptable", within the criteria of ±7% compared to IFCC RMP target values. However, percentage of "unacceptable" results of samples with Hb variants were 16% for Capillarys 2, 7% for Tina-quant, 51% for Variant II Turbo 2.0, 95% for G8 standard mode, and 89% for HA-8180. The Capillarys 2 and HA-8180 assay did not provide the results in 5 and 40 samples with Hb variants, respectively. HbA1c results from five routine assays in patients with relatively common Hb variants in Korea showed various degrees of bias compared to those of IFCC RMP. Therefore, laboratories should be aware of the limitation of their methods with respect to interference from Hb variants found commonly in their local population and suggest an alternative HbA1c quantification method.

  11. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications.

    Science.gov (United States)

    Chen, Xiaoyu; Schulz-Trieglaff, Ole; Shaw, Richard; Barnes, Bret; Schlesinger, Felix; Källberg, Morten; Cox, Anthony J; Kruglyak, Semyon; Saunders, Christopher T

    2016-04-15

    : We describe Manta, a method to discover structural variants and indels from next generation sequencing data. Manta is optimized for rapid germline and somatic analysis, calling structural variants, medium-sized indels and large insertions on standard compute hardware in less than a tenth of the time that comparable methods require to identify only subsets of these variant types: for example NA12878 at 50× genomic coverage is analyzed in less than 20 min. Manta can discover and score variants based on supporting paired and split-read evidence, with scoring models optimized for germline analysis of diploid individuals and somatic analysis of tumor-normal sample pairs. Call quality is similar to or better than comparable methods, as determined by pedigree consistency of germline calls and comparison of somatic calls to COSMIC database variants. Manta consistently assembles a higher fraction of its calls to base-pair resolution, allowing for improved downstream annotation and analysis of clinical significance. We provide Manta as a community resource to facilitate practical and routine structural variant analysis in clinical and research sequencing scenarios. Manta is released under the open-source GPLv3 license. Source code, documentation and Linux binaries are available from https://github.com/Illumina/manta. csaunders@illumina.com Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Comparison of gene-based rare variant association mapping methods for quantitative traits in a bovine population with complex familial relationships.

    Science.gov (United States)

    Zhang, Qianqian; Guldbrandtsen, Bernt; Calus, Mario P L; Lund, Mogens Sandø; Sahana, Goutam

    2016-08-17

    There is growing interest in the role of rare variants in the variation of complex traits due to increasing evidence that rare variants are associated with quantitative traits. However, association methods that are commonly used for mapping common variants are not effective to map rare variants. Besides, livestock populations have large half-sib families and the occurrence of rare variants may be confounded with family structure, which makes it difficult to disentangle their effects from family mean effects. We compared the power of methods that are commonly applied in human genetics to map rare variants in cattle using whole-genome sequence data and simulated phenotypes. We also studied the power of mapping rare variants using linear mixed models (LMM), which are the method of choice to account for both family relationships and population structure in cattle. We observed that the power of the LMM approach was low for mapping a rare variant (defined as those that have frequencies lower than 0.01) with a moderate effect (5 to 8 % of phenotypic variance explained by multiple rare variants that vary from 5 to 21 in number) contributing to a QTL with a sample size of 1000. In contrast, across the scenarios studied, statistical methods that are specialized for mapping rare variants increased power regardless of whether multiple rare variants or a single rare variant underlie a QTL. Different methods for combining rare variants in the test single nucleotide polymorphism set resulted in similar power irrespective of the proportion of total genetic variance explained by the QTL. However, when the QTL variance is very small (only 0.1 % of the total genetic variance), these specialized methods for mapping rare variants and LMM generally had no power to map the variants within a gene with sample sizes of 1000 or 5000. We observed that the methods that combine multiple rare variants within a gene into a meta-variant generally had greater power to map rare variants compared

  13. The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.

    Science.gov (United States)

    Both, Anna; Krauter, Jürgen; Damm, Frederik; Thol, Felicitas; Göhring, Gudrun; Heuser, Michael; Ottmann, Oliver; Lübbert, Michael; Wattad, Mohammed; Kanz, Lothar; Schlimok, Günter; Raghavachar, Aruna; Fiedler, Walter; Kirchner, Hartmut; Brugger, Wolfram; Schlegelberger, Brigitte; Heil, Gerhard; Ganser, Arnold; Wagner, Katharina

    2017-06-01

    Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity.

  14. Hemoglobin Variants: Biochemical Properties and Clinical Correlates

    Science.gov (United States)

    Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

    2013-01-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

  15. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  16. Warty Carcinoma Penis: An Uncommon Variant.

    Science.gov (United States)

    Thapa, Sushma; Ghosh, Arnab; Shrestha, Santosh; Ghartimagar, Dilasma; Narasimhan, Raghavan; Talwar, O P

    2017-01-01

    Penile carcinoma frequency varies widely in different parts of the world and comprises 1-10% of all the malignancies in males. Majority of the cases of penile carcinoma are squamous cell carcinoma of penis comprising 60% to 70% of all cases. Warty carcinoma of penis is an unusual neoplasm and a variant of penile squamous cell carcinoma comprising 5%-10% of all the variants. The other histological variants include basaloid, verrucous, papillary, sarcomatous, mixed, and adenosquamous carcinoma. The various histological entities with an exophytic papillary lesions including warty carcinoma are together referred to as the "verruciform" group of neoplasms. The warty carcinoma has to be differentiated from these lesions and is typically distinguished by histological features of hyperkeratosis, arborescent papillomatosis, acanthosis, and prominent koilocytosis with nuclear pleomorphism. We present a case of 65-year-old male with growth measuring 6 × 4 cm in the penis who underwent total penectomy and was diagnosed as warty carcinoma penis.

  17. Variants of Monteggia Type Injury: Case Reports

    Directory of Open Access Journals (Sweden)

    Kamudin NAF

    2015-03-01

    Full Text Available Background: Monteggia fracture-dislocation is rare in children. Various reports attest to its rarity, while recording the many variant of this injury. It is, therefore, easy to miss the diagnosis in the absence of proper clinical examination and radiographs. Case Report : This report highlights two rare variants of Monteggia fracture-dislocation seen in children. The first case was a 12-year old girl alleged to have fallen from a 15-feet tall tree and sustaining a combined type III Monteggia injury with ipsilateral Type II Salter-Harris injury of distal end radius with a metaphyseal fracture of the distal third of the ulna. The second case was a 13-year old who had sustained a closed fracture of atypical Type I Monteggia hybrid lesion, in a road traffic accident. Conclusion: This report highlights the rare variants of Monteggia fracture dislocation which could have been missed without proper clinical examinations and radiographs.

  18. Development of industrial variant specification systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer

    With globalisation and increased competition industrial companies must be prepared to satisfy individual customer needs and still stay competitive with regards to lead times, quality, and prices. These factors require companies to be better prepared to handle specification activities during order...... and the challenge of understanding the variant specification tasks and the connections between variant specification, product development, sales, manufacturing, and information technology. The present thesis seeks to meet this challenge with a procedure, concepts and tools. This is done through an extensive answer...... acquisition and order fulfilment, i.e. the creation of drawings, bill-of-materials, routings, product descriptions, quote letters etc. The present thesis is rooted in the assumption that variant specification systems supporting the cross-functional processes of order acquisition and order fulfilment must...

  19. A case of reninoma with variant angina

    Directory of Open Access Journals (Sweden)

    Hyung Ah Jo

    2014-06-01

    Full Text Available Reninoma is a tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia because of hypersecretion of renin. We present a case of a 29-year-old female patient with reninoma and concomitant variant angina. The patient had uncontrolled hypertension and elevated plasma renin activity and aldosterone levels. Imaging studies revealed a mass in the left kidney, which was further confirmed as a renin-producing lesion via selective venous catheterization. During the evaluation, the patient had acute-onset chest pain that was diagnosed as variant angina after a provocation test. After partial nephrectomy, the plasma renin activity and plasma aldosterone levels decreased and blood pressure normalized. We report a case of reninoma with variant angina.

  20. Inferior patellar pole fragmentation in children: just a normal variant?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, J.H.; Vogelius, Esben S.; Orth, Robert C.; Guillerman, R.P.; Jadhav, Siddharth P. [Texas Children' s Hospital, E.B. Singleton Pediatric Radiology, Houston, TX (United States)

    2015-06-15

    Fragmentary ossification of the inferior patella is often dismissed as a normal variant in children younger than 10 years of age. The purpose of this study was to determine whether fragmentary inferior patellar pole ossification is a normal variant or is associated with symptoms or signs of pathology using MRI and clinical exam findings as reference. A retrospective review was performed on 150 patients ages 5-10 years who underwent 164 knee radiography and MRI exams (45.1% male, mean age: 7.8 years). The presence or absence of inferior patellar pole fragmentation on radiography was correlated with the presence or absence of edema-like signal on MR images. Clinical notes were reviewed for the presence of symptoms or signs referable to the inferior patellar pole. These data were compared with a 1:1 age- and sex-matched control group without inferior pole fragmentation. Statistical analysis was performed using two-tailed t-tests. Forty of 164 (24.4%) knee radiographs showed fragmentary ossification of the inferior patella. Of these 40 knees, 62.5% (25/40) had edema-like signal of the inferior patellar bone marrow compared with 7.5% (3/40) of controls (P = 0.035). Patients with fragmentary ossification at the inferior patella had a significantly higher incidence of documented focal inferior patellar pain compared with controls (20% vs. 2.5%, P = 0.015). Inferior patellar pole fragmentation in children 5 to 10 years of age may be associated with localized symptoms and bone marrow edema-like signal and should not be routinely dismissed as a normal variant of ossification. (orig.)

  1. C5 variant is associated with decreased risk of coronary artery disease in outpatients with severe hypercholinesterasemia.

    Science.gov (United States)

    Nagayama, Daiji; Murano, Takeyoshi; Saiki, Atsuhito; Shirai, Kohji; Tatsuno, Ichiro

    2014-06-01

    Although the C5 variant of cholinesterase is known to be a cause of hypercholinesterasemia, the pathophysiological significance of the C5 variant and the C5 variant-related hypercholinesterasemia in cardiovascular diseases remain unclear. The present study aimed to clarify the pathophysiological significance of the C5 variant as a risk or protective factor for coronary artery disease (CAD) in patients with severe hypercholinesterasemia. Severe hypercholinesterasemia was defined as serum cholinesterase (ChE) activity >= 450 IU/L (>= 2.0 SD). We screened 11,648 consecutive outpatients between 2005 and 2011 at Toho University, Sakura Medical Center. In patients with severe hypercholinesterasemia, phenotyping of the C5 variant was conducted using polyacrylamide gel electrophoresis and alpha-naphthyl butyrate staining. 157 subjects (1.4% of 11,648 outpatients screened) were diagnosed with severe hypercholinesterasemia (mean serum ChE activity 574 ± 109 IU/L), and the frequency of the C5 variant was 45.2%. Subjects with the C5 variant had higher age, lower body mass index, milder dyslipidemia and liver dysfunction, and lower rates of hypertension and CAD compared with subjects without the C5 variant. Multivariate logistic regression model demonstrated that the presence of C5 variant independently lowered the risk of CAD, with odds ratio 0.071 (95% confidence interval (CI) 0.007 - 0.763, p = 0.029). The prevalence of the C5 variant was relatively high, and the C5 variant is associated with decreased risk of CAD in outpatients with severe hypercholinesterasemia.

  2. Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration.

    Science.gov (United States)

    Ferrara, Daniela; Seddon, Johanna M

    2015-07-01

    The complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized. To describe specific fundus features of a white population with the R1210C rare variant. Fundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database. The presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes. Images from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.

  3. Variant profiling of evolving prokaryotic populations

    Directory of Open Access Journals (Sweden)

    Markus Zojer

    2017-02-01

    Full Text Available Genomic heterogeneity of bacterial species is observed and studied in experimental evolution experiments and clinical diagnostics, and occurs as micro-diversity of natural habitats. The challenge for genome research is to accurately capture this heterogeneity with the currently used short sequencing reads. Recent advances in NGS technologies improved the speed and coverage and thus allowed for deep sequencing of bacterial populations. This facilitates the quantitative assessment of genomic heterogeneity, including low frequency alleles or haplotypes. However, false positive variant predictions due to sequencing errors and mapping artifacts of short reads need to be prevented. We therefore created VarCap, a workflow for the reliable prediction of different types of variants even at low frequencies. In order to predict SNPs, InDels and structural variations, we evaluated the sensitivity and accuracy of different software tools using synthetic read data. The results suggested that the best sensitivity could be reached by a union of different tools, however at the price of increased false positives. We identified possible reasons for false predictions and used this knowledge to improve the accuracy by post-filtering the predicted variants according to properties such as frequency, coverage, genomic environment/localization and co-localization with other variants. We observed that best precision was achieved by using an intersection of at least two tools per variant. This resulted in the reliable prediction of variants above a minimum relative abundance of 2%. VarCap is designed for being routinely used within experimental evolution experiments or for clinical diagnostics. The detected variants are reported as frequencies within a VCF file and as a graphical overview of the distribution of the different variant/allele/haplotype frequencies. The source code of VarCap is available at https://github.com/ma2o/VarCap. In order to provide this workflow to

  4. Variantes estruturalistas no ensino de Lacan

    OpenAIRE

    Riaviz, Eduardo

    2005-01-01

    Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão. Programa de Pós-Graduação em Literatura A presente tese estuda as variantes estruturalistas no ensino de Lacan. Para introduzir estas variantes, parte dos antecedentes desse ensino, i.e., dos textos de Lacan que ainda não são lacanianos. Mostra, nestes antecedentes, uma intuição estruturalista em Lacan, um estruturalismo em estado prático. Será justamente este proto-estruturalismo a permitir que L...

  5. Performance of genotype imputation for rare variants identified in exons and flanking regions of genes.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Genotype imputation has the potential to assess human genetic variation at a lower cost than assaying the variants using laboratory techniques. The performance of imputation for rare variants has not been comprehensively studied. We utilized 8865 human samples with high depth resequencing data for the exons and flanking regions of 202 genes and Genome-Wide Association Study (GWAS data to characterize the performance of genotype imputation for rare variants. We evaluated reference sets ranging from 100 to 3713 subjects for imputing into samples typed for the Affymetrix (500K and 6.0 and Illumina 550K GWAS panels. The proportion of variants that could be well imputed (true r(2>0.7 with a reference panel of 3713 individuals was: 31% (Illumina 550K or 25% (Affymetrix 500K with MAF (Minor Allele Frequency less than or equal 0.001, 48% or 35% with 0.0010.05. The performance for common SNPs (MAF>0.05 within exons and flanking regions is comparable to imputation of more uniformly distributed SNPs. The performance for rare SNPs (0.01variants identified in humans via targeted exon resequencing into additional samples with GWAS data, but imputation of very rare variants (MAF< = 0.005 will require reference panels with thousands of subjects.

  6. ISVASE: identification of sequence variant associated with splicing event using RNA-seq data.

    Science.gov (United States)

    Aljohi, Hasan Awad; Liu, Wanfei; Lin, Qiang; Yu, Jun; Hu, Songnian

    2017-06-28

    Exon recognition and splicing precisely and efficiently by spliceosome is the key to generate mature mRNAs. About one third or a half of disease-related mutations affect RNA splicing. Software PVAAS has been developed to identify variants associated with aberrant splicing by directly using RNA-seq data. However, it bases on the assumption that annotated splicing site is normal splicing, which is not true in fact. We develop the ISVASE, a tool for specifically identifying sequence variants associated with splicing events (SVASE) by using RNA-seq data. Comparing with PVAAS, our tool has several advantages, such as multi-pass stringent rule-dependent filters and statistical filters, only using split-reads, independent sequence variant identification in each part of splicing (junction), sequence variant detection for both of known and novel splicing event, additional exon-exon junction shift event detection if known splicing events provided, splicing signal evaluation, known DNA mutation and/or RNA editing data supported, higher precision and consistency, and short running time. Using a realistic RNA-seq dataset, we performed a case study to illustrate the functionality and effectiveness of our method. Moreover, the output of SVASEs can be used for downstream analysis such as splicing regulatory element study and sequence variant functional analysis. ISVASE is useful for researchers interested in sequence variants (DNA mutation and/or RNA editing) associated with splicing events. The package is freely available at https://sourceforge.net/projects/isvase/ .

  7. Genome-Wide Identification, Evolutionary, and Expression Analyses of Histone H3 Variants in Plants

    Directory of Open Access Journals (Sweden)

    Jinteng Cui

    2015-01-01

    Full Text Available Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development.

  8. Papillary Thyroid Cancer, Macrofollicular Variant: The Follow-Up and Analysis of Prognosis of 5 Patients

    Directory of Open Access Journals (Sweden)

    Varlık Erol

    2014-01-01

    Full Text Available Objective. The main aim of this study was to comparatively analyze the recurrence and prognosis of this rare variant with the literature by analyzing the follow-up data of 5 patients diagnosed with papillary cancer macrofollicular variant. Methods. The demographic data, radiological and pathological data, and prognostic data of 5 patients who underwent surgery for thyroid cancer and were diagnosed with papillary cancer macrofollicular variant pathologically were retrospectively analyzed. Results. The mean age of patients whose mean follow-up period was determined as 7.2 years was 41, and the male/female ratio was 4/1. All patients underwent total thyroidectomy. The pathology report of 2 patients (40% revealed macrofollicular variant of papillary microcancer, and 3 patients papillary cancer macrofollicular variant. Central dissection was performed in one patient (20% due to macroscopic pathologic lymph node and 4 metastatic lymph nodes were reported. Also, locoregional recurrence was present in 3 out of 5 patients (60%. Conclusions. Although an impression of earlier and increased risk of recurrence in papillary carcinoma with macrofollicular variant has been documented, more studies with extensive follow-up times and large populations are required.

  9. Neutralization-resistant variants of infectious hematopoietic necrosis virus have altered virulence and tissue tropism

    Science.gov (United States)

    Kim, C.H.; Winton, J.R.; Leong, J.C.

    1994-01-01

    Infectious hematopoietic necrosis virus (IHNV) is a rhabdovirus that causes an acute disease in salmon and trout. In this study, a correlation between changes in tissue tropism and specific changes in the virus genome appeared to be made by examining four IHNV neutralization-resistant variants (RB-1, RB-2, RB-3, and RB-4) that had been selected with the glycoprotein (G)-specific monoclonal antibody RB/B5. These variants were compared with the parental strain (RB-76) for their virulence and pathogenicity in rainbow trout after waterborne challenge. Variants RB-2, RB-3, and RB-4 were only slightly attenuated and showed distributions of viral antigen in the livers and hematopoietic tissues of infected fish similar to those of the parental strain. Variant RB-1, however, was highly attenuated and the tissue distribution of viral antigen in RB-1-infected fish was markedly different, with more viral antigen in brain tissue. The sequences of the G genes of all four variants and RB-76 were determined. No significant changes were found for the slightly attenuated variants, but RB-1 G had two changes at amino acids 78 and 218 that dramatically altered its predicted secondary structure. These changes are thought to be responsible for the altered tissue tropism of the virus. Thus, IHNV G, like that of rabies virus and vesicular stomatitis virus, plays an integral part in the pathogenesis of viral infection.

  10. Quantifying the Impact of Non-coding Variants on Transcription Factor-DNA Binding.

    Science.gov (United States)

    Zhao, Jingkang; Li, Dongshunyi; Seo, Jungkyun; Allen, Andrew S; Gordân, Raluca

    2017-05-01

    Many recent studies have emphasized the importance of genetic variants and mutations in cancer and other complex human diseases. The overwhelming majority of these variants occur in non-coding portions of the genome, where they can have a functional impact by disrupting regulatory interactions between transcription factors (TFs) and DNA. Here, we present a method for assessing the impact of non-coding mutations on TF-DNA interactions, based on regression models of DNA-binding specificity trained on high-throughput in vitro data. We use ordinary least squares (OLS) to estimate the parameters of the binding model for each TF, and we show that our predictions of TF-binding changes due to DNA mutations correlate well with measured changes in gene expression. In addition, by leveraging distributional results associated with OLS estimation, for each predicted change in TF binding we also compute a normalized score (z-score) and a significance value (p-value) reflecting our confidence that the mutation affects TF binding. We use this approach to analyze a large set of pathogenic non-coding variants, and we show that these variants lead to significant differences in TF binding between alleles, compared to a control set of common variants. Thus, our results indicate that there is a strong regulatory component to the pathogenic non-coding variants identified thus far.

  11. A Newly Identified Natural Splice Variant ASN Enhances Hepatitis B Virus Amplification.

    Science.gov (United States)

    Zhang, Xiumin; Zhu, Sibo; Zhu, Wei; Li, Aijun; Zhu, Naishuo

    2016-01-01

    Chronic hepatitis B virus (HBV) infection causes approximately one-third of all the cases of liver cirrhosis and more than three-quarters of hepatocellular carcinoma (HCC) worldwide. There are eight different genotypes (A-H) of HBV, among which B and C are the major types of HBV in China. There is a positive correlation between viral load and level of viral splicing variants and the high risk of HCC. The aim of this study was to investigate the splicing variants of HBV circulating in HCC patients. Twenty-four carcinoma and adjacent liver tissues collected from HCC patients were studied. Using reverse transcription-polymerase chain reaction (RT-PCR) and sequencing, we identified a new type of natural splice variant with nucleotides 2448-489 and 910-2120 deleted, and we named it ASN. We also found that a higher viral load and splicing variant level existed in liver carcinoma tissues compared to paracarcinoma tissues. In the investigation of our splicing variant, we found its enhancing effect on HBV replication in vitro. Although splicing variants are not essential for the replication of HBV, they may have an important influence.

  12. Functional characterization of BRCA1 gene variants by mini-gene splicing assay

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Dandanell, Mette; Jønson, Lars

    2014-01-01

    are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13 BRCA1 variants...... of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213-1G>A, c.670+1delG, c.4185+1G>A, and c.5075-1G......>C), whereas six BRCA1 variants were classified as neutral (c.-19-22_-19-21dupAT, c.302-15C>G, c.547+14delG, c.4676-20A>G, c.4987-21G>T, and c.5278-14C>G) and one BRCA1 variant remained unclassified (c.670+16G>A). In conclusion, our study emphasizes that in silico analysis and mini-gene splicing assays...

  13. Hirayama's Disease: A Rare Clinical Variant of Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Swati C Aundhakar

    2017-01-01

    Full Text Available Hirayama's disease is a rare clinical variant of amyotrophic lateral sclerosis where distal muscles are involved more compared to proximal muscles and vice-versa occurs only in 10% cases and so it is differentiated from O'Sullivan McLeod syndrome which involves only small muscles of single limb. Here, we present a case of Hirayama's disease where disease achieved a plateau after 3 years with no further progression. His electrophysiological studies, and clinical picture, and magnetic resonance imaging findings were consistent with a diagnosis of Hirayama's disease.

  14. Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Joanne D Stekler

    Full Text Available To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA but not consensus sequencing among subjects with primary HIV-1 infection.Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL among subjects with minority variants conferring intermediate or high-level resistance.Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62-147 days for 63 treated subjects without detectable mutations, 84 (IQR 56-109 days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60-162 days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9. Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6-2.4, p = .6 and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4-2.4, p = .9. Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure.Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.

  15. Rare human papillomavirus 16 E6 variants reveal significant oncogenic potential

    Directory of Open Access Journals (Sweden)

    Tommasino Massimo

    2011-06-01

    Full Text Available Abstract The aim of this study was to determine whether low prevalence human papillomavirus (HPV 16 E6 variants differ from high prevalence types in their functional abilities. We evaluated functions relevant to carcinogenesis for the rarely-detected European variants R8Q, R10G and R48W as compared to the commonly detected L83V. Human immortalized keratinocytes (NIKS stably transduced with the E6 variants were used in most functional assays. Low and high prevalence E6 variants displayed similar abilities in abrogation of growth arrest and inhibition of p53 elevation induced by actinomycin D. Differences were detected in the abilities to dysregulate stratification and differentiation of NIKS in organotypic raft cultures, modulate detachment induced apoptosis (anoikis and hyperactivate Wnt signaling. No distinctive phenotype could be assigned to include all rare variants. Like L83V, raft cultures derived from variants R10G and R48W similarly induced hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment with significantly lower expression of keratin 10. Unlike L83V, both variants, and particularly R48W, induced increased levels of anoikis upon suspension in semisolid medium. R8Q induced a unique phenotype characterized by thin organotypic raft cultures, low expression of keratin 10, and high expression of keratins 5 and 14 throughout all raft layers. Interestingly, in a reporter based assay R8Q exhibited a higher ability to augment TCF/β-catenin transcription. The data suggests that differences in E6 variant prevalence in cervical carcinoma may not be related to the carcinogenic potential of the E6 protein.

  16. Rarity of the Alzheimer Disease–Protective APP A673T Variant in the United States

    Science.gov (United States)

    Wang, Li-San; Naj, Adam C.; Graham, Robert R.; Crane, Paul K.; Kunkle, Brian W.; Cruchaga, Carlos; Gonzalez Murcia, Josue D.; Cannon-Albright, Lisa; Baldwin, Clinton T.; Zetterberg, Henrik; Blennow, Kaj; Kukull, Walter A.; Faber, Kelley M.; Schupf, Nicole; Norton, Maria C.; Tschanz, JoAnn T.; Munger, Ronald G.; Corcoran, Christopher D.; Rogaeva, Ekaterina; Lin, Chiao-Feng; Dombroski, Beth A.; Cantwell, Laura B.; Partch, Amanda; Valladares, Otto; Hakonarson, Hakon; St George-Hyslop, Peter; Green, Robert C.; Goate, Alison M.; Foroud, Tatiana M.; Carney, Regina M.; Larson, Eric B.; Behrens, Timothy W.; Kauwe, John S. K.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Mayeux, Richard; Schellenberg, Gerard D.

    2015-01-01

    IMPORTANCE Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both

  17. Rarity of the Alzheimer disease-protective APP A673T variant in the United States.

    Science.gov (United States)

    Wang, Li-San; Naj, Adam C; Graham, Robert R; Crane, Paul K; Kunkle, Brian W; Cruchaga, Carlos; Murcia, Josue D Gonzalez; Cannon-Albright, Lisa; Baldwin, Clinton T; Zetterberg, Henrik; Blennow, Kaj; Kukull, Walter A; Faber, Kelley M; Schupf, Nicole; Norton, Maria C; Tschanz, JoAnn T; Munger, Ronald G; Corcoran, Christopher D; Rogaeva, Ekaterina; Lin, Chiao-Feng; Dombroski, Beth A; Cantwell, Laura B; Partch, Amanda; Valladares, Otto; Hakonarson, Hakon; St George-Hyslop, Peter; Green, Robert C; Goate, Alison M; Foroud, Tatiana M; Carney, Regina M; Larson, Eric B; Behrens, Timothy W; Kauwe, John S K; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Mayeux, Richard; Schellenberg, Gerard D; Albert, Marilyn S; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Barber, Robert; Barmada, Michael; Barnes, Lisa L; Beach, Thomas G; Becker, James T; Beecham, Gary W; Beekly, Duane; Bennett, David A; Bigio, Eileen H; Bird, Thomas D; Blacker, Deborah; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burke, James R; Buxbaum, Joseph D; Cairns, Nigel J; Cao, Chuanhai; Carlson, Chris S; Carroll, Steven L; Chui, Helena C; Clark, David G; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; DeKosky, Steven T; Demirci, F Yesim; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Ertekin-Taner, Nilufer; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Glass, Jonathan D; Graff-Radford, Neill R; Growdon, John H; Hamilton, Ronald L; Hamilton-Nelson, Kara L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Jicha, Gregory A; Jin, Lee-Way; Jun, Gyungah; Jun, Gyungah; Kamboh, M Ilyas; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Gei; Lieberman, Andrew P; Lopez, Oscar L; Lunetta, Kathryn L; Lyketsos, Constantine G; Mack, Wendy J; Marson, Daniel C; Martin, Eden R; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, W Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Montine, Thomas J; Morris, John C; Murrell, Jill R; Olichney, John M; Parisi, Joseph E; Perry, William; Peskind, Elaine; Petersen, Ronald C; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reiman, Eric M; Reisberg, Barry; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rosen, Howard J; Rosenberg, Roger N; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Tsuang, Debby W; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vardarajan, Badri N; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Wishnek, Sarah; Woltjer, Randall L; Wright, Clinton B; Younkin, Steven G; Yu, Chang-En; Yu, Lei

    2015-02-01

    Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for

  18. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    Directory of Open Access Journals (Sweden)

    Douglas R Smith

    Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  19. Mining business process variants: Challenges, scenarios, algorithms

    NARCIS (Netherlands)

    Li, C.; Reichert, M.U.; Wombacher, Andreas

    During the last years a new generation of process-aware information systems has emerged, which enables process model configurations at buildtime as well as process instance changes during runtime. Respective model adaptations result in a large number of model variants that are derived from the same

  20. Probabilistic Transcriptome Assembly and Variant Graph Genotyping

    DEFF Research Database (Denmark)

    Sibbesen, Jonas Andreas

    that this approach outperforms existing state-of-the-art methods measured using sensitivity and precision on both simulated and real data. The second is a novel probabilistic method that uses exact alignment of k-mers to a set of variants graphs to provide unbiased estimates of genotypes in a population...

  1. HLogo: a parallel Haskell variant of Netlogo

    NARCIS (Netherlands)

    N. Bezirgiannis (Nikolaos); Prasetya, I.S.W.B.; Sakellariou, I.

    2016-01-01

    textabstractAgent-based Modeling (ABM) has become quite popular to the simulation community for its usability and wide area of applicability. However, speed is not usually a trait that ABM tools are characterized of attaining. This paper presents HLogo, a parallel variant of the NetLogo ABM

  2. XVCL: XML-based Variant Configuration Language

    DEFF Research Database (Denmark)

    Jarzabek, Stan; Basset, Paul; Zhang, Hongyu

    2003-01-01

    XVCL (XML-based Variant Configuration Language) is a meta-programming technique and tool that provides effective reuse mechanisms. XVCL is an open source software developed at the National University of Singapore. Being a modern and versatile version of Bassett's frames, a technology that has...

  3. Variants of the left aortic arch branches

    African Journals Online (AJOL)

    ORIGINAL ARTICLE. Variants of the left aortic arch branches. N Z Makhanya. MB ChB. R T Mamogale. MB 0113. N Khan. FCRaD (0). Department of Diagnostic Radiology. Medical University of Southern Africa. Abstract. The normal aorta has three branches from its arch, but variations in this pattern are not uncommon. Our.

  4. New genetic variants associated with prostate cancer

    Science.gov (United States)

    Researchers have newly identified 23 common genetic variants -- one-letter changes in DNA known as single-nucleotide polymorphisms or SNPs -- that are associated with risk of prostate cancer. These results come from an analysis of more than 10 million SNP

  5. Psychiatric misdiagnoses in Dandy-Walker variant.

    Science.gov (United States)

    Blaettner, C; Pfaffenberger, N M; Cartes-Zumelzu, F; Hofer, A

    2015-01-01

    Cases of intellectual impairment and aberrant behavior in patients with cerebellar diseases have been described since the early nineteenth century. Here, we report on a patient suffering from Dandy-Walker variant who presented with symptoms of obsessive compulsive disorder and delusional disorder. The current findings emphasize the potential relevance of focal cerebellar lesions as organic correlates of these disorders.

  6. Developing consistent pronunciation models for phonemic variants

    CSIR Research Space (South Africa)

    Davel, M

    2006-09-01

    Full Text Available from a lexicon containing variants. In this paper we (the authors) address both these issues by creating ‘pseudo-phonemes’ associated with sets of ‘generation restriction rules’ to model those pronunciations that are consistently realised as two or more...

  7. Mining Process Model Variants: Challenges, Techniques, Examples

    NARCIS (Netherlands)

    Li, C.

    2010-01-01

    During the last years a new generation of process-aware information systems has emerged, which enables process model configurations at buildtime as well as process instance changes during runtime. Respective model adaptations result in large collections of process model variants that are derived

  8. Cellobiohydrolase I gene and improved variants

    Science.gov (United States)

    Adney, William S [Golden, CO; Decker, Stephen R [Berthoud, CO; Mc Carter, Suzanne [San Carlos, CA; Baker, John O [Golden, CO; Nieves, Raphael [Lakewood, CO; Himmel, Michael E [Littleton, CO; Vinzant, Todd B [Golden, CO

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  9. Report of a rare anatomic variant

    DEFF Research Database (Denmark)

    De Brucker, Y; Ilsen, B; Muylaert, C

    2015-01-01

    We report the CT findings in a case of partial anomalous pulmonary venous return (PAPVR) from the left upper lobe in an adult. PAPVR is an anatomic variant in which one to three pulmonary veins drain into the right atrium or its tributaries, rather than into the left atrium. This results in a lef...

  10. PIN1 gene variants in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Siedlecki Janusz

    2009-11-01

    Full Text Available Abstract Background Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1 plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk. Methods We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD patients in comparison with healthy controls. Results Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk. In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed. Conclusion Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

  11. Allelic variants of melanocortin 3 receptor gene (MC3R) and weight loss in obesity

    DEFF Research Database (Denmark)

    L. Santos, José; De la Cruz, Rolando; Holst, Claus

    2011-01-01

    The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3...... receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets....

  12. FTO Obesity Risk Variants Are Linked to Adipocyte IRX3 Expression and BMI of Children - Relevance of FTO Variants to Defend Body Weight in Lean Children?

    Science.gov (United States)

    Landgraf, Kathrin; Scholz, Markus; Kovacs, Peter; Kiess, Wieland; Körner, Antje

    2016-01-01

    Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. Expression of IRX3 was higher in adipocytes compared to SVF. We found increased adipocyte-specific expression of IRX3 and IRX5 with the presence of the FTO risk haplotype in lean children, whereas it was unaffected by risk variants in obese peers. We further show that IRX3 expression was elevated in isolated adipocytes and AT of lean compared to obese children, particularly in UCP1-negative adipocytes, and inversely correlated with BMI SDS. Independent of BMI, IRX3 expression in adipocytes was significantly related to adipocyte hypertrophy, and subsequent associations with AT inflammation and HOMA-IR in the children. One interpretation of our observation of FTO risk variants linked to IRX3 expression and adipocyte size restricted to lean children, along with the decreased IRX3 expression in obese compared to lean peers, may reflect a defense mechanism for protecting body-weight, which is pertinent for lean children.

  13. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.

    Science.gov (United States)

    Rascovsky, Katya; Hodges, John R; Knopman, David; Mendez, Mario F; Kramer, Joel H; Neuhaus, John; van Swieten, John C; Seelaar, Harro; Dopper, Elise G P; Onyike, Chiadi U; Hillis, Argye E; Josephs, Keith A; Boeve, Bradley F; Kertesz, Andrew; Seeley, William W; Rankin, Katherine P; Johnson, Julene K; Gorno-Tempini, Maria-Luisa; Rosen, Howard; Prioleau-Latham, Caroline E; Lee, Albert; Kipps, Christopher M; Lillo, Patricia; Piguet, Olivier; Rohrer, Jonathan D; Rossor, Martin N; Warren, Jason D; Fox, Nick C; Galasko, Douglas; Salmon, David P; Black, Sandra E; Mesulam, Marsel; Weintraub, Sandra; Dickerson, Brad C; Diehl-Schmid, Janine; Pasquier, Florence; Deramecourt, Vincent; Lebert, Florence; Pijnenburg, Yolande; Chow, Tiffany W; Manes, Facundo; Grafman, Jordan; Cappa, Stefano F; Freedman, Morris; Grossman, Murray; Miller, Bruce L

    2011-09-01

    Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory

  14. Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder.

    Directory of Open Access Journals (Sweden)

    Brandi Rollins

    Full Text Available Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ, bipolar disorder (BD, and major depressive disorder (MDD in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA sequence have been reported in SZ and BD patients.Dorsolateral prefrontal cortex (DLPFC from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017 in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK was significant (p = 0.004 and independent of postmortem interval time.Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.

  15. Self-perception in a clinical sample of gender variant children.

    Science.gov (United States)

    Rijn, Anouk Balleur-van; Steensma, Thomas D; Kreukels, Baudewijntje P C; Cohen-Kettenis, Peggy T

    2013-07-01

    Gender variance (GV) in childhood has a negative impact on the self-concept of children in the general population and can lead to mental health problems and even suicidal ideation in adulthood. This study explored the self-concept of clinically referred gender variant children and examined potential risk factors. The Self-Perception Profile for Children was administered to 147 children, who were referred to a gender identity clinic. Their parents completed the Child Behaviour Checklist and the Gender Identity Questionnaire to assess the degree of GV. The referred children were at risk of developing a negative self-concept; more specifically gender variant girls had low scores on 'global self-worth', 'physical appearance' and 'behavioural conduct' compared to Dutch norms for girls. Gender variant boys had low scores on 'global self-worth', 'scholastic competence', 'athletic competence' and 'physical appearance' compared to Dutch norms for boys. Within the group of referred children, sex differences, but no age effects, were found. The referred girls felt more competent than the referred boys on 'athletic competence' and 'scholastic functioning'. For both boys and girls poor peer relations had a significant negative relationship with self-concept and more GV was related to a lower global self-worth. Clinically referred gender variant children seemed vulnerable to developing a negative self-concept. Poor peer relations and extreme GV might be mediating variables. Interventions might focus on enhancing acceptance of the environment and improving social skills of gender variant children.

  16. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Akbari, Mohammad R; Zhang, Shiyu; Fan, Isabel; Royer, Robert; Li, Song; Risch, Harvey; McLaughlin, John; Rosen, Barry; Sun, Ping; Narod, Steven A

    2011-11-01

    Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, pcancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.

  17. Association of the MTHFR A1298C variant with unexplained severe male infertility.

    Directory of Open Access Journals (Sweden)

    Abdelmajid Eloualid

    Full Text Available The methylenetetrahydrofolate reductase (MTHFR gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR = 3.372, 95% confidence interval CI = 1.27-8.238; p = 0.01431. The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants.

  18. Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility

    Science.gov (United States)

    Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

    2012-01-01

    The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR = 3.372, 95% confidence interval CI = 1.27–8.238; p = 0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

  19. Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.

    Science.gov (United States)

    Reinl, Erin L; Goodwin, Zane A; Raghuraman, Nandini; Lee, Grace Y; Jo, Erin Y; Gezahegn, Beakal M; Pillai, Meghan K; Cahill, Alison G; de Guzman Strong, Cristina; England, Sarah K

    2017-08-01

    Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ 2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173

  20. Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

    Science.gov (United States)

    Parker, Remai; Schiemann, Anja H; Langton, Elaine; Bulger, Terasa; Pollock, Neil; Bjorksten, Andrew; Gillies, Robyn; Hutchinson, David; Roxburgh, Richard; Stowell, Kathryn M

    2017-01-01

    Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, functional studies must demonstrate a correlation with the pathophysiology of malignant hyperthermia or central core disease. We assessed the pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis. The variants were identified in families affected by either malignant hyperthermia or central core disease. Four variants were introduced separately into human cDNA encoding the skeletal muscle ryanodine receptor. Following transient expression in HEK-293T cells, functional studies were carried out using calcium release assays in response to an agonist. Two previously characterized variants and wild-type skeletal muscle ryanodine receptor were used as controls. The p.Met4640Ile variant associated with central core disease showed no difference in calcium release compared to wild-type. The p.Val4849Ile variant associated with malignant hyperthermia was more sensitive to agonist than wild-type but did not reach statistical significance and two variants (p.Phe4857Ser and p.Asp4918Asn) associated with central core disease were completely inactive. The p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia, while the p.Phe4857Ser and p.Asp4918Asn variants should be classified as pathogenic for central core disease.

  1. HE4 Transcription- and Splice Variants-Specific Expression in Endometrial Cancer and Correlation with Patient Survival

    Directory of Open Access Journals (Sweden)

    Shi-Wen Jiang

    2013-11-01

    Full Text Available We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

  2. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

    Science.gov (United States)

    2014-01-01

    Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex

  3. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

    DEFF Research Database (Denmark)

    Thorleifsson, Gudmar; Walters, G Bragi; Gudbjartsson, Daniel F

    2009-01-01

    Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305...... individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P ... to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity....

  4. Dietary intake, FTO genetic variants and adiposity

    DEFF Research Database (Denmark)

    Qi, Qibin; Downer, Mary K; Oskari Kilpeläinen, Tuomas

    2015-01-01

    between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake...

  5. Processing of No-Release Variants in Connected Speech

    Science.gov (United States)

    LoCasto, Paul C.; Connine, Cynthia M.

    2011-01-01

    The cross modal repetition priming paradigm was used to investigate how potential lexically ambiguous no-release variants are processed. In particular we focus on segmental regularities that affect the variant's frequency of occurrence (voicing of the critical segment) and phonological context in which the variant occurs (status of the following…

  6. The power of multiplexed functional analysis of genetic variants.

    Science.gov (United States)

    Gasperini, Molly; Starita, Lea; Shendure, Jay

    2016-10-01

    New technologies have recently enabled saturation mutagenesis and functional analysis of nearly all possible variants of regulatory elements or proteins of interest in single experiments. Here we discuss the past, present, and future of such multiplexed (functional) assays for variant effects (MAVEs). MAVEs provide detailed insight into sequence-function relationships, and they may prove critical for the prospective clinical interpretation of genetic variants.

  7. GAVIN : Gene-Aware Variant INterpretation for medical sequencing

    NARCIS (Netherlands)

    van der Velde, K Joeri; de Boer, Eddy N; van Diemen, Cleo C; Sikkema-Raddatz, Birgit; Abbott, Kristin M; Knopperts, Alain; Franke, Lude; Sijmons, Rolf H; de Koning, Tom J; Wijmenga, Cisca; Sinke, Richard J; Swertz, Morris A

    2017-01-01

    We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated

  8. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant....

  9. LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure.

    Science.gov (United States)

    Riley, Lisa G; Rudinger-Thirion, Joëlle; Schmitz-Abe, Klaus; Thorburn, David R; Davis, Ryan L; Teo, Juliana; Arbuckle, Susan; Cooper, Sandra T; Campagna, Dean R; Frugier, Magali; Markianos, Kyriacos; Sue, Carolyn M; Fleming, Mark D; Christodoulou, John

    2016-01-01

    Pathogenic variants in mitochondrial aminoacyl-tRNA synthetases result in a broad range of mitochondrial respiratory chain disorders despite their shared role in mitochondrial protein synthesis. LARS2 encodes the mitochondrial leucyl-tRNA synthetase, which attaches leucine to its cognate tRNA. Sequence variants in LARS2 have previously been associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss (OMIM #615300). In this study, we report variants in LARS2 that are associated with a severe multisystem metabolic disorder. The proband was born prematurely with severe lactic acidosis, hydrops, and sideroblastic anemia. She had multisystem complications with hyaline membrane disease, impaired cardiac function, a coagulopathy, pulmonary hypertension, and progressive renal disease and succumbed at 5 days of age. Whole exome sequencing of patient DNA revealed compound heterozygous variants in LARS2 (c.1289C>T; p.Ala430Val and c.1565C>A; p.Thr522Asn). The c.1565C>A (p.Thr522Asn) LARS2 variant has previously been associated with Perrault syndrome and both identified variants are predicted to be damaging (SIFT, PolyPhen). Muscle and liver samples from the proband did not display marked mitochondrial respiratory chain enzyme deficiency. Immunoblotting of patient muscle and liver showed LARS2 levels were reduced in liver and complex I protein levels were reduced in patient muscle and liver. Aminoacylation assays revealed p.Ala430Val LARS2 had an 18-fold loss of catalytic efficiency and p.Thr522Asn a 9-fold loss compared to wild-type LARS2. We suggest that the identified LARS2 variants are responsible for the severe multisystem clinical phenotype seen in this baby and that mutations in LARS2 can result in variable phenotypes.

  10. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  11. Unusual variant of Cantrell′s pentalogy?

    Directory of Open Access Journals (Sweden)

    Kumar Basant

    2008-01-01

    Full Text Available A 12-hour-old male infant presented with prolapsed abdominal content through a defect on left side of chest wall with respiratory distress. A thorough clinical examination suggested absence of ectopia cordis, abdominal wall defect, and any bony anomaly. The child expired after 6 hours of admission because of respiratory distress and electrolyte imbalance. Is congenital defect of chest wall associated with diaphragmatic hernia without ectopia cordis and omphalocele, an unusual variant of Cantrell′s pentalogy?

  12. Novel RNA variants in colorectal cancers.

    Science.gov (United States)

    Hoff, Andreas M; Johannessen, Bjarne; Alagaratnam, Sharmini; Zhao, Sen; Nome, Torfinn; Løvf, Marthe; Bakken, Anne C; Hektoen, Merete; Sveen, Anita; Lothe, Ragnhild A; Skotheim, Rolf I

    2015-11-03

    With an annual estimated incidence of 1.4 million, and a five-year survival rate of 60%, colorectal cancer (CRC) is a major clinical burden. To identify novel RNA variants in CRC, we analyzed exon-level microarray expression data from a cohort of 202 CRCs. We nominated 25 genes with increased expression of their 3' parts in at least one cancer sample each. To efficiently investigate underlying transcript structures, we developed an approach using rapid amplification of cDNA ends followed by high throughput sequencing (RACE-seq). RACE products from the targeted genes in 23 CRC samples were pooled together and sequenced. We identified VWA2-TCF7L2, DHX35-BPIFA2 and CASZ1-MASP2 as private fusion events, and novel transcript structures for 17 of the 23 other candidate genes. The high-throughput approach facilitated identification of CRC specific RNA variants. These include a recurrent read-through fusion transcript between KLK8 and KLK7, and a splice variant of S100A2. Both of these were overrepresented in CRC tissue and cell lines from external RNA-seq datasets.

  13. [Dandy-Walker variant: Case report].

    Science.gov (United States)

    Cueva-Núñez, José E; Lozano-Bustillo, Alejandra; Irias-Álvarez, Merlyn S; Vásquez-Montes, Raúl F; Varela-González, Douglas M

    Dandy Walker variant is defined by a variable hypoplasia of the cerebellar vermix with or without posterior fossa increase and without tentorium elevation. describe the case of a rare disease and emphasise the need to clarify the aetiology of prenatal malformations, as well as its multidisciplinary management. A male patient, 8 years of age, with a history of Infantile Cerebral Palsy and epilepsy, who was admitted with a history of tonic-clonic seizures. He was admitted due to psycho-motor developmental delay. During his hospitalisation, he had multiple seizure episodes, controlled with anticonvulsants. A computerized tomography was performed, in which communication was observed between the cisterna magna and fourth ventricle (the latter increased in size). In addition, the cerebellar vermix showed a partial hypoplasia. All these findings were compatible with a variant of the Dandy Walker syndrome. Dandy Walker variant may be asymptomatic and the images found may not indicate them as the cause of developmental disorders, due to its association with multiple syndromes and chromosomal abnormalities. Clinical presentation and prognosis depends on the related disorders, and a multidisciplinary approach is important, because the treatment depends on the symptoms presented. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Evidences of abundant hemocyanin variants in shrimp Litopenaeus vannamei.

    Science.gov (United States)

    Zhao, Xianliang; Guo, Lingling; Lu, Xin; Lu, Hui; Wang, Fan; Zhong, Mingqi; Chen, Jiehui; Zhang, Yueling

    2016-09-01

    Hemocyanin (HMC) is a multifunctional immune molecule present in mollusks and arthropods and functions as an important antigen non-specific immune protein. Our previous evidences demonstrated that Litopenaeus vannamei HMC might display extensive molecular diversities. In this study, bioinformatics analysis showed dozens of variant sequences of the HMC subunit with higher molecular weight from L. vannamei (LvHMC). Three variant fragments, named as LvHMCV1-3, which shared 85-99% nucleotide identity with that of the classical form of LvHMC (AJ250830.1), were cloned and characterized. Spatial expression profiles showed that LvHMCV1-3 had different tissue-specific distribution, which were affected by stimulation with six pathogenic bacteria, including Escherichia coli K12, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio fluvialis, Streptococcus pyogenes and Staphylococcus aureus, with each variant fragment showing a specific stress pattern to different bacterial pathogens. Full length cDNA of LvHMCV3 was further cloned and characterized. The deduced amino acid sequence shared 92% identity with that of LvHMC, possessed a conserved structure characteristic of the HMC family and could be clustered into one branch along with other arthropod HMC in a phylogenetic tree. In addition, the recombinant protein of LvHMCV3 (rLvHMCV3) showed obvious agglutination activities against three aquaculture pathogenic bacteria including E. coli K12, V. parahaemolyticus and S.aureus at concentrations ranging from 31.25-62.5g/mL. It also showed obvious antibacterial activity against V. parahaemolyticus at concentrations 0.02-0.5mg/mL, and possessed the best inhibitive effects compared with those of rLvHMCV4 and rLvHMC. Co-injection of V. parahaemolyticus and rLvHMCV3 in L. vannamei showed significant decrease of the mortality rate at 24-72h after injection. Therefore, these studies suggested that L. vannamei had abundant HMC variants, which possessed obvious resistance to pathogenic

  15. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval

    DEFF Research Database (Denmark)

    Ghouse, Jonas; Have, Christian Theil; Weeke, Peter

    2015-01-01

    AIMS: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non...

  16. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    DEFF Research Database (Denmark)

    Scott, Robert A; Freitag, Daniel F; Li, Li

    2016-01-01

    . We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict...

  17. Imputation of low-frequency variants using the HapMap3 benefits from large, diverse reference sets

    OpenAIRE

    Jostins, Luke; Morley, Katherine I.; Barrett, Jeffrey C.

    2011-01-01

    Imputation allows the inference of unobserved genotypes in low-density data sets, and is often used to test for disease association at variants that are poorly captured by standard genotyping chips (such as low-frequency variants). Although much effort has gone into developing the best imputation algorithms, less is known about the effects of reference set choice on imputation accuracy. We assess the improvements afforded by increases in reference size and diversity, specifically comparing th...

  18. Variable phenotypes in individuals with grin2a sequence variants or deletions

    NARCIS (Netherlands)

    Vlaskamp, D.R.M.; Callenbach, P.M.C.; Rump, P.; Van Pinxteren-Nagler, E.; Willemsen, M.H.; Gunning, B.; de Geus, C.; Veenstra, Knol H.E.; Lunsing, R.J.; Dijkhuizen, T.; Vos, Y.J.; Brouwer, O.F.; Van Ravenswaaij-Arts, C.M.A.

    2016-01-01

    Purpose: The GRIN2A gene has been associated with epilepsies ranging from benign focal childhood epilepsies to severe epileptic encephalopathies. The aim of this study was to evaluate genotypes and phenotypes in individuals with GRIN2A deletions or variants. Method: We compared genotypes and

  19. The CHEK2 1100delC variant in Swedish colorectal cancer

    DEFF Research Database (Denmark)

    Djureinovic, Tatjana; Lindblom, Annika; Dalén, Johan

    2007-01-01

    . RESULTS: CHEK2 l100delC was found in 1.15% of familial and in 0.93% of unselected cases, compared to 0.66% of controls, showing no significant difference between groups. One out of 45 familial cases with a family history of breast cancer was shown to be a carrier. The variant was not identified in the 18...... families included in the linkage analysis. CONCLUSION: The CHEK2 1100delC was not significantly increased in Swedish colorectal cancer patients, however, in order to determine the role of the variant in colorectal cancer families with the history of breast cancer a larger sample size is needed....

  20. Estimating and interpreting FST: the impact of rare variants.

    Science.gov (United States)

    Bhatia, Gaurav; Patterson, Nick; Sankararaman, Sriram; Price, Alkes L

    2013-09-01

    In a pair of seminal papers, Sewall Wright and Gustave Malécot introduced FST as a measure of structure in natural populations. In the decades that followed, a number of papers provided differing definitions, estimation methods, and interpretations beyond Wright's. While this diversity in methods has enabled many studies in genetics, it has also introduced confusion regarding how to estimate FST from available data. Considering this confusion, wide variation in published estimates of FST for pairs of HapMap populations is a cause for concern. These estimates changed-in some cases more than twofold-when comparing estimates from genotyping arrays to those from sequence data. Indeed, changes in FST from sequencing data might be expected due to population genetic factors affecting rare variants. While rare variants do influence the result, we show that this is largely through differences in estimation methods. Correcting for this yields estimates of FST that are much more concordant between sequence and genotype data. These differences relate to three specific issues: (1) estimating FST for a single SNP, (2) combining estimates of FST across multiple SNPs, and (3) selecting the set of SNPs used in the computation. Changes in each of these aspects of estimation may result in FST estimates that are highly divergent from one another. Here, we clarify these issues and propose solutions.

  1. Phylogenetic interrelations between serological variants of Bacillus thuringiensis

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    Patyka N. V.

    2009-06-01

    Full Text Available Aim. B. thuringiensis (Bt are gram-positive spore-forming aerobic or facultative anaerobic bacteria able to form during sporulation species specific crystal-like inclusions of protein nature, consisting of particular thermolabile d-endotoxins. Serological Bt variants produce different entomotoxins; their synthesis in many respects depends on the conditions of cultivation. There was accumulated a vast information on the entomotoxins, their origin, synthesis, structure, toxic properties and mechanisms of action on insects. These bacteria are dominating in the microbiomethods of pest control in plants and animals. There are more than 70 serovariants of Bt selectively specific to the definite groups of host insects. However, the description of new variants not always looks justified considering the phylogenetic systematization based on phenotype signs. Methods. A comparative phylogenetic analysis of the Bt intraspecific interrelations was performed on the basis of the cloned 16S rRNA genes of entomopathogenic bacteria BtH1, BtH10, BtH14. Results. The phylogenetically homogeneous lines were investigated – a homology of 16S rRNA of the strains 1 and 10 ranged from 90,0 to 94,0 %; no distinct genetic isolation among the strains of 14th and 10th serovars was revealed. Conclusions. The comparison of nucleotides sequences of 16S rRNA has shown the existence of strains polymorphism within the group of entomopathogens BtH1, BtH10, BtH14, connected with their entomocide activity

  2. [VARIANT ANATOMY OF SPLENIC LIGAMENTS AND ARTERIES PASSING THROUGH THEM].

    Science.gov (United States)

    Gaivoronskiy, I V; Kotiv, B N; Alekseyev, V S; Nichiporuk, G I

    2015-01-01

    The research was performed on 15 non embalmed bodies and 32 abdominal complexes of adult individuals. The comparative study of variant anatomy of splenic ligaments and architectonics of arteries passing through them was carried out to substantiate the mobilization of splenopancreatic complex. Anatomical and angiographic restudied were carried out using preparation, morphometry, injection of gastric, pancreatic and splenic vascular bed with red lead suspension. It was established that the form and sizes of splenic ligaments and their interrelation with the branches of the splenic artery were variable. The minimal and maximal sizes of gastrolienal, phrenicosplenic and splenocolic ligaments differed 2-3 times. In most cases, spleen was fixed in abdominal cavity by many short ligaments. It was shown that architectonics and topography of main branches of spleen artery were determined by morphometric characteristics of the spleen proper and its ligaments. The knowledge of splenic ligament variant anatomy allows a new perspective to approach to substantiate different methods of the mobilization of spleno-pancreatic complex during surgical operations on organs of the upper part of the peritoneal cavity and organ-preserving surgery of the spleen.

  3. Processing morphological variants in searches of Latin text

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    Mark Greengrass

    1996-01-01

    Full Text Available A characteristic of natural-language text databases is that a user must be able to specify all of the variant forms of each query word if high recall is to be achieved. The most common type of word variants are those arising from morphology and thus most retrieval systems provide facilities for user-controlled right-hand (and occasionally left-hand truncation to allow the retrieval of all words with the same root. A stemming algorithm, or stemmer, is a computational procedure that reduces all words with the same root to a single form by stripping the root of its derivational and inflectional affixes. In most cases, only suffixes are stripped so that a stemmer provides an automatic equivalent of manual, right-hand truncation. Thus far, most work on stemmers has focused on present-day languages, but the increasing user of computers in the humanities has resulted in a need for comparable tools to facilitate searching in historical text databases. This paper summarises some of the initial results of a project here in Sheffield to develop such tools for databases of Latin text.

  4. Electre III method in assessment of variants of integrated urban public transport system in Cracow

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    Katarzyna SOLECKA

    2014-12-01

    Full Text Available There is a lot of methods which are currently used for assessment of urban public transport system development and operation e.g. economic analysis, mostly Cost-Benefit Analysis – CBA, Cost-Effectiveness Analysis - CEA, hybrid methods, measurement methods (survey e.g. among passengers and measurement of traffic volume, vehicles capacity etc., and multicriteria decision aiding methods (multicriteria analysis. The main aim of multicriteria analysis is the choice of the most desirable solution from among alternative variants according to different criteria which are difficult to compare against one another. There are several multicriteria methods for assessment of urban public transport system development and operation, e.g. AHP, ANP, Electre, Promethee, Oreste. The paper presents an application of one of the most popular variant ranking methods – Electre III method. The algorithm of Electre III method usage is presented in detail and then its application for assessment of variants of urban public transport system integration in Cracow is shown. The final ranking of eight variants of integration of urban public transport system in Cracow (from the best to the worst variant was drawn up with the application of the Electre III method. For assessment purposes 10 criteria were adopted: economical, technical, environmental, and social; they form a consistent criteria family. The problem was analyzed with taking into account different points of view: city authorities, public transport operators, city units responsible for transport management, passengers and others users. Separate models of preferences for all stakeholders were created.

  5. Catching hidden variation: systematic correction of reference minor allele annotation in clinical variant calling.

    Science.gov (United States)

    Barbitoff, Yury A; Bezdvornykh, Igor V; Polev, Dmitrii E; Serebryakova, Elena A; Glotov, Andrey S; Glotov, Oleg S; Predeus, Alexander V

    2017-10-26

    PurposeWe comprehensively assessed the influence of reference minor alleles (RMAs), one of the inherent problems of the human reference genome sequence.MethodsThe variant call format (VCF) files provided by the 1000 Genomes and Exome Aggregation Consortium (ExAC) consortia were used to identify RMA sites. All coding RMA sites were checked for concordance with UniProt and the presence of same codon variants. RMA-corrected predictions of functional effect were obtained with SIFT, PolyPhen-2, and PROVEAN standalone tools and compared with dbNSFP v2.9 for consistency.ResultsWe systematically characterized the problem of RMAs and identified several possible ways in which RMA could interfere with accurate variant discovery and annotation. We have discovered a systematic bias in the automated variant effect prediction at the RMA loci, as well as widespread switching of functional consequences for variants located in the same codon as the RMA. As a convenient way to address the problem of RMAs we have developed a simple bioinformatic tool that identifies variation at RMA sites and provides correct annotations for all such substitutions. The tool is available free of charge at http://rmahunter.bioinf.me.ConclusionCorrection of RMA annotation enhances the accuracy of next-generation sequencing-based methods in clinical practice.Genetics in Medicine advance online publication, 26 October 2017; doi:10.1038/gim.2017.168.

  6. Discriminatory power of common genetic variants in personalized breast cancer diagnosis

    Science.gov (United States)

    Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

    2016-03-01

    Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

  7. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.

    Science.gov (United States)

    Rodriguez-Flores, Juan L; Fakhro, Khalid; Hackett, Neil R; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Nabet Al-Marri, Ajayeb; Chouchane, Lotfi; Stadler, Dora J; Mezey, Jason G; Crystal, Ronald G

    2014-01-01

    Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared with 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Premarital genetic screening in Qatar tests for only four out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. © 2013 WILEY PERIODICALS, INC.

  8. Molecular Cloning, Carbohydrate Specificity and the Crystal Structure of Two Sclerotium rolfsii Lectin Variants.

    Science.gov (United States)

    Peppa, Vassiliki I; Venkat, Hemalatha; Kantsadi, Anastassia L; Inamdar, Shashikala R; Bhat, Ganapati G; Eligar, Sachin; Shivanand, Anupama; Chachadi, Vishwanath B; Satisha, Gonchigar J; Swamy, Bale M; Skamnaki, Vassiliki T; Zographos, Spyridon E; Leonidas, Demetres D

    2015-06-12

    SRL is a cell wall associated developmental-stage specific lectin secreted by Sclerotium rolfsii, a soil-born pathogenic fungus. SRL displays specificity for TF antigen (Galβ1→3GalNAc-α-Ser//Thr) expressed in all cancer types and has tumour suppressing effects in vivo. Considering the immense potential of SRL in cancer research, we have generated two variant gene constructs of SRL and expressed in E. coli to refine the sugar specificity and solubility by altering the surface charge. SSR1 and SSR2 are two different recombinant variants of SRL, both of which recognize TF antigen but only SSR1 binds to Tn antigen (GalNAcα-Ser/Thr). The glycan array analysis of the variants demonstrated that SSR1 recognizes TF antigen and their derivative with high affinity similar to SRL but showed highest affinity towards the sialylated Tn antigen, unlike SRL. The carbohydrate binding property of SSR2 remains unaltered compared to SRL. The crystal structures of the two variants were determined in free form and in complex with N-acetylglucosamine at 1.7 Å and 1.6 Å resolution, respectively. Structural analysis highlighted the structural basis of the fine carbohydrate specificity of the two SRL variants and results are in agreement with glycan array analysis.

  9. Molecular Cloning, Carbohydrate Specificity and the Crystal Structure of Two Sclerotium rolfsii Lectin Variants

    Directory of Open Access Journals (Sweden)

    Vassiliki I. Peppa

    2015-06-01

    Full Text Available SRL is a cell wall associated developmental-stage specific lectin secreted by Sclerotium rolfsii, a soil-born pathogenic fungus. SRL displays specificity for TF antigen (Galβ1→3GalNAc-α-Ser//Thr expressed in all cancer types and has tumour suppressing effects in vivo. Considering the immense potential of SRL in cancer research, we have generated two variant gene constructs of SRL and expressed in E. coli to refine the sugar specificity and solubility by altering the surface charge. SSR1 and SSR2 are two different recombinant variants of SRL, both of which recognize TF antigen but only SSR1 binds to Tn antigen (GalNAcα-Ser/Thr. The glycan array analysis of the variants demonstrated that SSR1 recognizes TF antigen and their derivative with high affinity similar to SRL but showed highest affinity towards the sialylated Tn antigen, unlike SRL. The carbohydrate binding property of SSR2 remains unaltered compared to SRL. The crystal structures of the two variants were determined in free form and in complex with N-acetylglucosamine at 1.7 Å and 1.6 Å resolution, respectively. Structural analysis highlighted the structural basis of the fine carbohydrate specificity of the two SRL variants and results are in agreement with glycan array analysis.

  10. Pilon: an integrated tool for comprehensive microbial variant detection and genome assembly improvement.

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    Bruce J Walker

    Full Text Available Advances in modern sequencing technologies allow us to generate sufficient data to analyze hundreds of bacterial genomes from a single machine in a single day. This potential for sequencing massive numbers of genomes calls for fully automated methods to produce high-quality assemblies and variant calls. We introduce Pilon, a fully automated, all-in-one tool for correcting draft assemblies and calling sequence variants of multiple sizes, including very large insertions and deletions. Pilon works with many types of sequence data, but is particularly strong when supplied with paired end data from two Illumina libraries with small e.g., 180 bp and large e.g., 3-5 Kb inserts. Pilon significantly improves draft genome assemblies by correcting bases, fixing mis-assemblies and filling gaps. For both haploid and diploid genomes, Pilon produces more contiguous genomes with fewer errors, enabling identification of more biologically relevant genes. Furthermore, Pilon identifies small variants with high accuracy as compared to state-of-the-art tools and is unique in its ability to accurately identify large sequence variants including duplications and resolve large insertions. Pilon is being used to improve the assemblies of thousands of new genomes and to identify variants from thousands of clinically relevant bacterial strains. Pilon is freely available as open source software.

  11. Pilon: An Integrated Tool for Comprehensive Microbial Variant Detection and Genome Assembly Improvement

    Science.gov (United States)

    Shea, Terrance; Priest, Margaret; Abouelliel, Amr; Sakthikumar, Sharadha; Cuomo, Christina A.; Zeng, Qiandong; Wortman, Jennifer; Young, Sarah K.; Earl, Ashlee M.

    2014-01-01

    Advances in modern sequencing technologies allow us to generate sufficient data to analyze hundreds of bacterial genomes from a single machine in a single day. This potential for sequencing massive numbers of genomes calls for fully automated methods to produce high-quality assemblies and variant calls. We introduce Pilon, a fully automated, all-in-one tool for correcting draft assemblies and calling sequence variants of multiple sizes, including very large insertions and deletions. Pilon works with many types of sequence data, but is particularly strong when supplied with paired end data from two Illumina libraries with small e.g., 180 bp and large e.g., 3–5 Kb inserts. Pilon significantly improves draft genome assemblies by correcting bases, fixing mis-assemblies and filling gaps. For both haploid and diploid genomes, Pilon produces more contiguous genomes with fewer errors, enabling identification of more biologically relevant genes. Furthermore, Pilon identifies small variants with high accuracy as compared to state-of-the-art tools and is unique in its ability to accurately identify large sequence variants including duplications and resolve large insertions. Pilon is being used to improve the assemblies of thousands of new genomes and to identify variants from thousands of clinically relevant bacterial strains. Pilon is freely available as open source software. PMID:25409509

  12. Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants.

    Science.gov (United States)

    Lin, Nina; Gonzalez, Oscar A; Registre, Ludy; Becerril, Carlos; Etemad, Behzad; Lu, Hong; Wu, Xueling; Lockman, Shahin; Essex, Myron; Moyo, Sikhulile; Kuritzkes, Daniel R; Sagar, Manish

    2016-06-01

    Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Identification of gain-of-function variants of the human prolactin receptor.

    Science.gov (United States)

    Goffin, Vincent; Bogorad, Roman L; Touraine, Philippe

    2010-01-01

    There is currently no known genetic disease linked to prolactin (PRL) or its receptor (PRLR) in humans. Recently, we identified three missense variants of the PRLR in patients presenting with breast tumors. Two of them (named PRLR(I146L) and PRLR(I76V)) had been reported earlier, but failed to draw much attention because the eventual impact of these substitutions on receptor properties remained unknown. In this chapter, we describe the various bioassays (cell types and readouts) that led to the discovery that both variants exhibit gain-of-function properties. Reconstituted cell models involving Ba/F3, HEK293, and MCF-7 cell lines all highlighted the constitutive, PRL-independent potency of PRLR(I146L) to trigger downstream signaling, leading to antiapoptotic and proliferation properties. The lower level of basal activity of PRLR(I76V) could be demonstrated only in the very sensitive Ba/F3 cell assay. While comparative analysis of ligands is a routine procedure in many labs, comparison of receptor variants de facto imposes the use of different cell clones (or population) in which each receptor variant is expressed individually. This is more delicate, as one must ensure that differences in biological responses really reflect differences in the intrinsic properties of receptor variants, and not any feature of cell clones/populations that are used, which could bias the interpretation. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. Codon-Optimized Luciola Italica Luciferase Variants for Mammalian Gene Expression in Culture and in Vivo

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    Casey A. Maguire

    2012-01-01

    Full Text Available Luciferases have proven to be useful tools in advancing our understanding of biologic processes. Having a multitude of bioluminescent reporters with different properties is highly desirable. We characterized codon-optimized thermostable green- and red-emitting luciferase variants from the Italian firefly Luciola italica for mammalian gene expression in culture and in vivo. Using lentivirus vectors to deliver and stably express these luciferases in mammalian cells, we showed that both variants displayed similar levels of activity and protein half-lives as well as similar light emission kinetics and higher stability compared to the North American firefly luciferase. Further, we characterized the red-shifted variant for in vivo bioluminescence imaging. Intramuscular injection of tumor cells stably expressing this variant into nude mice yielded a robust luciferase activity. Light emission peaked at 10 minutes post-D-luciferin injection and retained > 60% of signal at 1 hour. Similarly, luciferase activity from intracranially injected glioma cells expressing the red-shifted variant was readily detected and used as a marker to monitor tumor growth over time. Overall, our characterization of these codon-optimized luciferases lays the groundwork for their further use as bioluminescent reporters in mammalian cells.

  15. Targeted resequencing of candidate genes reveals novel variants associated with severe Behçet's uveitis.

    Science.gov (United States)

    Kim, Sang Jin; Lee, Seungbok; Park, Changho; Seo, Jeong-Sun; Kim, Jong-Il; Yu, Hyeong Gon

    2013-10-18

    Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent uveitis, oral and genital ulcers and skin lesions. To identify some pathogenic variants associated with severe Behçet's uveitis, we used targeted and massively parallel sequencing methods to explore the genetic diversity of target regions. A solution-based target enrichment kit was designed to capture whole-exonic regions of 132 candidate genes. Using a multiplexing strategy, 32 samples from patients with a severe type of Behçet's uveitis were sequenced with a Genome Analyzer IIx. We compared the frequency of each variant with that of 59 normal Korean controls, and selected five rare and eight common single-nucleotide variants as the candidates for a replication study. The selected variants were genotyped in 61 cases and 320 controls and, as a result, two rare and seven common variants showed significant associations with severe Behçet's uveitis (PMTFHR and MICA also replicated the previous reports at the gene level. The KIR3DL3 and KIR2DL4 genes are novel susceptibility genes that have not been reported in association with BD. In conclusion, this study showed that target enrichment and next-generation sequencing technologies can provide valuable information on the genetic predisposition for Behçet's uveitis.

  16. Three-dimensional modeling of glucose-6-phosphate dehydrogenase-deficient variants from German ancestry.

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    Farooq Kiani

    Full Text Available BACKGROUND: Loss of function of dimeric glucose-6-phosphate dehydrogenase (G6PD represents the most common inborn error of metabolism throughout the world affecting an estimated 400 million people. In Germany, this enzymopathy is very rare. METHODOLOGY/PRINCIPAL FINDINGS: On the basis of G6PD crystal structures, we have analyzed six G6PD variants of German ancestry by three-dimensional modeling. All mutations present in the German population are either close to one of the three G6P or NADP(+ units or to the interface of the two monomers. Two of the three mutated amino acids of G6PD Vancouver are closer to the binding site of NADP(+. The G6PD Aachen mutation is also closer to the second NADP(+ unit. The G6PD Wayne mutation is closer to the G6P binding region. These mutations may affect the binding of G6P and NADP(+ units. Three mutations, i.e. G6PD Munich, G6PD Riverside and G6PD Gastonia, lie closer to the interface of the two monomers. These may also affect the interface of two monomers. CONCLUSION: None of these G6PD variants share mutations with the common G6PD variants known from the Mediterranean, Near East, or Africa indicating that they have developed independently. The G6PD variants have been compared with mutants from other populations and the implications for survival of G6PD variants from natural selection have been discussed.

  17. The Plasmodium berghei RC strain is highly diverged and harbors putatively novel drug resistance variants

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    Warangkhana Songsungthong

    2017-10-01

    Full Text Available Background The current first line drugs for treating uncomplicated malaria are artemisinin (ART combination therapies. However, Plasmodium falciparum parasites resistant to ART and partner drugs are spreading, which threatens malaria control efforts. Rodent malaria species are useful models for understanding antimalarial resistance, in particular genetic variants responsible for cross resistance to different compounds. Methods The Plasmodium berghei RC strain (PbRC is described as resistant to different antimalarials, including chloroquine (CQ and ART. In an attempt to identify the genetic basis for the antimalarial resistance trait in PbRC, its genome was sequenced and compared with five other previously sequenced P. berghei strains. Results We found that PbRC is eight-fold less sensitive to the ART derivative artesunate than the reference strain PbANKA. The genome of PbRC is markedly different from other strains, and 6,974 single nucleotide variants private to PbRC were identified. Among these PbRC private variants, non-synonymous changes were identified in genes known to modulate antimalarial sensitivity in rodent malaria species, including notably the ubiquitin carboxyl-terminal hydrolase 1 gene. However, no variants were found in some genes with strong evidence of association with ART resistance in P. falciparum such as K13 propeller protein. Discussion The variants identified in PbRC provide insight into P. berghei genome diversity and genetic factors that could modulate CQ and ART resistance in Plasmodium spp.

  18. A Powerful Pathway-Based Adaptive Test for Genetic Association with Common or Rare Variants.

    Science.gov (United States)

    Pan, Wei; Kwak, Il-Youp; Wei, Peng

    2015-07-02

    In spite of the success of genome-wide association studies (GWASs), only a small proportion of heritability for each complex trait has been explained by identified genetic variants, mainly SNPs. Likely reasons include genetic heterogeneity (i.e., multiple causal genetic variants) and small effect sizes of causal variants, for which pathway analysis has been proposed as a promising alternative to the standard single-SNP-based analysis. A pathway contains a set of functionally related genes, each of which includes multiple SNPs. Here we propose a pathway-based test that is adaptive at both the gene and SNP levels, thus maintaining high power across a wide range of situations with varying numbers of the genes and SNPs associated with a trait. The proposed method is applicable to both common variants and rare variants and can incorporate biological knowledge on SNPs and genes to boost statistical power. We use extensively simulated data and a WTCCC GWAS dataset to compare our proposal with several existing pathway-based and SNP-set-based tests, demonstrating its promising performance and its potential use in practice. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Structural and functional insights into thermostable and organic solvent stable variant Pro247-Ser of Bacillus lipase.

    Science.gov (United States)

    Chopra, Nisha; Kumar, Arbind; Kaur, Jagdeep

    2017-10-31

    Thermostability of enzymes is an important issue in protein engineering and has been studied in detail. Still there is no hard and fast rule to define the conditions which will provide thermal stability. Understanding the various factors and mechanism responsible for thermal stability will add on new insights into our present knowledge in this area. Pro247-Ser variant was constructed based on homology modelling and rational design. It exhibited 60 fold increase in thermal stability at 60°C and+0.7M shift in C1/2 value for urea denaturation as compared to WT. Variant displayed noticeable tolerance to organic solvents. With decrease in Km, catalytic efficiency of Pro247-Ser variant was increased by 12 fold. The activity and stability assay including circular dichroism and fluorescence spectroscopy favoured increased thermal performance of variant. Hydrolytic activity of variant was found to be high in comparison to control for all p-nitrophenol esters investigated. The immobilized variant enzyme demonstrated nearly two fold enhanced conversion of methyl oleate than WT enzyme. The additional molecular interactions of variant residue might contribute to increased thermostability of lipase. The homology modeling predicted formation of additional hydrogen bonds between Ser247/O-Thr251/OG1 as well as Ser247/O-Glu250/N. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...... by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c...... to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification...

  1. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

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    Johnathan Cooper-Knock

    2017-11-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs. We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18. Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033. We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025. Our data are

  2. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

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    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  3. Current situation, genetic relationship and control measures of infectious bronchitis virus variants circulating in African regions

    Directory of Open Access Journals (Sweden)

    Khadija Khataby

    2016-08-01

    Three S1 gene hypervariable regions were studied and compared to the reference genotypes/serotypes that found emerging in African regions. This comparison was based on phylogenetic trees, nucleotide and amino-acid sequence analysis. It clearly appears that IBV variants reported in Africa, display a low genetic relationship between them and with the majority of the reference strains emerging in neighboring countries, except the case of variants from Libya and Egypt that show a high relatedness. Also the Massachusetts serotypes were the most prevalent co-circulating with both serotypes, Italy02 type in Morocco and Qx-like genotype in South part of the African continent. In order to control the IBV variants in African regions, an efficient vaccination strategy program should be implemented.

  4. Accurate and efficient method for smoothly space-variant Gaussian blurring.

    Science.gov (United States)

    Popkin, Timothy; Cavallaro, Andrea; Hands, David

    2010-05-01

    This paper presents a computationally efficient algorithm for smoothly space-variant Gaussian blurring of images. The proposed algorithm uses a specialized filter bank with optimal filters computed through principal component analysis. This filter bank approximates perfect space-variant Gaussian blurring to arbitrarily high accuracy and at greatly reduced computational cost compared to the brute force approach of employing a separate low-pass filter at each image location. This is particularly important for spatially variant image processing such as foveated coding. Experimental results show that the proposed algorithm provides typically 10 to 15 dB better approximation of perfect Gaussian blurring than the blended Gaussian pyramid blurring approach when using a bank of just eight filters.

  5. Polymorphic variants in the dopamine receptor D2 in women with endometriosis-related infertility.

    Science.gov (United States)

    Szczepańska, Malgorzata; Mostowska, Adrianna; Wirstlein, Przemyslaw; Skrzypczak, Jana; Misztal, Matthew; Jagodziński, Paweł P

    2015-08-01

    Data suggests that dopamine receptor DRD2 gene variants may contribute to hyperprolactinemia and that they may be risk factors for endometriosis-related infertility. The purpose of the present study was to determine whether nucleotide variants of the DRD2 gene may be associated with infertility related to endometriosis. Five DRD2 SNPs, rs1800497, rs6277, rs2283265, rs4245146 and rs4648317, which are located in different blocks of linkage disequilibrium, were studied in 151 cases and 381 controls. No significant differences between DRD2 rs1800497, rs6277, rs2283265, rs4245146 and rs4648317 genotype, allele nor haplotype frequencies were observed in women with endometriosis-related infertility compared with the control group. The present results did not confirm DRD2 gene variants to be genetic risk factors for endometriosis-related infertility.

  6. Variant-specific persistence of infections with human papillomavirus Types 31, 33, 45, 56 and 58 and risk of cervical intraepithelial neoplasia.

    Science.gov (United States)

    Xi, Long Fu; Schiffman, Mark; Koutsky, Laura A; Hughes, James P; Hulbert, Ayaka; Shen, Zhenping; Galloway, Denise A; Kiviat, Nancy B

    2016-09-01

    In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio = 1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage-associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants. © 2016 UICC.

  7. Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk.

    Science.gov (United States)

    Milligan, Caitlin; Omenda, Maxwel M; Chohan, Vrasha; Odem-Davis, Katherine; Richardson, Barbra A; Nduati, Ruth; Overbaugh, Julie

    2016-02-02

    Mother-to-child transmission (MTCT) of HIV provides a setting for studying immune correlates of protection. Neutralizing antibodies (NAbs) are suggested to contribute to a viral bottleneck during MTCT, but their role in blocking transmission is unclear, as studies comparing the NAb sensitivities of maternal viruses have yielded disparate results. We sought to determine whether transmitting mothers differ from nontransmitting mothers in the ability to neutralize individual autologous virus variants present at transmission. Ten transmitting and 10 nontransmitting HIV-infected mothers at high risk of MTCT were included in this study. Full-length HIV envelope genes (n = 100) were cloned from peripheral blood mononuclear cells obtained near transmission from transmitting mothers and at similar time points from nontransmitting mothers. Envelope clones were tested as pseudoviruses against contemporaneous, autologous maternal plasma in neutralization assays. The association between transmission and the log2 50% inhibitory concentration (IC50) for multiple virus variants per mother was estimated by using logistic regression with clustered standard errors. t tests were used to compare proportions of neutralization-resistant viruses. Overall, transmitting mothers had a median IC50 of 317 (interquartile range [IQR], 202 to 521), and nontransmitting mothers had a median IC50 of 243 (IQR, 95 to 594). Transmission risk was not significantly associated with autologous NAb activity (odds ratio, 1.25; P = 0.3). Compared to nontransmitting mothers, transmitting mothers had similar numbers of or fewer neutralization-resistant virus variants, depending on the IC50 neutralization resistance cutoff. In conclusion, HIV-infected mothers harbor mostly neutralization-sensitive viruses, although resistant variants were detected in both transmitting and nontransmitting mothers. These results suggest that MTCT during the breastfeeding period is not driven solely by the presence of maternal

  8. Analysis of mitochondrial DNA sequences in childhood encephalomyopathies reveals new disease-associated variants.

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    Aijaz A Wani

    Full Text Available BACKGROUND: Mitochondrial encephalomyopathies are a heterogeneous group of clinical disorders generally caused due to mutations in either mitochondrial DNA (mtDNA or nuclear genes encoding oxidative phosphorylation (OXPHOS. We analyzed the mtDNA sequences from a group of 23 pediatric patients with clinical and morphological features of mitochondrial encephalopathies and tried to establish a relationship of identified variants with the disease. METHODOLOGY/PRINCIPLE FINDINGS: Complete mitochondrial genomes were amplified by PCR and sequenced by automated DNA sequencing. Sequencing data was analyzed by SeqScape software and also confirmed by BLASTn program. Nucleotide sequences were compared with the revised Cambridge reference sequence (CRS and sequences present in mitochondrial databases. The data obtained shows that a number of known and novel mtDNA variants were associated with the disease. Most of the non-synonymous variants were heteroplasmic (A4136G, A9194G and T11916A suggesting their possibility of being pathogenic in nature. Some of the missense variants although homoplasmic were showing changes in highly conserved amino acids (T3394C, T3866C, and G9804A and were previously identified with diseased conditions. Similarly, two other variants found in tRNA genes (G5783A and C8309T could alter the secondary structure of Cys-tRNA and Lys-tRNA. Most of the variants occurred in single cases; however, a few occurred in more than one case (e.g. G5783A and A10149T. CONCLUSIONS AND SIGNIFICANCE: The mtDNA variants identified in this study could be the possible cause of mitochondrial encephalomyopathies with childhood onset in the patient group. Our study further strengthens the pathogenic score of known variants previously reported as provisionally pathogenic in mitochondrial diseases. The novel variants found in the present study can be potential candidates for further investigations to establish the relationship between their incidence and role

  9. Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

    Directory of Open Access Journals (Sweden)

    Mary S. Beattie

    2008-01-01

    Full Text Available Background: Missense (amino-acid changing variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1 interpreting the medical relevance of predictive scores is difficult; 2 the relationship between bioinformatics “predictors” (sequence conservation, protein structure and cancer susceptibility is not understood.Methodology/Principal Findings: We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [1]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general

  10. Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Irene Mademont-Soler

    Full Text Available Hypertrophic cardiomyopathy (HCM is the most prevalent inherited heart disease. Next-generation sequencing (NGS is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs deserves further evaluation.Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1 using Sanger sequencing (N = 84 or NGS (N = 303. In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease.The percentage of patients with pathogenic/likely pathogenic (P/LP variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001, mostly due to variants of unknown significance (VUS in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3% had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN.A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.

  11. Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

    Science.gov (United States)

    Yotti, Raquel; Espinosa, Maria Angeles; Pérez-Serra, Alexandra; Fernandez-Avila, Ana Isabel; Coll, Monica; Méndez, Irene; Iglesias, Anna; del Olmo, Bernat; Riuró, Helena; Cuenca, Sofía; Allegue, Catarina; Campuzano, Oscar; Picó, Ferran; Ferrer-Costa, Carles; Álvarez, Patricia; Castillo, Sergio; Garcia-Pavia, Pablo; Gonzalez-Lopez, Esther; Padron-Barthe, Laura; Díaz de Bustamante, Aranzazu; Darnaude, María Teresa; González-Hevia, José Ignacio; Brugada, Josep; Fernandez-Aviles, Francisco; Brugada, Ramon

    2017-01-01

    Introduction Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. Methods Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. Results The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. Conclusions A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM. PMID:28771489

  12. Melanoma risk associated with MC1R gene variants in Latvia and the functional analysis of rare variants.

    Science.gov (United States)

    Ozola, Aija; Azarjana, Kristīne; Doniņa, Simona; Proboka, Guna; Mandrika, Ilona; Petrovska, Ramona; Cēma, Ingrīda; Heisele, Olita; Eņģele, Ludmila; Streinerte, Baiba; Pjanova, Dace

    2013-03-01

    To evaluate the association of melanocortin 1 receptor gene (MC1R) variants with melanoma risk in a Latvian population, the MC1R gene was sequenced in 200 melanoma patients and 200 control persons. A functional study of previously uncharacterized, rare MC1R variants was also performed. In total, 26 different MC1R variants, including two novel variants Val165Ile and Val188Ile, were detected. The highest risk of melanoma was associated with the Arg151Cys variant (odds ratio (OR) 4.47, 95% confidence interval (CI) 2.19-9.14, PMC1R variants revealed that a subset of them is functionally relevant. Our results support the contribution of MC1R variants to a genetic predisposition to melanoma in Latvia. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. The Use of Non-Variant Sites to Improve the Clinical Assessment of Whole-Genome Sequence Data.

    Directory of Open Access Journals (Sweden)

    Alberto Ferrarini

    Full Text Available Genetic testing, which is now a routine part of clinical practice and disease management protocols, is often based on the assessment of small panels of variants or genes. On the other hand, continuous improvements in the speed and per-base costs of sequencing have now made whole exome sequencing (WES and whole genome sequencing (WGS viable strategies for targeted or complete genetic analysis, respectively. Standard WGS/WES data analytical workflows generally rely on calling of sequence variants respect to the reference genome sequence. However, the reference genome sequence contains a large number of sites represented by rare alleles, by known pathogenic alleles and by alleles strongly associated to disease by GWAS. It's thus critical, for clinical applications of WGS and WES, to interpret whether non-variant sites are homozygous for the reference allele or if the corresponding genotype cannot be reliably called. Here we show that an alternative analytical approach based on the analysis of both variant and non-variant sites from WGS data allows to genotype more than 92% of sites corresponding to known SNPs compared to 6% genotyped by standard variant analysis. These include homozygous reference sites of clinical interest, thus leading to a broad and comprehensive characterization of variation necessary to an accurate evaluation of disease risk. Altogether, our findings indicate that characterization of both variant and non-variant clinically informative sites in the genome is necessary to allow an accurate clinical assessment of a personal genome. Finally, we propose a highly efficient extended VCF (eVCF file format which allows to store genotype calls for sites of clinical interest while remaining compatible with current variant interpretation software.

  14. The Use of Non-Variant Sites to Improve the Clinical Assessment of Whole-Genome Sequence Data.

    Science.gov (United States)

    Ferrarini, Alberto; Xumerle, Luciano; Griggio, Francesca; Garonzi, Marianna; Cantaloni, Chiara; Centomo, Cesare; Vargas, Sergio Marin; Descombes, Patrick; Marquis, Julien; Collino, Sebastiano; Franceschi, Claudio; Garagnani, Paolo; Salisbury, Benjamin A; Harvey, John Max; Delledonne, Massimo

    2015-01-01

    Genetic testing, which is now a routine part of clinical practice and disease management protocols, is often based on the assessment of small panels of variants or genes. On the other hand, continuous improvements in the speed and per-base costs of sequencing have now made whole exome sequencing (WES) and whole genome sequencing (WGS) viable strategies for targeted or complete genetic analysis, respectively. Standard WGS/WES data analytical workflows generally rely on calling of sequence variants respect to the reference genome sequence. However, the reference genome sequence contains a large number of sites represented by rare alleles, by known pathogenic alleles and by alleles strongly associated to disease by GWAS. It's thus critical, for clinical applications of WGS and WES, to interpret whether non-variant sites are homozygous for the reference allele or if the corresponding genotype cannot be reliably called. Here we show that an alternative analytical approach based on the analysis of both variant and non-variant sites from WGS data allows to genotype more than 92% of sites corresponding to known SNPs compared to 6% genotyped by standard variant analysis. These include homozygous reference sites of clinical interest, thus leading to a broad and comprehensive characterization of variation necessary to an accurate evaluation of disease risk. Altogether, our findings indicate that characterization of both variant and non-variant clinically informative sites in the genome is necessary to allow an accurate clinical assessment of a personal genome. Finally, we propose a highly efficient extended VCF (eVCF) file format which allows to store genotype calls for sites of clinical interest while remaining compatible with current variant interpretation software.

  15. Human papillomavirus type 16 variants in cervical intraepithelial neoplasia and invasive carcinoma in San Luis Potosí City, Mexico.

    Science.gov (United States)

    López-Revilla, Rubén; Pineda, Marco A; Ortiz-Valdez, Julio; Sánchez-Garza, Mireya; Riego, Lina

    2009-02-16

    In San Luis Potosí City cervical infection by human papillomavirus type 16 (HPV16) associated to dysplastic lesions is more prevalent in younger women. In this work HPV16 subtypes and variants associated to low-grade intraepithelial lesions (LSIL), high-grade intraepithelial lesions (HSIL) and invasive cervical cancer (ICC) of 38 women residing in San Luis Potosí City were identified by comparing their E6 open reading frame sequences. Three European (E) variants (E-P, n = 27; E-T350G, n = 7; E-C188G, n = 2) and one AA-a variant (n = 2) were identified among the 38 HPV16 sequences analyzed. E-P variant sequences contained 23 single nucleotide changes, two of which (A334G, A404T) had not been described before and allowed the phylogenetic separation from the other variants. E-P A334G sequences were the most prevalent (22 cases, 57.9%), followed by the E-P Ref prototype (8 cases, 21.1%) and E-P A404T (1 case, 2.6%) sequences. The HSIL + ICC fraction was 0.21 for the E-P A334G variants and 0.00 for the E-P Ref variants. We conclude that in the women included in this study the HPV16 E subtype is 19 times more frequent than the AA subtype; that the circulating E variants are E-P (71.1%) > E-T350G (18.4%) > E-C188G (5.3%); that 71.0% of the E-P sequences carry the A334G single nucleotide change and appear to correspond to a HPV16 variant characteristic of San Luis Potosi City more oncogenic than the E-P Ref prototype.

  16. Technical and Economic Advantages of Turbo-Drive Variant with TRB Turbines over Turbo-Generator Variant in Low Power Engineering

    Directory of Open Access Journals (Sweden)

    N. V. Panteley

    2008-01-01

    Full Text Available The paper contains a comparative analysis of turbo-driven variant application with TRB turbines and turbo-generator variant in the low power engineering. High efficiency of steam-turbine drive application with TRB turbines is proved by calculation which is made on the basis of a SE-1250-140 network pump at one of the boilers of the Republic of Belarus taken as an example. Calculation has been made for the following steam parameters: turbo-drive input – 12 kgs/cm and 250 and parameters behind turbo-drive – 1kgs/cm. Comparative analysis has been prepared on the basis of data presented by BelNIPIenergoprom in respect of regional boiler No.3 of Mogilev.

  17. LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Alyssa Florwick

    2017-06-01

    Full Text Available Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases (‘laminopathies’ including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2, insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations (‘variants’ in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA. We identified 169 variants in the ExAC cohort, of which 37 (∼22% are disease-associated including p.I299V (allele frequency 0.0402%, p.G602S (allele frequency 0.0262% and p.R644C (allele frequency 0.124%, suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58, and was more frequent in African Americans (allele frequency 0.297%. The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%. The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B, p.R397C and p.R427C (predicted to perturb filament biogenesis, p.G638R and p.N660D (predicted to perturb prelamin A processing, and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein–protein interactions. Overall, this two-pronged strategy— mining a large database for missense variants in a single gene (LMNA, coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric

  18. Integrative analysis of functional genomic annotations and sequencing data to identify rare causal variants via hierarchical modeling

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    Marinela eCapanu

    2015-05-01

    Full Text Available Identifying the small number of rare causal variants contributing to disease has beena major focus of investigation in recent years, but represents a formidable statisticalchallenge due to the rare frequencies with which these variants are observed. In thiscommentary we draw attention to a formal statistical framework, namely hierarchicalmodeling, to combine functional genomic annotations with sequencing data with theobjective of enhancing our ability to identify rare causal variants. Using simulations weshow that in all configurations studied, the hierarchical modeling approach has superiordiscriminatory ability compared to a recently proposed aggregate measure of deleteriousness,the Combined Annotation-Dependent Depletion (CADD score, supportingour premise that aggregate functional genomic measures can more accurately identifycausal variants when used in conjunction with sequencing data through a hierarchicalmodeling approach

  19. Targeted s-gram matching: a novel n-gram matching technique for cross- and monolingual word form variants

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    Ari Pirkola

    2002-01-01

    Full Text Available We present a novel n-gram based string matching technique, which we call the targeted s-gram matching technique. In the technique, n-grams are classified into categories on the basis of character contiguity in words. The categories are then utilized in matching. The technique was compared with the conventional n-gram technique using adjacent characters as n-grams. Several types of words and word pairs were studied. English, German, and Swedish query keys were matched against their Finnish spelling variants and Finnish morphological variants using a target word list of 119 000 Finnish words. In all cross-lingual tests done, the targeted s-gram matching technique outperformed the conventional n-gram matching technique. The technique was highly effective also for monolingual word form variants. The effects of query key length and the length of the longest common subsequence (LCS of the variants on the performance of s-grams were analyzed.

  20. Research progress of behavioral variant frontotemporal dementia

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    Xiao-hua GU

    2015-07-01

    Full Text Available There is no epidemiological data of frontotemporal dementia (FTD in China. The application of updated diagnostic criteria, publishing of frontotemporal lobar degeneration (FTLD consensus in China, development of multimodal imaging and biomarkers promote the clinical understanding on behavioral variant frontotemporal dementia (bvFTD. There is still no drugs treating FTD approved by U.S. Food and Drug Administration (FDA. Multidisciplinary intervention may delay the progression of bvFTD. DOI: 10.3969/j.issn.1672-6731.2015.07.006

  1. Space-variant polarized Airy beam

    CERN Document Server

    Chen, Hao

    2015-01-01

    We experimentally generate an Airy beam with polarization structure while keeping its original amplitude and phase profile intact. This class of Airy beam preserves the acceleration properties. By monitoring their initial polarization structure we have provided insight concerning the self-healing mechanism of Airy beams. We investigate both theoretically and experimentally the self-healing polarization properties of the space-variant polarized Airy beams. Amplitude as well as the polarization structure tends to reform during propagation in spite of the severe truncation of the beam by finite apertures.

  2. Sex steroids and variants of gender identity.

    Science.gov (United States)

    Meyer-Bahlburg, Heino F L

    2013-09-01

    This article summarizes for the practicing endocrinologist the current literature on the psychobiology of the development of gender identity and its variants in individuals with disorders of sex development (DSD) or with non-DSD transgenderism. Gender reassignment remains the treatment of choice for strong and persistent gender dysphoria in both categories, but more research is needed on the short-term and long-term effects of puberty-suppressing medications and cross-sex hormones on brain and behavior. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Multisystem altruistic metadynamics—Well-tempered variant

    Science.gov (United States)

    Hošek, Petr; Kříž, Pavel; Toulcová, Daniela; Spiwok, Vojtěch

    2017-03-01

    Metadynamics method has been widely used to enhance sampling in molecular simulations. Its original form suffers two major drawbacks, poor convergence in complex (especially biomolecular) systems and its serial nature. The first drawback has been addressed by introduction of a convergent variant known as well-tempered metadynamics. The second was addressed by introduction of a parallel multisystem metadynamics referred to as altruistic metadynamics. Here, we combine both approaches into well-tempered altruistic metadynamics. We provide mathematical arguments and trial simulations to show that it accurately predicts free energy surfaces.

  4. Multisystem altruistic metadynamics-Well-tempered variant.

    Science.gov (United States)

    Hošek, Petr; Kříž, Pavel; Toulcová, Daniela; Spiwok, Vojtěch

    2017-03-28

    Metadynamics method has been widely used to enhance sampling in molecular simulations. Its original form suffers two major drawbacks, poor convergence in complex (especially biomolecular) systems and its serial nature. The first drawback has been addressed by introduction of a convergent variant known as well-tempered metadynamics. The second was addressed by introduction of a parallel multisystem metadynamics referred to as altruistic metadynamics. Here, we combine both approaches into well-tempered altruistic metadynamics. We provide mathematical arguments and trial simulations to show that it accurately predicts free energy surfaces.

  5. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

    Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L

    2014-01-01

    BACKGROUND: Reduced forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) are strong predictors of mortality and lung function is higher among individuals with exceptional longevity. However, genetic factors associated with lung function in individuals...... with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia...

  6. Oral fibrolipoma: A rare histological variant

    Directory of Open Access Journals (Sweden)

    Treville Pereira

    2014-01-01

    Full Text Available Lipomas are benign soft tissue mesenchymal neoplasms. Fibrolipoma is a histological variant of lipoma that mostly affects the buccal mucosa and causes functional and cosmetic disabilities. The diagnosis and differentiation of fibrolipoma with clinically similar lesions such as fibroma and pleomorphic adenoma is very essential for a correct treatment plan and complete follow-up. This article presents a case of a 35-year-old female with a fibrolipoma on the lingual marginal gingiva of the mandibular left third molar.

  7. Elevated Oestrogen Receptor Splice Variant ERαΔ5 Expression in Tumour-adjacent Hormone-responsive Tissue

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    Pierre L. Martin-Hirsch

    2010-11-01

    Full Text Available Susceptibility to prostate or endometrial cancer is linked with obesity, a state of oestrogen excess. Oestrogen receptor (ER splice variants may be responsible for the tissue-level of ER activity. Such micro-environmental regulation may modulate cancer initiation and/or progression mechanisms. Real-time reverse transcriptase (RT polymerase chain reaction (PCR was used to quantitatively assess the levels of four ER splice variants (ERαΔ3, ERαΔ5, ERβ2 and ERβ5, plus the full-length parent isoforms ERα and ERβ1, in high-risk [tumour-adjacent prostate (n = 10 or endometrial cancer (n = 9] vs. low-risk [benign prostate (n = 12 or endometrium (n = 9], as well as a comparison of UK (n = 12 vs. Indian (n = 15 benign prostate. All three tissue groups expressed the ER splice variants at similar levels, apart from ERαΔ5. This splice variant was markedly raised in all of the tumour-adjacent prostate samples compared to benign tissues. Immunofluorescence analysis for ERβ2 in prostate tissue demonstrated that such splice variants are present in comparable, if not greater, amounts as the parent full-length isoform. This small pilot study demonstrates the ubiquitous nature of ER splice variants in these tissue sites and suggests that ERαΔ5 may be involved in progression of prostate adenocarcinoma.

  8. HDR Image Quality Enhancement Based on Spatially Variant Retinal Response

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    Horiuchi Takahiko

    2010-01-01

    Full Text Available There is a growing demand for being able to display high dynamic range (HDR images on low dynamic range (LDR devices. Tone mapping is a process for enhancing HDR image quality on an LDR device by converting the tonal values of the original image from HDR to LDR. This paper proposes a new tone mapping algorithm for enhancing image quality by deriving a spatially-variant operator for imitating S-potential response in human retina, which efficiently improves local contrasts while conserving good global appearance. The proposed tone mapping operator is studied from a system construction point of view. It is found that the operator is regarded as a natural extension of the Retinex algorithm by adding a global adaptation process to the local adaptation. The feasibility of the proposed algorithm is examined in detail on experiments using standard HDR images and real HDR scene images, comparing with conventional tone mapping algorithms.

  9. Depletion interactions effected by different variants of fd virus.

    Science.gov (United States)

    July, Christoph; Lang, Peter R

    2010-12-21

    The depletion interaction between a probe sphere and a flat wall induced by fd virus is investigated by means of total internal reflection microscopy (TIRM). The viruses serve as a model system for monodisperse, rod-like colloids. We find that the experimental potentials are well described by the first-order density approximation up to an fd content of several overlap concentrations. This is in accordance with higher order density theory as confirmed by numerical calculations. Since the first-order analytical description still holds for all measurements, this exemplifies that higher order terms of the theory are unimportant for our system. Comparing the potentials induced by wild-type fd to those induced by a more rigid fd variant, it can be shown that the influence of the virus stiffness is beyond our experimental resolution and plays only a negligible role for the measured depletion potentials.

  10. A Splice Variant of Bardet-Biedl Syndrome 5 (BBS5 Protein that Is Selectively Expressed in Retina.

    Directory of Open Access Journals (Sweden)

    Susan N Bolch

    of photoreceptors, where BBS5 is also localized. Like BBS5, the binding of BBS5L to arrestin1 can be modulated by phosphorylation through protein kinase C.In this study we have identified a novel splice variant of BBS5 that appears to be expressed only in the retina. The BBS5 splice variant is expressed at approximately 10% of full-length BBS5 level. No unique functional or localization properties could be identified for the splice variant compared to BBS5.

  11. Rare, Potentially Pathogenic Variants in ZNF469 Are Not Enriched in Keratoconus in a Large Australian Cohort of European Descent.

    Science.gov (United States)

    Lucas, Sionne E M; Zhou, Tiger; Blackburn, Nicholas B; Mills, Richard A; Ellis, Jonathan; Leo, Paul; Souzeau, Emmanuelle; Ridge, Bronwyn; Charlesworth, Jac C; Brown, Matthew A; Lindsay, Richard; Craig, Jamie E; Burdon, Kathryn P

    2017-12-01

    The Zinc Finger Protein 469 (ZNF469) gene has been proposed as a candidate gene for keratoconus due to the association of an upstream polymorphism (rs9938149) with the disease in two independent studies, and the role of the gene in the autosomal recessive disease Brittle Cornea Syndrome. Coding variants in ZNF469 have been assessed for association with keratoconus in several small studies, with conflicting results. We assessed rare, potentially pathogenic variants in ZNF469 for enrichment in keratoconus patients in a cohort larger than all previous studies combined. ZNF469 was sequenced in 385 Australian keratoconus patients of European descent, 346 population controls, and 230 ethnically matched screened controls by either whole exome sequencing or targeted gene sequencing. The frequency of rare and very rare potentially pathogenic variants was compared between cases and controls using χ2 or Fisher's exact tests and further explored using a gene based test (Sequence Kernel Association Test [SKAT]), weighting on the rarity of variants. A total of 49 rare, including 33 very rare, potentially pathogenic variants were identified across all groups. No enrichment of rare or very rare potentially pathogenic variants in ZNF469 was observed in our cases compared to the control groups following analysis using χ2 or Fisher's exact tests. This finding was further supported by the SKAT results, which found no significant difference in the frequency of variants predicted to be damaging between cases and either control group (P = 0.06). Rare variants in ZNF469 do not contribute to keratoconus susceptibility and do not account for the association at rs9938149.

  12. Cas9 Variants Expand the Target Repertoire in Caenorhabditis elegans.

    Science.gov (United States)

    Bell, Ryan T; Fu, Becky X H; Fire, Andrew Z

    2016-02-01

    The proliferation of CRISPR/Cas9-based methods in Caenorhabditis elegans has enabled efficient genome editing and precise genomic tethering of Cas9 fusion proteins. Experimental designs using CRISPR/Cas9 are currently limited by the need for a protospacer adjacent motif (PAM) in the target with the sequence NGG. Here we report the characterization of two modified Cas9 proteins in C. elegans that recognize NGA and NGCG PAMs. We found that each variant could stimulate homologous recombination with a donor template at multiple loci and that PAM specificity was comparable to that of wild-type Cas9. To directly compare effectiveness, we used CRISPR/Cas9 genome editing to generate a set of assay strains with a common single-guide RNA (sgRNA) target sequence, but that differ in the juxtaposed PAM (NGG, NGA, or NGCG). In this controlled setting, we determined that the NGA PAM Cas9 variant can be as effective as wild-type Cas9. We similarly edited a genomic target to study the influence of the base following the NGA PAM. Using four strains with four NGAN PAMs differing only at the fourth position and adjacent to the same sgRNA target, we observed that efficient homologous replacement was attainable with any base in the fourth position, with an NGAG PAM being the most effective. In addition to demonstrating the utility of two Cas9 mutants in C. elegans and providing reagents that permit CRISPR/Cas9 experiments with fewer restrictions on potential targets, we established a means to benchmark the efficiency of different Cas9::PAM combinations that avoids variations owing to differences in the sgRNA sequence. Copyright © 2016 by the Genetics Society of America.

  13. Cas9 Variants Expand the Target Repertoire in Caenorhabditis elegans

    Science.gov (United States)

    Bell, Ryan T.; Fu, Becky X. H.; Fire, Andrew Z.

    2016-01-01

    The proliferation of CRISPR/Cas9-based methods in Caenorhabditis elegans has enabled efficient genome editing and precise genomic tethering of Cas9 fusion proteins. Experimental designs using CRISPR/Cas9 are currently limited by the need for a protospacer adjacent motif (PAM) in the target with the sequence NGG. Here we report the characterization of two modified Cas9 proteins in C. elegans that recognize NGA and NGCG PAMs. We found that each variant could stimulate homologous recombination with a donor template at multiple loci and that PAM specificity was comparable to that of wild-type Cas9. To directly compare effectiveness, we used CRISPR/Cas9 genome editing to generate a set of assay strains with a common single-guide RNA (sgRNA) target sequence, but that differ in the juxtaposed PAM (NGG, NGA, or NGCG). In this controlled setting, we determined that the NGA PAM Cas9 variant can be as effective as wild-type Cas9. We similarly edited a genomic target to study the influence of the base following the NGA PAM. Using four strains with four NGAN PAMs differing only at the fourth position and adjacent to the same sgRNA target, we observed that efficient homologous replacement was attainable with any base in the fourth position, with an NGAG PAM being the most effective. In addition to demonstrating the utility of two Cas9 mutants in C. elegans and providing reagents that permit CRISPR/Cas9 experiments with fewer restrictions on potential targets, we established a means to benchmark the efficiency of different Cas9::PAM combinations that avoids variations owing to differences in the sgRNA sequence. PMID:26680661

  14. Variants and pitfalls on radioiodine scans in pediatric patients with differentiated thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Mostafa, Mohamed; Vali, Reza; Chan, Jeffrey; Omarkhail, Yusuaf; Shammas, Amer [University of Toronto, Nuclear Medicine Division, Department of Medical Imaging, The Hospital for Sick Children, Toronto, Ontario (Canada)

    2016-10-15

    Potentially false-positive findings on radioiodine scans in children with differentiated thyroid carcinoma can mimic functioning thyroid tissue and functioning thyroid carcinomatous tissue. Such false-positive findings comprise variants and pitfalls that can vary slightly in children as compared with adults. To determine the patterns and frequency of these potential false-positive findings on radioiodine scans in children with differentiated thyroid carcinoma. We reviewed a total of 223 radioiodine scans from 53 pediatric patients (mean age 13.3 years, 37 girls) with differentiated thyroid carcinoma. Focal or regional activity that likely did not represent functioning thyroid tissue or functioning thyroid carcinomatous tissue were categorized as variants or pitfalls. The final diagnosis was confirmed by reviewing the concurrent and follow-up clinical data, correlative ultrasonography, CT scanning, serum thyroglobulin and antithyroglobulin antibody levels. We calculated the frequency of these variants and pitfalls from diagnostic and post-therapy radioiodine scans. The most common variant on the radioiodine scans was the thymic activity (24/223, 10.8%) followed by the cardiac activity (8/223, 3.6%). Salivary contamination and star artifact, caused by prominent thyroid remnant, were the most important observed pitfalls. Variants and pitfalls that mimic functioning thyroid tissue or functioning thyroid carcinomatous tissue on radioiodine scan in children with differentiated thyroid carcinoma are not infrequent, but they decrease in frequency on successive radioiodine scans. Potential false-positive findings can be minimized with proper knowledge of the common variants and pitfalls in children and correlation with clinical, laboratory and imaging data. (orig.)

  15. Multiple linear combination (MLC) regression tests for common variants adapted to linkage disequilibrium structure.

    Science.gov (United States)

    Yoo, Yun Joo; Sun, Lei; Poirier, Julia G; Paterson, Andrew D; Bull, Shelley B

    2017-02-01

    By jointly analyzing multiple variants within a gene, instead of one at a time, gene-based multiple regression can improve power, robustness, and interpretation in genetic association analysis. We investigate multiple linear combination (MLC) test statistics for analysis of common variants under realistic trait models with linkage disequilibrium (LD) based on HapMap Asian haplotypes. MLC is a directional test that exploits LD structure in a gene to construct clusters of closely correlated variants recoded such that the majority of pairwise correlations are positive. It combines variant effects within the same cluster linearly, and aggregates cluster-specific effects in a quadratic sum of squares and cross-products, producing a test statistic with reduced degrees of freedom (df) equal to the number of clusters. By simulation studies of 1000 genes from across the genome, we demonstrate that MLC is a well-powered and robust choice among existing methods across a broad range of gene structures. Compared to minimum P-value, variance-component, and principal-component methods, the mean power of MLC is never much lower than that of other methods, and can be higher, particularly with multiple causal variants. Moreover, the variation in gene-specific MLC test size and power across 1000 genes is less than that of other methods, suggesting it is a complementary approach for discovery in genome-wide analysis. The cluster construction of the MLC test statistics helps reveal within-gene LD structure, allowing interpretation of clustered variants as haplotypic effects, while multiple regression helps to distinguish direct and indirect associations. © 2016 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

  16. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants.

    Science.gov (United States)

    Belkadi, Aziz; Bolze, Alexandre; Itan, Yuval; Cobat, Aurélie; Vincent, Quentin B; Antipenko, Alexander; Shang, Lei; Boisson, Bertrand; Casanova, Jean-Laurent; Abel, Laurent

    2015-04-28

    We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ∼3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs.

  17. A selective splicing variant of hepcidin mRNA in hepatocellular carcinoma cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Toki, Yasumichi [Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido 078-8510 (Japan); Sasaki, Katsunori, E-mail: k-sasaki@asahikawa-med.ac.jp [Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Hokkaido 078-8510 (Japan); Tanaka, Hiroki [Department of Legal Medicine, Asahikawa Medical University, Hokkaido 078-8510 (Japan); Yamamoto, Masayo; Hatayama, Mayumi; Ito, Satoshi; Ikuta, Katsuya; Shindo, Motohiro; Hasebe, Takumu; Nakajima, Shunsuke; Sawada, Koji; Fujiya, Mikihiro [Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido 078-8510 (Japan); Torimoto, Yoshihiro [Oncology Center, Asahikawa Medical University Hospital, Hokkaido 078-8510 (Japan); Ohtake, Takaaki; Kohgo, Yutaka [Department of Gastroenterology, International University of Health and Welfare Hospital, Tochigi 329-2763 (Japan)

    2016-08-05

    Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells. - Highlights: • An aberrant splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene. • Absolute quantification of hepcidin mRNA by digital PCR amplification. • Hepatoma-derived cell lines have significant copies of variant-type hepcidin mRNA. • Truncated preprohepcidin is secreted from cells without posttranslational cleavage.

  18. Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.

    Science.gov (United States)

    Singh, Bhupendra; Owens, Kjerstin M; Bajpai, Prachi; Desouki, Mohamed Mokhtar; Srinivasasainagendra, Vinodh; Tiwari, Hemant K; Singh, Keshav K

    2015-01-01

    Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic

  19. Association between MTHFR variant and diabetic neuropathy.

    Science.gov (United States)

    Kakavand Hamidi, Armita; Radfar, Mania; Amoli, Mahsa M

    2017-04-26

    Methylene-tetrahydrofolate reductase (MTHFR) gene variant may play an important role in the pathophysiology of diabetes and its complications due to its influence on plasma homocysteine levels and also its effect on scavenging peroxynitrite radicals. Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to investigate the relationship between diabetic neuropathy and MTHFR gene C677T and 1298A ⁄C polymorphisms. Patients with type 2 diabetes N=248 were enrolled in the study, consisting of patients with neuropathy (N=141) and patients without neuropathy (N=107). MTHFR C677T polymorphism was analyzed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) of genomic DNA for genotyping of samples. 1298A/C polymorphism was evaluated using ARMS-PCR. There was a significant difference in MTHFR polymorphism between the groups with and without neuropathy. Our results suggest that MTHFR 677 variant confer risk for diabetic neuropathy among Iranian patients with type 2 diabetes. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  20. COMT gene locus: new functional variants

    Science.gov (United States)

    Meloto, Carolina B.; Segall, Samantha K.; Smith, Shad; Parisien, Marc; Shabalina, Svetlana A.; Rizzatti-Barbosa, Célia M.; Gauthier, Josée; Tsao, Douglas; Convertino, Marino; Piltonen, Marjo H.; Slade, Gary Dmitri; Fillingim, Roger B.; Greenspan, Joel D.; Ohrbach, Richard; Knott, Charles; Maixner, William; Zaykin, Dmitri; Dokholyan, Nikolay V.; Reenilä, Ilkka; Männistö, Pekka T.; Diatchenko, Luda

    2015-01-01

    Abstract Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3′ untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. PMID:26207649

  1. Anatomic variants in Dandy-Walker complex.

    Science.gov (United States)

    Jurcă, Maria Claudia; Kozma, Kinga; Petcheşi, CodruŢa Diana; Bembea, Marius; Pop, Ovidiu Laurean; MuŢiu, Gabriela; Coroi, Mihaela Cristiana; Jurcă, Alexandru Daniel; Dobjanschi, Luciana

    2017-01-01

    Dandy-Walker complex (DWC) is a malformative association of the central nervous system. DWC includes four different types: Dandy-Walker malformation (vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa); Dandy-Walker variant (vermis hypoplasia, cystic dilatation of the fourth ventricle, normal posterior fossa); mega cysterna magna (large posterior fossa, normal vermis and fourth ventricle) and posterior fossa arachnoid cyst. We present and discuss four cases with different morphological and clinical forms of the Dandy-Walker complex. In all four cases, diagnosis was reached by incorporation of clinical (macrocephaly, seizures) and imaging [X-ray, computed tomography (CT), magnetic resonance imaging (MRI)] data. Two patients were diagnosed with Dandy-Walker complex, one patient was diagnosed with Dandy-Walker variant in a rare association with neurofibromatosis and one patient was diagnosed with a posterior fossa arachnoid cyst associated with left-sided Claude Bernard-Horner syndrome, congenital heart disease (coarctation of the aorta, mitral stenosis) and gastroesophageal reflux. In all forms of DWC, the clinical, radiological and functional manifestations are variable and require adequate diagnostic and therapeutic measures.

  2. Flavonoids as Inhibitors of Human Butyrylcholinesterase Variants

    Directory of Open Access Journals (Sweden)

    Maja Katalinić

    2014-01-01

    Full Text Available The inhibition of butyrylcholinesterase (BChE, EC 3.1.1.8 appears to be of interest in treating diseases with symptoms of reduced neurotransmitter levels, such as Alzheimer’s disease. However, BCHE gene polymorphism should not be neglected in research since it could have an effect on the expected outcome. Several well-known cholinergic drugs (e.g. galantamine, huperzine and rivastigmine originating from plants, or synthesised as derivatives of plant compounds, have shown that herbs could serve as a source of novel target-directed compounds. We focused our research on flavonoids, biologically active polyphenolic compounds found in many plants and plant-derived products, as BChE inhibitors. All of the tested flavonoids: galangin, quercetin, fisetin and luteolin reversibly inhibited usual, atypical, and fluoride-resistant variants of human BChE. The inhibition potency increased in the following order, identically for all three BChE variants: luteolin

  3. A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration

    Science.gov (United States)

    Hagenbuchner, Judith; Kiechl-Kohlendorfer, Ursula; Obexer, Petra; Ausserlechner, Michael J.

    2013-01-01

    Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apoptotic Bcl2-family member Myeloid cell leukemia-1 (Mcl1) from human neuroblastoma and leukemia cells. This Mcl1L variant lacks a 45 bp sequence that codes for 15 highly conserved amino acids ranging from Gly158 to Asp172. This region is part of the so called PEST-sequence of Mcl1L and contains two phosphorylation sites (Ser159 and Thr163) that regulate Mcl1L stability. A caspase 3/caspase 8 cleavage site at Asp157 which has been reported to be critical for death-receptor-induced apoptosis and for the conversion of Mcl1L into a pro-apoptotic protein is also missing in this novel variant. Importantly, Mcl1LdelGly158-Asp172 bound significantly more pro-apoptotic Bim compared to Mcl1L and showed increased anti-proliferative and anti-apoptotic activity compared to Mcl1L during death receptor-induced cell death. This suggests that this novel Mcl1L variant efficiently protects tumor cells against extrinsic death signalling and therefore may provide a survival advantage for highly aggressive tumors. PMID:23872733

  4. The prevalence of PAI-1 4G/5G gene variant in Serbian population

    Directory of Open Access Journals (Sweden)

    Đorđević Valentina

    2013-01-01

    Full Text Available Introduction: Plasminogen activator inhibitor 1 (PAI-1 has a major role in inhibition of firinolysis and normal haemostasis. The presence of the PAI-1 4G/4G genotype leads to increased expression of PAI-1. High blood level of PAI-1 is associated with many diseases such as thrombosis, cerebral insult, myocardial infarction, pregnancy loss, preeclampsia, insulin resistance, type 2 diabetes, breast cancer and asthma. In this study, the prevalence of PAI-1 4G/5G gene variant was determined in healthy subjects from Serbian population. Methods: The study was carried out in a group of 210 healthy subjects (105 women and 105 men. The presence of PAI-1 4G/5G gene variant was detected by PCR-RFLP analysis. Results: The prevalence of PAI-1 4G/4G genotype was 34.76% and it was increased compared to PAI-1 5G/5G genotype (19.05%. The most frequent was PAI-1 4G/5G genotype (46.19%. Allelic frequency for 4G allele was higher (0.58 compared to 5G allele (0.42. Conclusions: The prevalence of PAI-1 4G/5G gene variant in Serbian population is similar to the neighboring populations. Results of this study represent the first data for Serbian population. This study could be useful for further research where the role of PAI-1 4G/5G gene variant will be assessed in the pathogenesis of many diseases.

  5. Examination of candidate exonic variants for association to Alzheimer disease in the Amish.

    Directory of Open Access Journals (Sweden)

    Laura N D'Aoust

    Full Text Available Alzheimer disease (AD is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and from linkage regions implicated previous studies in the full dataset, new associations could be confirmed. The most significant result (p = 0.0012 was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions.

  6. Examination of candidate exonic variants for association to Alzheimer disease in the Amish.

    Science.gov (United States)

    D'Aoust, Laura N; Cummings, Anna C; Laux, Renee; Fuzzell, Denise; Caywood, Laura; Reinhart-Mercer, Lori; Scott, William K; Pericak-Vance, Margaret A; Haines, Jonathan L

    2015-01-01

    Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and from linkage regions implicated previous studies in the full dataset, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions.

  7. BBCAnalyzer: a visual approach to facilitate variant calling

    OpenAIRE

    Sandmann, S.; Graaf, A.O. de; Dugas, M.

    2017-01-01

    Background Deriving valid variant calling results from raw next-generation sequencing data is a particularly challenging task, especially with respect to clinical diagnostics and personalized medicine. However, when using classic variant calling software, the user usually obtains nothing more than a list of variants that pass the corresponding caller?s internal filters. Any expected mutations (e.g. hotspot mutations), that have not been called by the software, need to be investigated manually...

  8. Copy number variants in patients with short stature

    OpenAIRE

    van Duyvenvoorde, Hermine A.; Lui, Julian C.; Kant, Sarina G; Oostdijk, Wilma; Gijsbers, Antoinet CJ; Hoffer, Mariëtte JV; Karperien, Marcel; Walenkamp, Marie JE; Noordam, Cees; Voorhoeve, Paul G; Mericq, Verónica; Alberto M. Pereira; Claahsen-van der Grinten, Hedi L.; van Gool, Sandy A; Breuning, Martijn H

    2013-01-01

    Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variant...

  9. Evaluation of persistence of resistant variants with ultra-deep pyrosequencing in chronic hepatitis C patients treated with telaprevir.

    Directory of Open Access Journals (Sweden)

    Xiomara V Thomas

    Full Text Available BACKGROUND & AIMS: Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment. METHODS: Fifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103 were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline. RESULTS: Resistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing. CONCLUSION: In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare.

  10. A unified phylogeny-based nomenclature for histone variants.

    Science.gov (United States)

    Talbert, Paul B; Ahmad, Kami; Almouzni, Geneviève; Ausió, Juan; Berger, Frederic; Bhalla, Prem L; Bonner, William M; Cande, W Zacheus; Chadwick, Brian P; Chan, Simon W L; Cross, George A M; Cui, Liwang; Dimitrov, Stefan I; Doenecke, Detlef; Eirin-López, José M; Gorovsky, Martin A; Hake, Sandra B; Hamkalo, Barbara A; Holec, Sarah; Jacobsen, Steven E; Kamieniarz, Kinga; Khochbin, Saadi; Ladurner, Andreas G; Landsman, David; Latham, John A; Loppin, Benjamin; Malik, Harmit S; Marzluff, William F; Pehrson, John R; Postberg, Jan; Schneider, Robert; Singh, Mohan B; Smith, M Mitchell; Thompson, Eric; Torres-Padilla, Maria-Elena; Tremethick, David John; Turner, Bryan M; Waterborg, Jakob Harm; Wollmann, Heike; Yelagandula, Ramesh; Zhu, Bing; Henikoff, Steven

    2012-06-21

    Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  11. A unified phylogeny-based nomenclature for histone variants

    Directory of Open Access Journals (Sweden)

    Talbert Paul B

    2012-06-01

    Full Text Available Abstract Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.

  12. Population structure analysis using rare and common functional variants

    Directory of Open Access Journals (Sweden)

    Ding Lili

    2011-11-01

    Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

  13. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members.

    Science.gov (United States)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco; Hansen, Thomas V O; Pedersen, Inge S; Gutiérrez-Enríquez, Sara; Menéndez, Mireia; Fachal, Laura; Santamariña, Marta; Steffensen, Ane Y; Jønson, Lars; Agata, Simona; Whiley, Phillip; Tognazzo, Silvia; Tornero, Eva; Jensen, Uffe B; Balmaña, Judith; Kruse, Torben A; Goldgar, David E; Lázaro, Conxi; Diez, Orland; Spurdle, Amanda B; Vega, Ana

    2012-04-01

    Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of

  14. Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study

    Science.gov (United States)

    Przybelski, Scott A.; Weigand, Stephen D.; Ivnik, Robert J.; Vemuri, Prashanthi; Gunter, Jeffrey L.; Senjem, Matthew L.; Shiung, Maria M.; Boeve, Bradley F.; Knopman, David S.; Parisi, Joseph E.; Dickson, Dennis W.; Petersen, Ronald C.; Jack, Clifford R.; Josephs, Keith A.

    2009-01-01

    The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one

  15. Comparison of the technical and economic parameters of different variants of the nuclear fuel cycle reactors of the nuclear power plants

    Science.gov (United States)

    Adamov, E. O.; Rachkov, V. I.; Tolstoukhov, D. A.; Panov, S. A.

    2016-12-01

    The article presents the comparative economic analysis of the variants of implementation of the fuel cycles for fast and thermal reactors. Calculations are carried out for the formed reference conditions by the cost of processing stages of the fuel cycles for the foreign and expert Russian information sources. The comparative data on the resource supply, absolute and specific costs of the fuel cycle variants for the whole life cycle of the thermal power plant projects with the fast and thermal reactors are considered. The conclusions of the efficiency of the fuel cycle variants for the assumed reference conditions of the calculation are made.

  16. A distinct subtype of ``metatropic dysplasia variant`` characterised by advanced carpal skeletal age and subluxation of the radial heads

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, G. [Department of Radiology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu Shimotsuga-gun, Tochigi-ken 321-02 (Japan); Satoh, Masato [Department of Orthopedics, Saitama Children`s Medical Center, Saitama (Japan); Aihara, Toshinori [Department of Radiology, Saitama Children`s Medical Center, Saitama (Japan); Aida, Noriko [Department of Radiology, Kanagawa Children`s Medical Center, Yokohama (Japan); Yamamoto, Takehisa [Department of Pediatrics, Osaka University School of Medicine, Osaka (Japan); Ozono, Keiichi [Department of Environmental Medicine, Osaka Medical Center and Institute for Maternal and Child Health, Osaka (Japan)

    1998-02-01

    Background. ``Metatropic dysplasia variants`` are a group of bone dysplasias whose skeletal abnormalities are similar to, but milder than, those of classical metatropic dysplasia. The genetic and phenotypic heterogeneity has not been thoroughly elucidated. Objective. The objective was to designate a distinct subtype of these metatropic dysplasia variants. Materials and methods. The subjects were four Japanese patients, two sporadic cases and two siblings, who all had identical skeletal changes. The radiological features in these patients were compared with those of previously reported metatropic dysplasia variants. Results. Moderate platyspondyly with pear-shaped and/or anterior-tongued vertebral bodies, halberd pelvis, and dumbbell deformity of the tubular bones were regarded as hallmarks of metatropic dysplasia variants. The peculiar skeletal change in our patients was advanced carpal skeletal age in childhood, unlike most patients reported as metatropic dysplasia variants who manifest delayed carpal ossification. Another hallmark was congenital dislocation of the radial heads. A description of a patient with similar skeletal changes was found in the literature. Conclusion. These patients are considered to represent a distinct subgroup of metatropic dysplasia variants. It remains unknown whether the present siblings represent an autosomal recessive trait or an autosomal dominant trait with germinal mosaicism related to increased paternal age. (orig.) With 3 figs., 10 refs.

  17. Characterization of coding synonymous and non-synonymous variants in ADAMTS13 using ex vivo and in silico approaches.

    Directory of Open Access Journals (Sweden)

    Nathan C Edwards

    Full Text Available Synonymous variations, which are defined as codon substitutions that do not change the encoded amino acid, were previously thought to have no effect on the properties of the synthesized protein(s. However, mounting evidence shows that these "silent" variations can have a significant impact on protein expression and function and should no longer be considered "silent". Here, the effects of six synonymous and six non-synonymous variations, previously found in the gene of ADAMTS13, the von Willebrand Factor (VWF cleaving hemostatic protease, have been investigated using a variety of approaches. The ADAMTS13 mRNA and protein expression levels, as well as the conformation and activity of the variants have been compared to that of wild-type ADAMTS13. Interestingly, not only the non-synonymous variants but also the synonymous variants have been found to change the protein expression levels, conformation and function. Bioinformatic analysis of ADAMTS13 mRNA structure, amino acid conservation and codon usage allowed us to establish correlations between mRNA stability, RSCU, and intracellular protein expression. This study demonstrates that variants and more specifically, synonymous variants can have a substantial and definite effect on ADAMTS13 function and that bioinformatic analysis may allow development of predictive tools to identify variants that will have significant effects on the encoded protein.

  18. Compact variant-rich customized sequence database and a fast and sensitive database search for efficient proteogenomic analyses.

    Science.gov (United States)

    Park, Heejin; Bae, Junwoo; Kim, Hyunwoo; Kim, Sangok; Kim, Hokeun; Mun, Dong-Gi; Joh, Yoonsung; Lee, Wonyeop; Chae, Sehyun; Lee, Sanghyuk; Kim, Hark Kyun; Hwang, Daehee; Lee, Sang-Won; Paek, Eunok

    2014-12-01

    In proteogenomic analysis, construction of a compact, customized database from mRNA-seq data and a sensitive search of both reference and customized databases are essential to accurately determine protein abundances and structural variations at the protein level. However, these tasks have not been systematically explored, but rather performed in an ad-hoc fashion. Here, we present an effective method for constructing a compact database containing comprehensive sequences of sample-specific variants--single nucleotide variants, insertions/deletions, and stop-codon mutations derived from Exome-seq and RNA-seq data. It, however, occupies less space by storing variant peptides, not variant proteins. We also present an efficient search method for both customized and reference databases. The separate searches of the two databases increase the search time, and a unified search is less sensitive to identify variant peptides due to the smaller size of the customized database, compared to the reference database, in the target-decoy setting. Our method searches the unified database once, but performs target-decoy validations separately. Experimental results show that our approach is as fast as the unified search and as sensitive as the separate searches. Our customized database includes mutation information in the headers of variant peptides, thereby facilitating the inspection of peptide-spectrum matches. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Pressure versus temperature unfolding of ribonuclease A: an FTIR spectroscopic characterization of 10 variants at the carboxy-terminal site.

    Science.gov (United States)

    Torrent, J; Rubens, P; Ribó, M; Heremans, K; Vilanova, M

    2001-04-01

    FTIR spectroscopy was used to characterize and compare the temperature- and pressure-induced unfolding of ribonuclease A and a set of its variants engineered in a hydrophobic region of the C-terminal part of the molecule postulated as a CFIS. The results show for all the ribonucleases investigated, a cooperative, two-state, reversible unfolding transition using both pressure and temperature. The relative stabilities, among the different sites and different variants at the same site, monitored either through the changes in the position of the maximum of the amide I' band and the tyrosine band, or the maximum of the band assigned to the beta-sheet structure, corroborate the results of a previous study using fourth-derivative UV absorbance spectroscopy. In addition, variants at position 108 are the most critical for ribonuclease structure and stability. The V108G variant seems to present a greater conformational flexibility than the other variants. The pressure- and temperature-denaturated states of all the ribonucleases characterized retained some secondary structure. However, their spectral maxima were centered at different wavenumbers, which suggests that pressure- and temperature-denaturated states do not have the same structural characteristics. Nevertheless, there was close correlation between the pressure and temperature midpoint transition values for the whole series of protein variants, which indicated a common tendency of stability toward pressure and heat.

  20. VAT: a computational framework to functionally annotate variants in personal genomes within a cloud-computing environment.

    Science.gov (United States)

    Habegger, Lukas; Balasubramanian, Suganthi; Chen, David Z; Khurana, Ekta; Sboner, Andrea; Harmanci, Arif; Rozowsky, Joel; Clarke, Declan; Snyder, Michael; Gerstein, Mark

    2012-09-01

    The functional annotation of variants obtained through sequencing projects is generally assumed to be a simple intersection of genomic coordinates with genomic features. However, complexities arise for several reasons, including the differential effects of a variant on alternatively spliced transcripts, as well as the difficulty in assessing the impact of small insertions/deletions and large structural variants. Taking these factors into consideration, we developed the Variant Annotation Tool (VAT) to functionally annotate variants from multiple personal genomes at the transcript level as well as obtain summary statistics across genes and individuals. VAT also allows visualization of the effects of different variants, integrates allele frequencies and genotype data from the underlying individuals and facilitates comparative analysis between different groups of individuals. VAT can either be run through a command-line interface or as a web application. Finally, in order to enable on-demand access and to minimize unnecessary transfers of large data files, VAT can be run as a virtual machine in a cloud-computing environment. VAT is implemented in C and PHP. The VAT web service, Amazon Machine Image, source code and detailed documentation are available at vat.gersteinlab.org.

  1. Ischemic stroke in Ukrainian population: possible involvement of the F2 G20210A, F5 G1691A and MTHFR C677T gene variants

    Directory of Open Access Journals (Sweden)

    Kuznetsova S. M.

    2010-07-01

    Full Text Available Aim. To evaluate a possible involvement of the F2, F5, MTHFR gene variants into ischemic stroke pathogenesis in population of Ukraine. Methods. Polymorphic variants were analyzed in unrelated 183 stroke patients, 100 individuals from the general population of Ukraine and 88 healthy individuals elder than 65 years using PCR followed by RFLP analysis. Results. Unfavourable polymorphic variants F2 20210A, F5 1691A and MTHFR 677T were observed more frequently in patients with ischemic stroke comparing to control groups. Conclusions. F5 1691A and MTHFR 677T polymorphic variants are associated with the occurrence of ischemic stroke in women. F2 20210A is associated with the occurrence of ischemic stroke in men. Cumulative risk factor for stroke development is revealed in a combination of unfavorable polymorphic variants 20210A, 1691A and 677T of F2, F5 and MTHFR genes.

  2. Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.

    Science.gov (United States)

    Wang, Shengfeng; Qian, Frank; Zheng, Yonglan; Ogundiran, Temidayo; Ojengbede, Oladosu; Zheng, Wei; Blot, William; Nathanson, Katherine L; Hennis, Anselm; Nemesure, Barbara; Ambs, Stefan; Olopade, Olufunmilayo I; Huo, Dezheng

    2018-01-04

    Few studies have evaluated the performance of existing breast cancer risk prediction models among women of African ancestry. In replication studies of genetic variants, a change in direction of the risk association is a common phenomenon. Termed flip-flop, it means that a variant is risk factor in one population but protective in another, affecting the performance of risk prediction models. We used data from the genome-wide association study (GWAS) of breast cancer in the African diaspora (The Root consortium), which included 3686 participants of African ancestry from Nigeria, USA, and Barbados. Polygenic risk scores (PRSs) were constructed from the published odds ratios (ORs) of four sets of susceptibility loci for breast cancer. Discrimination capacity was measured using the area under the receiver operating characteristic curve (AUC). Flip-flop phenomenon was observed among 30~40% of variants across studies. Using the 34 variants with consistent directionality among previous studies, we constructed a PRS with AUC of 0.531 (95% confidence interval [CI]: 0.512-0.550), which is similar to the PRS using 93 variants and ORs from European ancestry populations (AUC = 0.525, 95% CI: 0.506-0.544). Additionally, we found the 34-variant PRS has good discriminative accuracy in women with family history of breast cancer (AUC = 0.586, 95% CI: 0.532-0.640). We found that PRS based on variants identified from prior GWASs conducted in women of European and Asian ancestries did not provide a comparable degree of risk stratification for women of African ancestry. Further large-scale fine-mapping studies in African ancestry populations are desirable to discover population-specific genetic risk variants.

  3. H(+) -ATPase-defective variants of Lactobacillus delbrueckii subsp. bulgaricus contribute to inhibition of postacidification of yogurt during chilled storage.

    Science.gov (United States)

    Wang, Xinhui; Ren, Hongyang; Liu, Dayu; Wang, Bing; Zhu, Wenyou; Wang, Wei

    2013-02-01

    Continued acid production by Lactobacillus delbrueckii subsp. bulgaricus during the chilled storage of yogurt is the major cause of postacidification, resulting in a short shelf life. Two H(+) -ATPase defective variants of L. delbrueckii subsp. bulgaricus were successfully isolated and their H(+) -ATPase activities were reduced by 51.3% and 34.3%, respectively. It was shown that growth and acid production of variants were remarkably inhibited. The variants were more sensitive to acidic condition and had a significant rate for inactivation of H(+) -ATPase by N, N-dicyclohexylcarbodiimide (DCCD), along with a low H(+) -extrusion, suggesting that H(+) -ATPase is direct response for H(+) -extrusion. In addition, the variants were also more sensitive to NaCl, while H(+) -ATPase activities of variants and parent strain were significantly enhanced by NaCl stress. Obviously, H(+) -ATPase might be involved in Na(+) transportation. Furthermore, variants were inoculated in fermented milk to ferment yogurt. There was no significant difference in flavor, whereas the postacidification of yogurt during chilled storage was remarkably inhibited. It is suggested that application of L. delbrueckii subsp. bulgaricus with reduced H(+) -ATPase activity in yogurt fermentation is one of effect, economic and simple avenues of inhibiting postacidification of yogurt during refrigerated storage, giving a longer shelf life. During yogurt fermentation, continued acid production by Lactobacillus delbrueckii subsp. bulgaricus during the chilled storage of yogurt leads to milk fermentation with high postacidification, resulting in a short shelf life. In this work, 2 acid-sensitive variant strains of L. delbrueckii subsp. bulgaricus were isolated. The characteristics related to H(+) -ATPase were compared and it was observed that milk fermented by the variants had lower postacidification, giving a longer shelf life. Application of L. delbrueckii subsp. bulgaricus with reduced H(+) -ATPase activity

  4. Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.

    Directory of Open Access Journals (Sweden)

    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats with the asymptomatic infection of BN (Brown Norway. Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains, displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus named Hse6 towards the end of chromosome 4 (160.89-174Mb containing the Vwf (von Willebrand factor gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism. Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008 after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.

  5. Aequorin variants with improved bioluminescence properties.

    Science.gov (United States)

    Dikici, E; Qu, X; Rowe, L; Millner, L; Logue, C; Deo, S K; Ensor, M; Daunert, S

    2009-04-01

    The photoprotein aequorin has been widely used as a bioluminescent label in immunoassays, for the determination of calcium concentrations in vivo, and as a reporter in cellular imaging. It is composed of apoaequorin (189 amino acid residues), the imidazopyrazine chromophore coelenterazine and molecular oxygen. The emission characteristics of aequorin can be changed by rational design of the protein to introduce mutations in its structure, as well as by substituting different coelenterazine analogues to yield semi-synthetic aequorins. Variants of aequorin were created by mutating residues His16, Met19, Tyr82, Trp86, Trp108, Phe113 and Tyr132. Forty-two aequorin mutants were prepared and combined with 10 different coelenterazine analogues in a search for proteins with different emission wavelengths, altered decay kinetics and improved stability. This spectral tuning strategy resulted in semi-synthetic photoprotein mutants with significantly altered bioluminescent properties.

  6. A compendium of genetic variant data

    DEFF Research Database (Denmark)

    Cardoso, Joao; Schöning, Lars Yannik; Herrgard, Markus

    2014-01-01

    Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress conditi...... obtained from distinct experiments. This compendium of genetic variant is a critical step to develop approaches to automatically and systematically characterize mutated strains in the future.......Laboratory strains are genetically unstable if exposed to selective pressure as encountered, for example, during molecular cloning, fermentation, or adaptive laboratory evolution experiments. This genetic variation is the consequence of an adaptation process of the microorganism to stress...... conditions, e.g., high pressure or temperature, nutrient limitation, or toxic byproduct concentrations. The evolved strains display then new phenotypes: tolerance to a toxic byproduct or higher temperature, improved production rate of a byproduct, or higher uptake rates of nutrients. To understand...

  7. Sturge -Weber Syndrome - Three Classic variants

    Directory of Open Access Journals (Sweden)

    R S Sathawane

    2006-01-01

    Full Text Available Sturge-Weber syndrome (SWS, also known as encephalotrigeminal angiomatosis, a sporadic, non-familial, congenital disorder consists of congenital hamartomatous malformations that may affect the eye, skin and central nervous system at different times. Sturge-Weber syndrome is classified as 1 Complete trisymptomatic: - when all three organ systems i.e. eye, skin and CNS are involved 2 Incomplete bisymptomatic:- when the involvement is either oculocutaneous or neurocutaneous, and 3 Incomplete monosymptomatic: when there is only neural or cutaneous involvement. Failure of proper vascular development is believed to be the most likely cause of this condition. The malformed blood vessels or hemangiomas may lead to port-wine stain, epilepsy and glaucoma depending on its location. Three classic variants with typical findings are discussed.

  8. LEWY BODY VARIANT OF ALZHEIMER DISEASE

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    Jera Jeruc

    2003-10-01

    Full Text Available Background. Clinicopathological studies indicate that Alzheimer’s disease (AD is the most common neurodegenerative cause of dementia, the other frequent causes are AD combined with diffuse Lewy bodies and dementia with Lewy bodies (DLB by itself. When histological features of AD and DLB are found together in one brain we speak about Lewy body variant of AD (LBVAD. Beside global cognitive impairment LBVAD patients show signs of subcortical dementia and mild extrapiramidal signs.Methods and results. We present two patients with post-mortem diagnosis of LBVAD. Clinical and pathomorphological characteristics of the disease are discussed.Conclusions. Post-mortem studies show that LBVAD is the second most common cause of dementia, following AB.

  9. Current conveyors variants, applications and hardware implementations

    CERN Document Server

    Senani, Raj; Singh, A K

    2015-01-01

    This book serves as a single-source reference to Current Conveyors and their use in modern Analog Circuit Design. The authors describe the various types of current conveyors discovered over the past 45 years, details of all currently available, off-the-shelf integrated circuit current conveyors, and implementations of current conveyors using other, off-the-shelf IC building blocks. Coverage includes prominent bipolar/CMOS/Bi-CMOS architectures of current conveyors, as well as all varieties of starting from third generation current conveyors to universal current conveyors, their implementations and applications. •Describes all commercially available off-the-shelf IC current conveyors, as well as hardware implementations of current conveyors using other off-the-shelf ICs; • Describes numerous variants of current conveyors evolved over the past forty five years; • Describes a number of Bipolar/CMOS/Bi-CMOS architectures of current conveyors, along with their characteristic features; • Includes a comprehe...

  10. Genetic variants in periodontal health and disease

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrescu, Alexandrina L. [Tromsoe Univ. (Norway). Inst. of Clinical Dentistry; Kobayashi, Junya [Kyoto Univ. (Japan). Dept. of Genome Repair Dynamics

    2010-07-01

    Periodontitis is a complex, multifactorial disease and its susceptibility is genetically determined. The present book systematically reviews the evidence of the association between the genetic variants and periodontitis progression and/or treatment outcomes. Genetic syndromes known to be associated with periodontal disease, the candidate gene polymorphisms investigated in relation to periodontitis, the heritability of chronic and aggressive periodontitis, as well as common guidelines for association studies are described. This growing understanding of the role of genetic variation in inflammation and periodontal chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. The book represents a new concept in periodontology with its pronounced focus on understanding through knowledge rather than presenting the presently valid answers. Connections between genetics and periodontology are systematically reviewed and covered in detail. (orig.)

  11. Multicentric variant of peripheral ossifying fibroma

    Directory of Open Access Journals (Sweden)

    Srikanth A Choudary

    2014-01-01

    Full Text Available Peripheral ossifying fibroma (POF is a solitary over growth of the gingiva known to arise from the cells of the periodontal ligament. The lesions usually start as a painless overgrowth of the interdental papilla unless associated with trauma and gradually involve the other counter parts of the gingiva. The lesion is more considered to be an inflammatory or reactive process rather than to be neoplastic. Here, the authors present a unique case of multiple POF in a young male adult aged 24 years where surgical excision was carried out quadrant wise. The biopsy specimen from multiple sites revealed similar histopathologic features consistent with POF, but also with the multicentric presentation of POF, which is a unique phenomenon. Multicentric variant of POF is indeed a rare case being only the second case so far which has been documented. Management of such case needs a multidisciplinary approach to prevent the recurrence along with regular long time follow-up.

  12. Expression of activation-induced cytidine deaminase splicing variants in patients with ankylosing spondylitis.

    Science.gov (United States)

    Kim, Ji-Young; Yoon, Hee-Kyung; Song, Seung Taek; Park, Seok-Rae; Shim, Seung-Cheol

    2017-12-01

    To investigate the expression patterns of activation-induced cytidine deaminase (AID) variants in peripheral blood mononuclear cells (PBMCs) of patients with ankylosing spondylitis (AS) and examine their clinical implications, we isolated PBMCs from healthy controls (HC, n = 33) and patients with AS (n = 62), and measured mRNA expression of AID variants and translesion synthesis (TLS) polymerases using quantitative real-time polymerase chain reaction. The proportion of patients with AS in whom AID splicing variant (sv) 2 was expressed was significantly higher than that of HC (p = .031). 80.7% of AS patients were treated with tumour necrosis factor inhibitor (TNFi). Significantly higher proportion of the TNFi-treated group expressed sv2 compared to the TNF-naïve group (p = .037). And we compared the level of AID variants expression between the TNFi-treated group and the TNF-naïve group. The expression levels of AID full-length (FL) and sv1 were significantly lower in the TNFi-treated group than the TNF-naïve group (FL: p = .002, sv1: p = .045). In addition, we investigated mRNA expression levels of translesion synthesis (TLS) polymerases in PBMCs from patients with AS and HC. The expression level of TLS pol ι was significantly lower in patients with AS than in HC (p = .007). In conclusion, AS patients expressed significantly higher levels of sv2 than HC. TNFi treatment restored the gene expression of the AID variants (FL, sv1, and sv2) in patients with AS. A clear understanding of the underlying cellular and molecular mechanisms will help to identify the pathogenesis of AS better and to develop novel therapeutic targets.

  13. Successive Respiratory Syncytial Virus Epidemics in Local Populations Arise from Multiple Variant Introductions, Providing Insights into Virus Persistence

    Science.gov (United States)

    Otieno, James R.; Ngama, Mwanajuma; Mwihuri, Alexander G.; Medley, Graham F.; Cane, Patricia A.; Nokes, D. James

    2015-01-01

    ABSTRACT Respiratory syncytial virus (RSV) is a global respiratory pathogen of humans, with infection occurring characteristically as recurrent seasonal epidemics. Unlike influenza viruses, little attention has been paid to the mechanism underlying worldwide spread and persistence of RSV and how this may be discerned through an improved understanding of the introduction and persistence of RSV in local communities. We analyzed 651 attachment (G) glycoprotein nucleotide sequences of RSV B collected over 11 epidemics (2002 to 2012) in Kilifi, Kenya, and contemporaneous data collected elsewhere in Kenya and 18 other countries worldwide (2002 to 2012). Based on phylogeny, genetic distance and clustering patterns, we set out pragmatic criteria to classify local viruses into distinct genotypes and variants, identifying those newly introduced and those locally persisting. Three genotypes were identified in the Kilifi data set: BA (n = 500), SAB1 (n = 148), and SAB4 (n = 3). Recurrent RSV epidemics in the local population were composed of numerous genetic variants, most of which have been newly introduced rather than persisting in the location from season to season. Global comparison revealed that (i) most Kilifi variants do not cluster closely with strains from outside Kenya, (ii) some Kilifi variants were closely related to those observed outside Kenya (mostly Western Europe), and (iii) many variants were circulating elsewhere but were never detected in Kilifi. These results are consistent with the hypothesis that year-to-year presence of RSV at the local level (i.e., Kilifi) is achieved primarily, but not exclusively, through introductions from a pool of variants that are geographically restricted (i.e., to Kenya or to the region) rather than global. IMPORTANCE The mechanism by which RSV persists and reinvades local populations is poorly understood. We investigated this by studying the temporal patterns of RSV variants in a rural setting in tropical Africa and comparing

  14. Protective Effect of Human Endogenous Retrovirus K dUTPase Variants on Psoriasis Susceptibility

    Science.gov (United States)

    Lai, Olivia Y.; Chen, Haoyan; Michaud, Henri-Alexandre; Hayashi, Genki; Kuebler, Peter J.; Hultman, Gustaf K.; Ariza, Maria-Eugenia; Williams, Marshall V.; Batista, Mariana D.; Nixon, Douglas F.; Foerster, John; Bowcock, Anne M.; Liao, Wilson

    2012-01-01

    Previous genetic and functional studies have implicated the human endogenous retrovirus K (HERV-K) dUTPase located within the PSORS1 locus in the MHC region as a candidate psoriasis gene. Here, we describe a variant discovery and case-control association study of HERV-K dUTPase variants in 708 psoriasis cases and 349 healthy controls. Five common HERV-K dUTPase variants were found to be highly associated with psoriasis, with the strongest association occurring at the missense SNP rs3134774 (K158R, p=3.28 × 10-15, OR=2.36 [1.91-2.92]). After adjusting the association of the HERV-K dUTPase variants for the potential confounding effects of HLA alleles associated with psoriasis, the HERV-K SNPs rs9264082 and rs3134774 remained significantly associated. Haplotype analysis revealed that HERV-K haplotypes containing the non-risk alleles for rs3134774 and rs9264082 significantly reduced the risk of psoriasis. Functional testing showed higher antibody responses against recombinant HERV-K dUTPase in psoriasis patients compared to controls (pT-cell responses against a single HERV-K dUTPase peptide (ppsoriasis susceptibility, and suggest the need for additional studies to clarify the role of this dUTPase in the pathogenesis of psoriasis. PMID:22437317

  15. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects.

    Science.gov (United States)

    Burgess, Stephen; Thompson, Simon G

    2015-02-15

    A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This "multivariable Mendelian randomization" approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

  16. Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

    Science.gov (United States)

    Chen, Wuyan; Perritt, Ashley F; Morissette, Rachel; Dreiling, Jennifer L; Bohn, Markus-Frederik; Mallappa, Ashwini; Xu, Zhi; Quezado, Martha; Merke, Deborah P

    2016-09-01

    Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity. © 2016 WILEY PERIODICALS, INC.

  17. Rare ATAD5 missense variants in breast and ovarian cancer patients.

    Science.gov (United States)

    Maleva Kostovska, Ivana; Wang, Jing; Bogdanova, Natalia; Schürmann, Peter; Bhuju, Sabin; Geffers, Robert; Dürst, Matthias; Liebrich, Clemens; Klapdor, Rüdiger; Christiansen, Hans; Park-Simon, Tjoung-Won; Hillemanns, Peter; Plaseska-Karanfilska, Dijana; Dörk, Thilo

    2016-06-28

    ATAD5/ELG1 is a protein crucially involved in replication and maintenance of genome stability. ATAD5 has recently been identified as a genomic risk locus for both breast and ovarian cancer through genome-wide association studies. We aimed to investigate the spectrum of coding ATAD5 germ-line mutations in hospital-based series of patients with triple-negative breast cancer or serous ovarian cancer compared with healthy controls. The ATAD5 coding and adjacent splice site regions were analyzed by targeted next-generation sequencing of DNA samples from 273 cancer patients, including 114 patients with triple-negative breast cancer and 159 patients with serous epithelial ovarian cancer, and from 276 healthy females. Among 42 different variants identified, twenty-two were rare missense substitutions, of which 14 were classified as pathogenic by at least one in silico prediction tool. Three of four novel missense substitutions (p.S354I, p.H974R and p.K1466N) were predicted to be pathogenic and were all identified in ovarian cancer patients. Overall, rare missense variants with predicted pathogenicity tended to be enriched in ovarian cancer patients (14/159) versus controls (11/276) (p = 0.05, 2df). While truncating germ-line variants in ATAD5 were not detected, it remains possible that several rare missense variants contribute to genetic susceptibility toward epithelial ovarian carcinomas. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Live attenuated nephropathogenic infectious bronchitis virus vaccine provides broad cross protection against new variant strains.

    Science.gov (United States)

    Lim, T-H; Kim, M-S; Jang, J-H; Lee, D-H; Park, J-K; Youn, H-N; Lee, J-B; Park, S-Y; Choi, I-S; Song, C-S

    2012-01-01

    Infectious bronchitis virus (IBV) infections cause great economic losses to the poultry industry worldwide, and the emergence of new variant strains complicates disease control. The present study investigated the genetic and protectotypic features of newly emerged Korean IBV strains. A phylogenetic analysis showed that several recent isolates formed 2 different clusters (new cluster 1 and 2), which were distinct from other preexisting clusters. New cluster 1 IBV strains represented recombinants between Korean nephropathogenic strain KM91 and the QXIBV strain. New cluster 2 IBV strains showed low amino acid homology (vaccines (H120 and K2 strain) against these new isolates. In cross-protection studies, the H120 strain did not provide sufficient protection against these variants. However, highly attenuated nephropathogenic IBV vaccine, K2 strain, provided significantly higher levels of protection against variants compared with chickens vaccinated with H120 (P vaccine could be helpful for the reduction of economic losses caused by newly evolving IBV recombinants (new cluster 1) and variants (new cluster 2).

  19. Phenotypic comparisons of consensus variants versus laboratory resurrections of Precambrian proteins.

    Science.gov (United States)

    Risso, Valeria A; Gavira, Jose A; Gaucher, Eric A; Sanchez-Ruiz, Jose M

    2014-06-01

    Consensus-sequence engineering has generated protein variants with enhanced stability, and sometimes, with modulated biological function. Consensus mutations are often interpreted as the introduction of ancestral amino acid residues. However, the precise relationship between consensus engineering and ancestral protein resurrection is not fully understood. Here, we report the properties of proteins encoded by consensus sequences derived from a multiple sequence alignment of extant, class A β-lactamases, as compared with the properties of ancient Precambrian β-lactamases resurrected in the laboratory. These comparisons considered primary sequence, secondary, and tertiary structure, as well as stability and catalysis against different antibiotics. Out of the three consensus variants generated, one could not be expressed and purified (likely due to misfolding and/or low stability) and only one displayed substantial stability having substrate promiscuity, although to a lower extent than ancient β-lactamases. These results: (i) highlight the phenotypic differences between consensus variants and laboratory resurrections of ancestral proteins; (ii) question interpretations of consensus proteins as phenotypic proxies of ancestral proteins; and (iii) support the notion that ancient proteins provide a robust approach toward the preparation of protein variants having large numbers of mutational changes while possessing unique biomolecular properties. © 2014 Wiley Periodicals, Inc.

  20. MAI-free performance of PMU-OFDM transceiver in time-variant environment

    Science.gov (United States)

    Tadjpour, Layla; Tsai, Shang-Ho; Kuo, C.-C. J.

    2005-06-01

    An approximately multi-user OFDM transceiver was introduced to reduce the multi-access interference (MAI ) due to the carrier frequency offset (CFO) to a negligible amount via precoding by Tsai, Lin and Kuo. In this work, we investigate the performance of this precoded multi-user (PMU) OFDM system in a time-variant channel environment. We analyze and compare the MAI effect caused by time-variant channels in the PMU-OFDM and the OFDMA systems. Generally speaking, the MAI effect consists of two parts. The first part is due to the loss of orthogonality among subchannels for all users while the second part is due to the CFO effect caused by the Doppler shift. Simulation results show that, although OFDMA outperforms the PMU-OFDM transceiver in a fast time-variant environment without CFO, PMU-OFDM outperforms OFDMA in a slow time-variant channel via the use of M/2 symmetric or anti-symmetric codewords of M Hadamard-Walsh codes.

  1. Increased expression of the type IV secretion system in piliated Neisseria gonorrhoeae variants.

    Science.gov (United States)

    Salgado-Pabón, Wilmara; Du, Ying; Hackett, Kathleen T; Lyons, Katelynn M; Arvidson, Cindy Grove; Dillard, Joseph P

    2010-04-01

    Neisseria gonorrhoeae produces a type IV secretion system that secretes chromosomal DNA. The secreted DNA is active in the transformation of other gonococci in the population and may act to transfer antibiotic resistance genes and variant alleles for surface antigens, as well as other genes. We observed that gonococcal variants that produced type IV pili secreted more DNA than variants that were nonpiliated, suggesting that the process may be regulated. Using microarray analysis, we found that a piliated strain showed increased expression of the gene for the putative type IV secretion coupling protein TraD, whereas a nonpiliated variant showed increased expression of genes for transcriptional and translational machinery, consistent with its higher growth rate compared to that of the piliated strain. These results suggested that type IV secretion might be controlled by either traD expression or growth rate. A mutant with a deletion in traD was found to be deficient in DNA secretion. Further mutation and complementation analysis indicated that traD is transcriptionally and translationally coupled to traI, which encodes the type IV secretion relaxase. We were able to increase DNA secretion in a nonpiliated strain by inserting a gene cassette with a strong promoter to drive the expression of the putative operon containing traI and traD. Together, these data suggest a model in which the type IV secretion system apparatus is made constitutively, while its activity is controlled through regulation of traD and traI.

  2. On human disease-causing amino acid variants: statistical study of sequence and structural patterns

    Science.gov (United States)

    Alexov, Emil

    2015-01-01

    Statistical analysis was carried out on large set of naturally occurring human amino acid variations and it was demonstrated that there is a preference for some amino acid substitutions to be associated with diseases. At an amino acid sequence level, it was shown that the disease-causing variants frequently involve drastic changes of amino acid physico-chemical properties of proteins such as charge, hydrophobicity and geometry. Structural analysis of variants involved in diseases and being frequently observed in human population showed similar trends: disease-causing variants tend to cause more changes of hydrogen bond network and salt bridges as compared with harmless amino acid mutations. Analysis of thermodynamics data reported in literature, both experimental and computational, indicated that disease-causing variants tend to destabilize proteins and their interactions, which prompted us to investigate the effects of amino acid mutations on large databases of experimentally measured energy changes in unrelated proteins. Although the experimental datasets were linked neither to diseases nor exclusory to human proteins, the observed trends were the same: amino acid mutations tend to destabilize proteins and their interactions. Having in mind that structural and thermodynamics properties are interrelated, it is pointed out that any large change of any of them is anticipated to cause a disease. PMID:25689729

  3. Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

    Directory of Open Access Journals (Sweden)

    Hellen Houlleberghs

    2017-05-01

    Full Text Available Lynch syndrome (LS is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.

  4. Functional characteristics of the Staphylococcus aureus δ-toxin allelic variant G10S.

    Science.gov (United States)

    Cheung, Gordon Y C; Yeh, Anthony J; Kretschmer, Dorothee; Duong, Anthony C; Tuffuor, Kwame; Fu, Chih-Lung; Joo, Hwang-Soo; Diep, Binh A; Li, Min; Nakamura, Yuumi; Nunez, Gabriel; Peschel, Andreas; Otto, Michael

    2015-12-10

    Staphylococcus aureus δ-toxin is a member of the phenol-soluble modulin (PSM) peptide family. PSMs have multiple functions in staphylococcal pathogenesis; for example, they lyse red and white blood cells and trigger inflammatory responses. Compared to other PSMs, δ-toxin is usually more strongly expressed but has only moderate cytolytic capacities. The amino acid sequences of S. aureus PSMs are well conserved with two exceptions, one of which is the δ-toxin allelic variant G10S. This variant is a characteristic of the subspecies S. argenteus and S. aureus sequence types ST1 and ST59, the latter representing the most frequent cause of community-associated infections in Asia. δ-toxin G10S and strains expressing that variant from plasmids or the genome had significantly reduced cytolytic and pro-inflammatory capacities, including in a strain background with pronounced production of other PSMs. However, in murine infection models, isogenic strains expressing the two δ-toxin variants did not cause measurable differences in disease severity. Our findings indicate that the widespread G10S allelic variation of the δ-toxin locus has a significant impact on key pathogenesis mechanisms, but more potent members of the PSM peptide family may overshadow that impact in vivo.

  5. Multiple loss-of-function variants of taste receptors in modern humans

    Science.gov (United States)

    Fujikura, K.

    2015-01-01

    Despite recent advances in the knowledge of interindividual taste differences, the underlying genetic backgrounds have remained to be fully elucidated. Much of the taste variation among different mammalian species can be explained by pseudogenization of taste receptors. Here I investigated whether the most recent disruptions of taste receptor genes segregate with their intact forms in modern humans by analyzing 14 ethnically diverse populations. The results revealed an unprecedented prevalence of 25 segregating loss-of-function (LoF) taste receptor variants, identifying one of the most pronounced cases of functional population diversity in the human genome. LoF variant frequency in taste receptors (2.10%) was considerably higher than the overall LoF frequency in human genome (0.16%). In particular, molecular evolutionary rates of candidate sour (14.7%) and bitter (1.8%) receptors were far higher in humans than those of sweet (0.02%), salty (0.05%), and umami (0.17%) receptors compared with other carnivorous mammals, although not all of the taste receptors were identified. Many LoF variants are population-specific, some of which arose even after population differentiation, not before divergence of the modern and archaic human. I conclude that modern humans might have been losing some sour and bitter receptor genes because of high-frequency LoF variants. PMID:26307445

  6. The clinical implications of variants of vena cava inferior and aorta on retroperitoneal surgery

    Directory of Open Access Journals (Sweden)

    S. V. Mukhtarulina

    2014-12-01

    Full Text Available Objective: to study variants of retroperitoneal vascular structure and its clinical implications on retroperitoneal surgery in patients with cervical cancer IA–IIB stage.Materials and methods. 101 patients who underwent paraaortic and bilateral pelvic lymphadenectomy were included in this study. 10 patients of the first group with anomalies of inferior vena cava, renal arteries and veins, common iliac vein and ovarian vessels were compared with 91 patients of the second group without anomalies.Results. Variants of major retroperitoneal vascular structure were present in 10 (9.9 % patients. Supernumerary renal arteries and veins observed in 5 (4.9 % patients; retroaortic left renal vein type I and II – in 3 (3.0 % patients. Double vena cava inferior detected in 1 (1.0 % patient. Patients with variants of retroperitoneal vascular structures hadn’t vessel injury. There was no difference in intraoperative hemorrhage, transfusion red blood cell, rate of intraoperative hemoglobin and removed paraaortic lymph nodes between the groups. Risk factors for intraoperative bleeding in patients with cervical cancer, depending on the presence or absence of anomalies of retroperitoneal vessels had no significant difference.Conclusion. Despite the fact that the variants of retroperitoneal vascular structures are rare (9.9 %, the success of retroperitoneal surgery is associated with the knowledge of vascular variations which decrease serious, life-threatening complications.

  7. The clinical implications of variants of vena cava inferior and aorta on retroperitoneal surgery

    Directory of Open Access Journals (Sweden)

    S. V. Mukhtarulina

    2014-01-01

    Full Text Available Objective: to study variants of retroperitoneal vascular structure and its clinical implications on retroperitoneal surgery in patients with cervical cancer IA–IIB stage.Materials and methods. 101 patients who underwent paraaortic and bilateral pelvic lymphadenectomy were included in this study. 10 patients of the first group with anomalies of inferior vena cava, renal arteries and veins, common iliac vein and ovarian vessels were compared with 91 patients of the second group without anomalies.Results. Variants of major retroperitoneal vascular structure were present in 10 (9.9 % patients. Supernumerary renal arteries and veins observed in 5 (4.9 % patients; retroaortic left renal vein type I and II – in 3 (3.0 % patients. Double vena cava inferior detected in 1 (1.0 % patient. Patients with variants of retroperitoneal vascular structures hadn’t vessel injury. There was no difference in intraoperative hemorrhage, transfusion red blood cell, rate of intraoperative hemoglobin and removed paraaortic lymph nodes between the groups. Risk factors for intraoperative bleeding in patients with cervical cancer, depending on the presence or absence of anomalies of retroperitoneal vessels had no significant difference.Conclusion. Despite the fact that the variants of retroperitoneal vascular structures are rare (9.9 %, the success of retroperitoneal surgery is associated with the knowledge of vascular variations which decrease serious, life-threatening complications.

  8. Treatment of spelling variants in Setswana monolingual dictionaries

    African Journals Online (AJOL)

    user

    Abstract: This paper argues that the Setswana language is characterised by spelling variants which are a consequence of ... be pronunciation variants, as those found, for instance, in words such as data. (deɪtə or dɑ:tə), ...... idiom is "an independent lexical item having an opaque meaning" (Svensén. 2009: 194). Treatment ...

  9. Growth differentiation factor 9 gene variants in Sudanese desert ...

    African Journals Online (AJOL)

    Certain variants in the growth differentiation factor 9 (GDF9) gene have major effects on the ovulation rate in sheep. The aim of this study was to analyse GDF9 variability in the Sudanese desert sheep ecotypes Ashgar, Dubasi and Watish, and to test identified variants for association with litter size. For this purpose, ewes of ...

  10. Association analysis identifies ZNF750 regulatory variants in psoriasis

    Directory of Open Access Journals (Sweden)

    Birnbaum Ramon Y

    2011-12-01

    Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

  11. Exact solutions for nonlinear variants of Kadomtsev–Petviashvili (n ...

    Indian Academy of Sciences (India)

    Exact solutions for nonlinear variants of Kadomtsev–Petviashvili (, ) equation using functional variable method. M Mirzazadeh M Eslami. Volume 81 Issue ... The functional variable method is used to establish compactons, solitons, solitary patterns and periodic solutions for these variants. This method is a powerful tool for ...

  12. Prevalence of haemoglobin variants among the Ika ethnic nationality ...

    African Journals Online (AJOL)

    Background: Haemoglobin genotype is an important blood component that determines haemoglobinopathies. Distribution of haemoglobin variants was investigated among the Ika ethnic nationality of Delta State, Nigeria. Aim: The resent study was conducted to determine the prevalence of haemoglobin variants and also to ...

  13. Genetic polymorphism of milk protein variants and their association ...

    African Journals Online (AJOL)

    To the best of our knowledge, this is the first detailed study involving frequency distribution of genetic variants and their effects on milk yield in Bos indicus Sahiwal cattle of Pakistan. Keywords: Genetic variant, milk protein genes, Sahiwal cattle. African Journal of Biotechnology, Vol. 13(4), pp. 555-565, 22 January, 2014 ...

  14. Managing Process Variants in the Process Life Cycle

    NARCIS (Netherlands)

    Hallerbach, A.; Bauer, Th.; Reichert, M.U.

    2007-01-01

    When designing process-aware information systems, often variants of the same process have to be specified. Each variant then constitutes an adjustment of a particular process to specific requirements building the process context. Current Business Process Management (BPM) tools do not adequately

  15. Isolation and characterization of human rhinovirus antigenic variants

    Energy Technology Data Exchange (ETDEWEB)

    Watson, D.G.

    1985-01-01

    Isolation of antigenic variants of human rhinovirus types 2, 14, and 17 was attempted by plaquing untreated virus (P-isolates), selecting variants in the presence of homologous antiserum (C-isolates), and by selecting variants in the presence of antibody following 5-fluorouracil mutagenesis (M-isolates). All viruses were triple-plaque purified and purity neutralization tested prior to isolate selection. Based on a fourfold reduction in neutralizing antibody titer to homologous antiserum, no antigenic variation was found in P-isolates from the three serotypes examined. Antigenic variants of all three serotypes could be isolated by the antiserum selection method (C-isolates). However, antigenic variants of RV17 were isolated at a much higher frequency and showed a larger degree of variation than those of RV2 and RV14. At least two of the variants selected, RV17 (C301) and RV2 (M803), failed to be neutralized by the known 89 rhinovirus antiserum. SDS-polyacrylamide gel electrophoresis of (/sup 35/S) methionine-labelled virion polypeptides revealed that each serotype had a characteristic pattern and that selected RV2 and RV17 isolates had patterns identical to those of the prototype strains. By isoelectric focusing an antigenic variant of RV2 was shown to contain altered virion polypeptides VP1 and VP2 whereas two RV17 antigenic variants demonstrated alterations only in the VP1 polypeptide.

  16. Copy number variants in patients with short stature

    NARCIS (Netherlands)

    Duyvenvoorde, H.A. van; Lui, J.C.; Kant, S.G.; Oostdijk, W.; Gijsbers, A.C.; Hoffer, M.J.V.; Karperien, M.; Walenkamp, M.J.; Noordam, C.; Voorhoeve, P.G.; Mericq, V.; Pereira, A.M.; Claahsen-van der Grinten, H.L.; Gool, S.A. van; Breuning, M.H.; Losekoot, M.; Baron, J.; Ruivenkamp, C.A.; Wit, J.M.

    2014-01-01

    Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals

  17. Hepatitis E Virus Variant in Farmed Mink, Denmark

    DEFF Research Database (Denmark)

    Krog, Jesper Schak; Breum, Solvej Østergaard; Jensen, Trine Hammer

    2013-01-01

    Hepatitis E virus (HEV) is a zoonotic virus for which pigs are the primary animal reservoir. To investigate whether HEV occurs in mink in Denmark, we screened feces and tissues from domestic and wild mink. Our finding of a novel HEV variant supports previous findings of HEV variants in a variety...

  18. Treatment of Spelling Variants in Setswana Monolingual Dictionaries

    African Journals Online (AJOL)

    This paper argues that the Setswana language is characterised by spelling variants which are a consequence of multiple factors. It considers spelling variants found amongst individual words as well as those found in multi-word expressions (MWEs). It argues that spelling variation may be a result of historical fissions and ...

  19. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    2008-01-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  20. Phenotypes and genotypes in individuals with SMC1A variants

    DEFF Research Database (Denmark)

    Huisman, Sylvia; Mulder, Paul A; Redeker, Egbert

    2017-01-01

    SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an ...

  1. Expression and secretion of defined cutinase variants by Aspergillus awamori

    NARCIS (Netherlands)

    Gemeren, I.A. van; Beijersbergen, A.; Hondel, C.A.M.J.J. van den; Verrips, C.T.

    1998-01-01

    Several cutinase variants derived by molecular modelling and site- directed mutagenesis of a cutinase gene from Fusarium solani pisi are poorly secreted by Saccharomyces cerevisiae. The majority of these variants are successfully produced by the filamentous fungus Aspergillus awamori. However, the

  2. Variant Anatomy of the External Jugular Vein | Olabu | Anatomy ...

    African Journals Online (AJOL)

    Variant anatomy of the external jugular vein is important when performing invasive procedures in the neck. Although there are a number of case reports on some of these variations, there are few descriptive cross-sectional regarding the same. This study therefore aimed at describing the variant anatomy of the external ...

  3. -116A and K BCHE gene variants associated with obesity and hypertriglyceridemia in adolescents from Southern Brazil.

    Science.gov (United States)

    Chaves, Thaís Jannuzzi; Leite, Neiva; Milano, Gerusa Eisfeld; Milano, Gisele Eisfeld; Souza, Ricardo Lehtonen Rodrigues; Chautard-Freire-Maia, Eleidi Alice; Furtado-Alle, Lupe

    2013-03-25

    Butyrylcholinesterase (BChE) has been associated to body mass index (BMI), weight, cholesterol and triglyceride levels. -116A (rs1126680) and K (A539T, 1615A, rs1803274) BCHE gene variants had previously been associated to BChE activity, weight and BMI variance in adults. The present study examined -116A and K variants, BChE activity, anthropometric and biochemical variables associated with obesity in adolescents (120 obese and 150 non-obese from Curitiba, Brazil). Both -116A and K variants were found with significantly lower frequencies (pobese adolescents when compared with non-obese adolescents and with the general population. Mean BChE activity (KU/L) was significantly higher in obese adolescents when compared with non-obese adolescents and with the general population. Analyzing only the obese adolescents, it was found that carriers of the -116A variant showed lower BChE activity and higher triglyceride levels than homozygotes for the usual allele. Indeed, obese carriers of the -116A variant had triglyceride levels considered high according to reference values for serum triglycerides in Brazilian adolescents. These results show: (1) a protective effect of -116A and K variants on juvenile obesity risk, suggesting a role for the BCHE gene on juvenile onset obesity different from that observed on adult onset obesity and (2) an association of the -116A variant with hypertriglyceridemia in obese adolescents probably because of its effect on lowering BChE activity and consequently diminishing the enzyme capability of maintaining homeostasis on lipid metabolism during the metabolic stress caused by obesity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  4. Correlation between leukoaraiosis volume and circle of Willis variants.

    Science.gov (United States)

    Saba, Luca; Raz, Eytan; Fatterpekar, Girish; Montisci, Roberto; di Martino, Michele; Bassareo, Pier Paolo; Piga, Mario

    2015-01-01

    The Circle of Willis (COW) is the main collateral system between the bilateral carotid systems and the posterior circulation. COW normal variants are encountered in up to 62% of subjects. We hypothesize that, in patients with carotid artery stenosis, the presence of COW variants is a risk factor for leukoaraiosis. Forty-seven patients (mean age 72.1 ± 9 years, males = 39) with carotid artery stenosis admitted for carotid endarterectomy were included and underwent an admission brain MRI/MRA. Two neuroradiologists evaluated the COW variants. FLAIR-leukoaraiosis lesion-volume was performed using a semiautomated segmentation technique. Mann-Whitney and Pearson correlations were conducted to identify the correlation between the FLAIR-leukoaraiosis lesion-volume and the COW variants. ROC analysis was performed to evaluate the AUC of FLAIR-leukoaraiosis lesion-volume and presence/absence of COW variants. Pearson correlation demonstrated that the leukoaraiosis lesion-volume is significantly associated with the COW variants number (rho = .358, P = .0215). When patients were dicotomized in two subgroups, with and without COW variants, the lesion-volume was significantly higher in the variants group (P = .0405). The ROC curve analysis showed an AUC of .688 (SE = .083, 95%CI = .525-.823) with a statistically significant P = .0225, between the presence of COW variants and the FLAIR-leukoaraiosis lesion-volume. The presence and the number of COW variants are associated with a higher leukoaraiosis volume in patients with significant internal carotid artery stenosis. Copyright © 2014 by the American Society of Neuroimaging.

  5. Bayesian detection of causal rare variants under posterior consistency.

    KAUST Repository

    Liang, Faming

    2013-07-26

    Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  6. Treatment and survival of patients harboring histological variants of glioblastoma.

    Science.gov (United States)

    Ortega, Alicia; Nuño, Miriam; Walia, Sartaaj; Mukherjee, Debraj; Black, Keith L; Patil, Chirag G

    2014-10-01

    It is unclear whether the survival difference observed between glioblastoma (GBM), giant cell glioblastoma (gcGBM), and gliosarcoma (GSM) patients is due to differences in tumor histology, patient demographics, and/or treatment regimens. The USA National Cancer Database was utilized to evaluate patients diagnosed with GBM, gcGBM, and GSM between 1998 and 2011. Kaplan-Meier survival estimates and Cox proportional hazards models were utilized to estimate overall survival. A cohort of 69,935 patients was analyzed; 67,509 (96.5%) of these patients had GBM, 592 (0.9%) gcGBM, and 1834 (2.6%) GSM. The median age for GBM and GSM patients was 61 versus 56 years for gcGBM (p<0.0001). Higher extent of resection (p<0.0001) and radiation (p=0.001) were observed in gcGBM patients compared to other histologies. Multivariate analysis showed that gcGBM patients had a 20% reduction in the hazards of mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.93) compared to GBM, while GSM patients trended towards higher hazards of mortality (HR 1.04, 95% CI 0.96-1.12) than the GBM cohort. Previous studies have suggested a disparity in the survival of patients with GBM tumors and their histological variants. Using a large cohort of patients treated at hospitals nationwide, this study found a 20% reduction in the hazards of mortality in gcGBM patients compared to GBM. Similarly, gcGBM patients had a 24% reduction in the hazards of mortality compared to the GSM cohort. GSM patients had a 3% increase in the hazards of mortality compared to GBM. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. HIV-1 genetic variants in Kyrgyzstan

    Directory of Open Access Journals (Sweden)

    V Laga

    2012-11-01

    Full Text Available Objectives: During the last two decades, HIV-1 has been spreading rapidly in former Soviet Union republics including Kyrgyzstan. The current molecular monitoring of HIV-infection epidemic is carried out in Russia only with no or limited data from the other FSU countries. The aim of this work was to investigate the prevalence of HIV-1 genetic variants circulating in Kyrgyzstan. Methods: Blood collection from the HIV-infected patients was carried out by local specialists with the informed consent and the questionnaire was answered by each of the patients. The total number of samples was 100. The washed cell pellets were transferred to Moscow following with proviral DNA extraction, PCR amplification and gag, pol and env genes sequencing. The phylogenetic analysis of nucleotide sequences using neighbor-joining method was carried out by MEGA 3 program. The preliminary data were obtained in 22 samples isolated from PBMC of HIV-infected patients from Kyrgyzstan. Results: Among the samples studied 6 (27.3% samples belonged to a subtype CRF02_AG, 16 samples - to subtype A (A1. One of the samples belonging to CRF02_AG, probably, is a recombinant between CRF02_AG and A1. There was no major drug resistance mutations in the samples studied. The minor mutations were presented in small proportions: 1 in PR (L10I, 6 in RT (A62V - in 3 samples, V108G, E138A, Y181F, M184I, L210M - on one sample and 1 in IN (L74M. It was impossible to associate the distribution of mutations with HIV-1 genetic variant. The V3 loop (env gene in 17 samples was analyzed for tropism using geno2pheno program; all samples were found to be R5-viruses. Conclusion: The HIV-1 subtype A seems to dominate in Kyrgyzstan like in other FSU countries. The recombinant CRF02_AG epidemiologically linked to Uzbekistan is quite widespread. The rest of Kyrgyzstan collection is under investigation and the data will be refined soon.

  8. Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy.

    Science.gov (United States)

    Leon Rodriguez, Daniel A; Acosta-Herrera, Marialbert; Carmona, F David; Dolade, Nuria; Vargas, Sofia; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2018-01-01

    Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy.

  9. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism

    Science.gov (United States)

    Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya

    2017-01-01

    We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5’-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5’-splice site of the first intron of the canine OCA2 gene. PMID:28973042

  10. A de novo variant in the ASPRV1 gene in a dog with ichthyosis

    Science.gov (United States)

    Bauer, Anina; Galichet, Arnaud; Jagannathan, Vidhya; Sayar, Beyza S.; Wiener, Dominique J.; Müller, Eliane J.; Roosje, Petra; Welle, Monika M.

    2017-01-01

    Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding “aspartic peptidase, retroviral-like 1”, which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses. PMID:28249031

  11. A de novo variant in the ASPRV1 gene in a dog with ichthyosis.

    Directory of Open Access Journals (Sweden)

    Anina Bauer

    2017-03-01

    Full Text Available Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase. The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro. ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.

  12. A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

    Directory of Open Access Journals (Sweden)

    Mirjam Frischknecht

    Full Text Available The identification of quantitative trait loci (QTL such as height and their underlying causative variants is still challenging and often requires large sample sizes. In humans hundreds of loci with small effects control the heritable portion of height variability. In domestic animals, typically only a few loci with comparatively large effects explain a major fraction of the heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS using a small cohort of only 48 animals and the Illumina equine SNP70 BeadChip. Fine-mapping revealed a shared haplotype block of 793 kb in small Shetland ponies. The HMGA2 gene, known to be associated with height in horses and many other species, was located in the associated haplotype. After closing a gap in the equine reference genome we identified a non-synonymous variant in the first exon of HMGA2 in small Shetland ponies. The variant was predicted to affect the functionally important first AT-hook DNA binding domain of the HMGA2 protein (c.83G>A; p.G28E. We assessed the functional impact and found impaired DNA binding of a peptide with the mutant sequence in an electrophoretic mobility shift assay. This suggests that the HMGA2 variant also affects DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. The identified HMGA2 variant also segregates in several other pony breeds but was not found in regular-sized horse breeds. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.

  13. Halvade-RNA: Parallel variant calling from transcriptomic data using MapReduce.

    Science.gov (United States)

    Decap, Dries; Reumers, Joke; Herzeel, Charlotte; Costanza, Pascal; Fostier, Jan

    2017-01-01

    Given the current cost-effectiveness of next-generation sequencing, the amount of DNA-seq and RNA-seq data generated is ever increasing. One of the primary objectives of NGS experiments is calling genetic variants. While highly accurate, most variant calling pipelines are not optimized to run efficiently on large data sets. However, as variant calling in genomic data has become common practice, several methods have been proposed to reduce runtime for DNA-seq analysis through the use of parallel computing. Determining the effectively expressed variants from transcriptomics (RNA-seq) data has only recently become possible, and as such does not yet benefit from efficiently parallelized workflows. We introduce Halvade-RNA, a parallel, multi-node RNA-seq variant calling pipeline based on the GATK Best Practices recommendations. Halvade-RNA makes use of the MapReduce programming model to create and manage parallel data streams on which multiple instances of existing tools such as STAR and GATK operate concurrently. Whereas the single-threaded processing of a typical RNA-seq sample requires ∼28h, Halvade-RNA reduces this runtime to ∼2h using a small cluster with two 20-core machines. Even on a single, multi-core workstation, Halvade-RNA can significantly reduce runtime compared to using multi-threading, thus providing for a more cost-effective processing of RNA-seq data. Halvade-RNA is written in Java and uses the Hadoop MapReduce 2.0 API. It supports a wide range of distributions of Hadoop, including Cloudera and Amazon EMR.

  14. Altered Proteome of Burkholderia pseudomallei Colony Variants Induced by Exposure to Human Lung Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Anis Rageh Al-Maleki

    Full Text Available Burkholderia pseudomallei primary diagnostic cultures demonstrate colony morphology variation associated with expression of virulence and adaptation proteins. This study aims to examine the ability of B. pseudomallei colony variants (wild type [WT] and small colony variant [SCV] to survive and replicate intracellularly in A549 cells and to identify the alterations in the protein expression of these variants, post-exposure to the A549 cells. Intracellular survival and cytotoxicity assays were performed followed by proteomics analysis using two-dimensional gel electrophoresis. B. pseudomallei SCV survive longer than the WT. During post-exposure, among 259 and 260 protein spots of SCV and WT, respectively, 19 were differentially expressed. Among SCV post-exposure up-regulated proteins, glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase (CbbA and betaine aldehyde dehydrogenase were associated with adhesion and virulence. Among the down-regulated proteins, enolase (Eno is implicated in adhesion and virulence. Additionally, post-exposure expression profiles of both variants were compared with pre-exposure. In WT pre- vs post-exposure, 36 proteins were differentially expressed. Of the up-regulated proteins, translocator protein, Eno, nucleoside diphosphate kinase (Ndk, ferritin Dps-family DNA binding protein and peptidyl-prolyl cis-trans isomerase B were implicated in invasion and virulence. In SCV pre- vs post-exposure, 27 proteins were differentially expressed. Among the up-regulated proteins, flagellin, Eno, CbbA, Ndk and phenylacetate-coenzyme A ligase have similarly been implicated in adhesion, invasion. Protein profiles differences post-exposure provide insights into association between morphotypic and phenotypic characteristics of colony variants, strengthening the role of B. pseudomallei morphotypes in pathogenesis of melioidosis.

  15. Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations.

    Science.gov (United States)

    Sun, Jielin; Chang, Bao-Li; Isaacs, Sarah D; Wiley, Kathleen E; Wiklund, Fredrik; Stattin, Pär; Duggan, David; Carpten, John D; Trock, Bruce J; Partin, Alan W; Walsh, Patrick C; Grönberg, Henrik; Xu, Jianfeng; Isaacs, William B; Zheng, S Lilly

    2008-09-01

    A strong cumulative effect of five genetic variants and family history on prostate cancer risk was recently reported in a Swedish population (CAPS). We carried out this study to confirm the finding in two U.S. study populations and perform a combined analysis to obtain a more stable estimate of the odds ratio (OR) for prostate cancer. We evaluated three SNPs at 8q24 and one SNP each at 17q12 and 17q24.3 in two study populations in the U.S. The first was a hospital-based case-control study population at Johns Hopkins Hospital (JHH), including 1,563 prostate cancer patients and 576 control subjects. The second was the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, including 1,172 prostate cancer patients and 1,157 control subjects. We confirmed a cumulative effect of five risk variants on prostate cancer risk. Based on a total of 5,628 cases and 3,514 controls from JHH, CGEMS, and CAPS, men who carry any combination of 1, 2, 3, and 4 or more of these five risk variants have an estimated OR (95% CI) of 1.41 (1.20-1.67), 1.88 (1.59-2.22), 2.36 (1.95-2.85), and 3.80 (2.77-5.22) for prostate cancer, respectively, compared to men who do not have any of these five risk variants. When family history was included, the cumulative effect was stronger. These results provide an important confirmation for the cumulative effect of five genetic risk variants on prostate cancer risk. The more stable OR estimates of the cumulative effect of these six risk factors are a major step toward individual risk characterization for this disease. (c) 2008 Wiley-Liss, Inc.

  16. Effects of CYP2C19 variants on methadone metabolism in vitro.

    Science.gov (United States)

    Lan, Tian; Yuan, Ling-Jing; Hu, Xiao-Xia; Zhou, Quan; Wang, Jun; Huang, Xiang-Xin; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin

    2017-04-01

    CYP2C19 is an important member of the cytochrome P450 (CYP450) enzyme super family and is responsible for clearing approximately 10% of commonly used clinical drugs that undergo phase I metabolism. Genetic polymorphisms of CYP2C19 significantly influence the efficacy and safety of some drugs, which might cause undesirable adverse effects or cure failure at standard dosages. The aim of this study was to clarify the catalytic activities of 31 CYP2C19 alleles on the oxidative in vitro metabolism of methadone. Insect microsomes expressing the CYP2C19 alleles were incubated with 50-2000 μM methadone for 30 min at 37 °C and terminated by cooling to -80 °C immediately. Methadone and its metabolite EDDP were analyzed by an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system. Of the 31 tested CYP2C19 allelies variants, CYP2C19*1 is the wild-type. Compared with CYP2C19*1, two CYP2C19 variants (CYP2C19*3 and *35FS) had no detectable enzyme activity, one variant L16F exhibited slightly increased intrinsic clearance values, and one variant N277K showed no significant difference. In addition, 26 variants exhibited significantly decreased values (from 1.48% to 80.40%). These findings suggest that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2C19 alleles. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Directory of Open Access Journals (Sweden)

    Esther Erdei

    Full Text Available A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR.Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia, or oral squamous cell carcinoma (SCCA were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption.Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70. The transforming growth factor beta-1 (TGFβ-1 -509 C/T polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79. The matrix metalloproteinase gene (MMP-1 variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53 compared to people with ancestral alleles.Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  18. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Science.gov (United States)

    Erdei, Esther; Luo, Li; Sheng, Huiping; Maestas, Erika; White, Kirsten A M; Mackey, Amanda; Dong, Yan; Berwick, Marianne; Morse, Douglas E

    2013-01-01

    A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR). Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia), or oral squamous cell carcinoma (SCCA) were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs) were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption. Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α) -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70). The transforming growth factor beta-1 (TGFβ-1 -509 C/T) polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79). The matrix metalloproteinase gene (MMP-1) variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53) compared to people with ancestral alleles. Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  19. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

    Directory of Open Access Journals (Sweden)

    Madleina Caduff

    Full Text Available We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G. The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5'-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1. Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2 in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5'-splice site of the first intron of the canine OCA2 gene.

  20. A de novo variant in the ASPRV1 gene in a dog with ichthyosis.

    Science.gov (United States)

    Bauer, Anina; Waluk, Dominik P; Galichet, Arnaud; Timm, Katrin; Jagannathan, Vidhya; Sayar, Beyza S; Wiener, Dominique J; Dietschi, Elisabeth; Müller, Eliane J; Roosje, Petra; Welle, Monika M; Leeb, Tosso

    2017-03-01

    Ichthyoses are a heterogeneous group of inherited cornification disorders characterized by generalized dry skin, scaling and/or hyperkeratosis. Ichthyosis vulgaris is the most common form of ichthyosis in humans and caused by genetic variants in the FLG gene encoding filaggrin. Filaggrin is a key player in the formation of the stratum corneum, the uppermost layer of the epidermis and therefore crucial for barrier function. During terminal differentiation of keratinocytes, the precursor profilaggrin is cleaved by several proteases into filaggrin monomers and eventually processed into free amino acids contributing to the hydration of the cornified layer. We studied a German Shepherd dog with a novel form of ichthyosis. Comparing the genome sequence of the affected dog with 288 genomes from genetically diverse non-affected dogs we identified a private heterozygous variant in the ASPRV1 gene encoding "aspartic peptidase, retroviral-like 1", which is also known as skin aspartic protease (SASPase). The variant was absent in both parents and therefore due to a de novo mutation event. It was a missense variant, c.1052T>C, affecting a conserved residue close to an autoprocessing cleavage site, p.(Leu351Pro). ASPRV1 encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. By immunofluorescence staining we showed that the filaggrin expression pattern was altered in the affected dog. Thus, our findings provide strong evidence that the identified de novo variant is causative for the ichthyosis in the affected dog and that ASPRV1 plays an essential role in skin barrier formation. ASPRV1 is thus a novel candidate gene for unexplained human forms of ichthyoses.

  1. A Non-Synonymous HMGA2 Variant Decreases Height in Shetland Ponies and Other Small Horses.

    Science.gov (United States)

    Frischknecht, Mirjam; Jagannathan, Vidhya; Plattet, Philippe; Neuditschko, Markus; Signer-Hasler, Heidi; Bachmann, Iris; Pacholewska, Alicja; Drögemüller, Cord; Dietschi, Elisabeth; Flury, Christine; Rieder, Stefan; Leeb, Tosso

    2015-01-01

    The identification of quantitative trait loci (QTL) such as height and their underlying causative variants is still challenging and often requires large sample sizes. In humans hundreds of loci with small effects control the heritable portion of height variability. In domestic animals, typically only a few loci with comparatively large effects explain a major fraction of the heritability. We investigated height at withers in Shetland ponies and mapped a QTL to ECA 6 by genome-wide association (GWAS) using a small cohort of only 48 animals and the Illumina equine SNP70 BeadChip. Fine-mapping revealed a shared haplotype block of 793 kb in small Shetland ponies. The HMGA2 gene, known to be associated with height in horses and many other species, was located in the associated haplotype. After closing a gap in the equine reference genome we identified a non-synonymous variant in the first exon of HMGA2 in small Shetland ponies. The variant was predicted to affect the functionally important first AT-hook DNA binding domain of the HMGA2 protein (c.83G>A; p.G28E). We assessed the functional impact and found impaired DNA binding of a peptide with the mutant sequence in an electrophoretic mobility shift assay. This suggests that the HMGA2 variant also affects DNA binding in vivo and thus leads to reduced growth and a smaller stature in Shetland ponies. The identified HMGA2 variant also segregates in several other pony breeds but was not found in regular-sized horse breeds. We therefore conclude that we identified a quantitative trait nucleotide for height in horses.

  2. Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds.

    Science.gov (United States)

    Webster, Matthew T; Kamgari, Nona; Perloski, Michele; Hoeppner, Marc P; Axelsson, Erik; Hedhammar, Åke; Pielberg, Gerli; Lindblad-Toh, Kerstin

    2015-06-23

    The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

  3. Venous variants and anomalies on routine abdominal multi-detector row CT

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    Koc, Zafer [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)]. E-mail: koczafer@gmail.com; Ulusan, Serife [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Oguzkurt, Levent [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Tokmak, Naime [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)

    2007-02-15

    Objective: This study aims to determine the types and prevalence rates of anatomic variations of the hepatic veins, portal vein, inferior vena cava and renal veins, and to establish statistical correlations between various anomalies and frequency differences between male and female using multi-detector row computed tomography (CT). Materials and methods: One thousand one hundred and twenty patients (588 men, 532 women) were evaluated with routine abdominal CT. Frequencies of different variants were noted and compared, and correlations between three categories of variation were tested. Results: In total, 1261 abdominal vein variants and anomalies were identified in 756 (67.5%) of 1120 patients. Six hundred and forty-two hepatic vein variants were detected in 468 (41.8%) patients. One or more inferior right hepatic veins were identified in 356 (31.8%) individuals, and tributary hepatic veins were detected in 147 (13.1%) patients. Portal vein variations and anomalies were observed in 307 (27.4%) cases. The most frequent of these was trifurcation (139 patients, 12.4%). A total of 311 inferior vena cava and renal vein variants were identified in 258 (23%) cases. Six patients (0.5%) exhibited inferior vena cava anomalies, 62 (5.5%) had circumaortic renal veins, 53 (4.7%) had retroaortic renal veins, and 210 (18.8%) had multiple renal veins. Conclusion: The prevalence of abdominal vein variations is high, and routine abdominal CT demonstrates these abnormalities very well. The data suggest that hepatic vein variants and multiple right renal veins are more frequent in women than in men, and that hepatic vein variation is correlated with portal vein variation.

  4. OCA2 splice site variant in German Spitz dogs with oculocutaneous albinism.

    Science.gov (United States)

    Caduff, Madleina; Bauer, Anina; Jagannathan, Vidhya; Leeb, Tosso

    2017-01-01

    We investigated a German Spitz family where the mating of a black male to a white female had yielded three puppies with an unexpected light brown coat color, lightly pigmented lips and noses, and blue eyes. Combined linkage and homozygosity analysis based on a fully penetrant monogenic autosomal recessive mode of inheritance identified a critical interval of 15 Mb on chromosome 3. We obtained whole genome sequence data from one affected dog, three wolves, and 188 control dogs. Filtering for private variants revealed a single variant with predicted high impact in the critical interval in LOC100855460 (XM_005618224.1:c.377+2T>G LT844587.1:c.-45+2T>G). The variant perfectly co-segregated with the phenotype in the family. We genotyped 181 control dogs with normal pigmentation from diverse breeds including 22 unrelated German Spitz dogs, which were all homozygous wildtype. Comparative sequence analyses revealed that LOC100855460 actually represents the 5'-end of the canine OCA2 gene. The CanFam 3.1 reference genome assembly is incorrect and separates the first two exons from the remaining exons of the OCA2 gene. We amplified a canine OCA2 cDNA fragment by RT-PCR and determined the correct full-length mRNA sequence (LT844587.1). Variants in the OCA2 gene cause oculocutaneous albinism type 2 (OCA2) in humans, pink-eyed dilution in mice, and similar phenotypes in corn snakes, medaka and Mexican cave tetra fish. We therefore conclude that the observed oculocutaneous albinism in German Spitz is most likely caused by the identified variant in the 5'-splice site of the first intron of the canine OCA2 gene.

  5. Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder.

    Science.gov (United States)

    Tang, Ruqi; Noh, Hyun Ji; Wang, Dongqing; Sigurdsson, Snaevar; Swofford, Ross; Perloski, Michele; Duxbury, Margaret; Patterson, Edward E; Albright, Julie; Castelhano, Marta; Auton, Adam; Boyko, Adam R; Feng, Guoping; Lindblad-Toh, Kerstin; Karlsson, Elinor K

    2014-03-14

    Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.

  6. Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

    Directory of Open Access Journals (Sweden)

    Lorelei D. Shoemaker

    2016-01-01

    Full Text Available Moyamoya disease (MMD is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10–12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K in Asian cases (P = 6.01×10−5 that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10−4 and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10−4 and non-RNF213 founder mutation (P = 1.51×10−3 cases was ZXDC (p.P562L, a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10−4 and non-RNF213 founder mutation cases (P = 5.31×10−5. These findings further support the East Asian origins of the RNF213 (p.R4810K variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.

  7. SeqArray-a storage-efficient high-performance data format for WGS variant calls.

    Science.gov (United States)

    Zheng, Xiuwen; Gogarten, Stephanie M; Lawrence, Michael; Stilp, Adrienne; Conomos, Matthew P; Weir, Bruce S; Laurie, Cathy; Levine, David

    2017-08-01

    Whole-genome sequencing (WGS) data are being generated at an unprecedented rate. Analysis of WGS data requires a flexible data format to store the different types of DNA variation. Variant call format (VCF) is a general text-based format developed to store variant genotypes and their annotations. However, VCF files are large and data retrieval is relatively slow. Here we introduce a new WGS variant data format implemented in the R/Bioconductor package 'SeqArray' for storing variant calls in an array-oriented manner which provides the same capabilities as VCF, but with multiple high compression options and data access using high-performance parallel computing. Benchmarks using 1000 Genomes Phase 3 data show file sizes are 14.0 Gb (VCF), 12.3 Gb (BCF, binary VCF), 3.5 Gb (BGT) and 2.6 Gb (SeqArray) respectively. Reading genotypes in the SeqArray package are two to three times faster compared with the htslib C library using BCF files. For the allele frequency calculation, the implementation in the SeqArray package is over 5 times faster than PLINK v1.9 with VCF and BCF files, and over 16 times faster than vcftools. When used in conjunction with R/Bioconductor packages, the SeqArray package provides users a flexible, feature-rich, high-performance programming environment for analysis of WGS variant data. http://www.bioconductor.org/packages/SeqArray. zhengx@u.washington.edu. Supplementary data are available at Bioinformatics online.

  8. Identification of a novel functional deletion variant in the 5'-UTR of the DJ-1 gene

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    Warnich Louise

    2009-10-01

    Full Text Available Abstract Background DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD. Various mutations in the DJ-1 (PARK7 gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in DJ-1 and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient. Methods The possible effect of the deletion on promoter activity was investigated using a Dual-Luciferase Reporter assay. The DJ-1 5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (in silico cis-regulatory analysis of DJ-1 promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH™ and rVISTA platforms. Results A novel 16 bp deletion variant (g.-6_+10del was identified in DJ-1 which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2-M17 cells compared to the wild-type (P Conclusion This is the first report of a functional DJ-1 promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the DJ-1 promoter and whether this variant confers a risk for PD.

  9. TRPM4 non-selective cation channel variants in long QT syndrome.

    Science.gov (United States)

    Hof, Thomas; Liu, Hui; Sallé, Laurent; Schott, Jean-Jacques; Ducreux, Corinne; Millat, Gilles; Chevalier, Philippe; Probst, Vincent; Guinamard, Romain; Bouvagnet, Patrice

    2017-03-18

    Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4). Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current. This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4-/- mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.

  10. Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

    Science.gov (United States)

    Shoemaker, Lorelei D.; Clark, Michael J.; Patwardhan, Anil; Chandratillake, Gemma; Garcia, Sarah; Chen, Rong; Morgan, Alexander A.; Leng, Nan; Kirk, Scott; Chen, Richard; Cook, Douglas J.; Snyder, Michael; Steinberg, Gary K.

    2015-01-01

    Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10–12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10−5) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10−4) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10−4) and non-RNF213 founder mutation (P = 1.51×10−3) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10−4) and non-RNF213 founder mutation cases (P = 5.31×10−5). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis. PMID:26530418

  11. Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq

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    Al-Musawi Bassam MS

    2012-03-01

    Full Text Available Abstract Background Although G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent. Methods A total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT, with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP for four deficient molecular variants, namely G6PD Mediterranean (563 C→T, Chatham (1003 G→A, A- (202 G→A and Aures (143 T→C. A subset of those with the Mediterranean variant, were further investigated for the 1311 (C→T silent mutation. Results G6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%. Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%, G6PD Chatham in 5 cases (5.0%, G6PD A- in two cases (2.0%, and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%. Conclusions Three polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to other Asian Arab countries, neighboring Turkey and Iran.

  12. Effect of Two Lipoprotein (a-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis

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    Hong Wang

    2016-11-01

    Full Text Available Two genetic variants (rs3798220 and rs10455872 in the apolipoprotein (a gene (LPA have been implicated in cardiovascular disease (CVD, presumably through their association with lipoprotein (a [Lp(a] levels. While Lp(a is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a-associated genetic variants are also associated with markers of thrombosis (i.e., plasminogen levels and fibrinolysis. In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA and recruited 146 subjects according to the carrier and noncarrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a were 2.62- and 1.73-fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with noncarriers (P = 2.04 × 10−17 and P = 1.64 × 10−6, respectively. By contrast, there was no difference in plasminogen concentrations between carriers and noncarriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and noncarriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis.

  13. Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia.

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    Dimitra Georgiadou

    Full Text Available Apolipoprotein E (apoE is a major protein of the lipoprotein transport system that plays important roles in lipid homeostasis and protection from atherosclerosis. ApoE is characterized by structural plasticity and thermodynamic instability and can undergo significant structural rearrangements as part of its biological function. Mutations in the 136-150 region of the N-terminal domain of apoE, reduce its low density lipoprotein (LDL receptor binding capacity and have been linked with lipoprotein disorders, such as type III hyperlipoproteinemia (HLP in humans. However, the LDL-receptor binding defects for these apoE variants do not correlate well with the severity of dyslipidemia, indicating that these variants may carry additional properties that contribute to their pathogenic potential.In this study we examined whether three type III HLP predisposing apoE3 variants, namely R136S, R145C and K146E affect the biophysical properties of the protein. Circular dichroism (CD spectroscopy revealed that these mutations do not significantly alter the secondary structure of the protein. Thermal and chemical unfolding analysis revealed small thermodynamic alterations in each variant compared to wild-type apoE3, as well as effects in the reversibility of the unfolding transition. All variants were able to remodel multillamelar 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC vesicles, but R136S and R145C had reduced kinetics. Dynamic light scattering analysis indicated that the variant R136S exists in a higher-order oligomerization state in solution. Finally, 1-anilinonaphthalene-8-sulfonic acid (ANS binding suggested that the variant R145C exposes a larger amount of hydrophobic surface to the solvent.Overall, our findings suggest that single amino acid changes in the functionally important region 136-150 of apoE3 can affect the molecule's stability and conformation in solution and may underlie functional consequences. However, the magnitude and the non

  14. High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.

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    Mitja I Kurki

    2014-01-01

    Full Text Available 3% of the population develops saccular intracranial aneurysms (sIAs, a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA, and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6 were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9; 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8; 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11 and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9. Two of the associations (5q31.3, 6q24.2 replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6% than in the Netherlands (0.3%. Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12. The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

  15. Identification of genomic variants putatively targeted by selection during dog domestication.

    Science.gov (United States)

    Cagan, Alex; Blass, Torsten

    2016-01-12

    Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight-or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest

  16. Variants of polypeptides having cellulolytic enhancing activity and polynucleotides encoding same

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    Sweeney, Matt; Wogulis, Mark

    2017-11-14

    The present invention relates to polypeptide having cellulolytic enhancing activity variants. The present invention also relates to polynucleotides encoding the variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

  17. COMPARATIVE EVALUATION OF THE EFFICACY OF ...

    African Journals Online (AJOL)

    Global Journal

    chemical weathering and evaporation, i.e. about 50% of diesel fuel decomposes without the action of hydrocarbon oxidizing microorganisms. This trend was also observed in all the variants of the experiment, i.e., by comparing the residual petroleum hydrocarbon content at the 1st week of the experiment to the total.

  18. DETERMINATION OF LEVEL EXPRESSION OF mRNA SPLICING VARIANTS FOR DR3 IN BLOOD CELLS IN INFECTIOUS MONONUCLEOSIS

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    V. D. Cvetkova

    2016-01-01

    Full Text Available The DR3 «death receptor» plays an important role in the initiation of apoptosis, proliferation, or inflammation. This receptor is shown to be involved in various diseases, including infectious conditions. Different variants of mRNA DR3 are formed as a result of alternative splicing. These variant transcripts encode membrane and soluble forms of the receptor which have different functions. Features of their expression and contribution of individual DR3 variants to the immune pathogenesis of infectious mononucleosis (IM are poorely understood.The purpose of this work was to develop, validate and test the techniques of DR3 gene expression assays, as well as to evaluate the DR3 mRNA splice variants by means of real-time RT-PCR and RT-PCR in the IM patients.The original version of real-time RT-PCR allowed to determine relative amounts of DR3 mRNA, DR3 membrane variants (LARD1a + LARD8, and ratios of mRNAs encoding membrane and soluble forms of the receptor. The technique proved to be specific and sensitive (a semi-quantitative detection limit = 34-35 cycles when tested in healthy volunteers and patients with acute infectious mononucleosis (AIM. Lower expression levels were shown for two alternative membrane variants of DR3 mRNA (LARD1b and DR3beta thus regarding these isoforms as minor fractions. The relative levels of total DR3 mRNA expression were decreased in patients with AIM, as compared to healthy volunteers, whereas mRNA expression of membrane receptor variants did not differ between IM and controls.To determine a qualitative contribution of either LARD1a and LARD8 variants into the expression of membrane forms of DR3, a two-step «nested» version of RT-PCR has been developed. It was shown that, in majority of control and IM samples, both main LARD1a, and alternative LARD8 membrane forms are contributing to mRNA expression of membrane DR3 variants.The presented methods for evaluation of expression and occurrence of DR3 mRNA variants allow

  19. The Clinical Significance of Unknown Sequence Variants in BRCA Genes

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    Calò, Valentina; Bruno, Loredana; Paglia, Laura La; Perez, Marco; Margarese, Naomi [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy); Gaudio, Francesca Di [Department of Medical Biotechnologies and Legal Medicine, University of Palermo, Palermo (Italy); Russo, Antonio, E-mail: lab-oncobiologia@usa.net [Department of Surgery and Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, University of Palermo, Via del Vespro 127, 90127 Palermo (Italy)

    2010-09-10

    Germline mutations in BRCA1/2 genes are responsible for a large proportion of hereditary breast and/or ovarian cancers. Many highly penetrant predisposition alleles have been identified and include frameshift or nonsense mutations that lead to the translation of a truncated protein. Other alleles contain missense mutations, which result in amino acid substitution and intronic variants with splicing effect. The discovery of variants of uncertain/unclassified significance (VUS) is a result that can complicate rather than improve the risk assessment process. VUSs are mainly missense mutations, but also include a number of intronic variants and in-frame deletions and insertions. Over 2,000 unique BRCA1 and BRCA2 missense variants have been identified, located throughout the whole gene (Breast Cancer Information Core Database (BIC database)). Up to 10–20% of the BRCA tests report the identification of a variant of uncertain significance. There are many methods to discriminate deleterious/high-risk from neutral/low-risk unclassified variants (i.e., analysis of the cosegregation in families of the VUS, measure of the influence of the VUSs on the wild-type protein activity, comparison of sequence conservation across multiple species), but only an integrated analysis of these methods can contribute to a real interpretation of the functional and clinical role of the discussed variants. The aim of our manuscript is to review the studies on BRCA VUS in order to clarify their clinical relevance.

  20. NECTAR: a database of codon-centric missense variant annotations.

    Science.gov (United States)

    Gong, Sungsam; Ware, James S; Walsh, Roddy; Cook, Stuart A

    2014-01-01

    NECTAR (Non-synonymous Enriched Coding muTation ARchive; http://nectarmutation.org) is a database and web application to annotate disease-related and functionally important amino acids in human proteins. A number of tools are available to facilitate the interpretation of DNA variants identified in diagnostic or research sequencing. These typically identify previous reports of DNA variation at a given genomic location, predict its effects on transcript and protein sequence and may predict downstream functional consequences. Previous reports and functional annotations are typically linked by the genomic location of the variant observed. NECTAR collates disease-causing variants and functionally important amino acid residues from a number of sources. Importantly, rather than simply linking annotations by a shared genomic location, NECTAR annotates variants of interest with details of previously reported variation affecting the same codon. This provides a much richer data set for the interpretation of a novel DNA variant. NECTAR also identifies functionally equivalent amino acid residues in evolutionarily related proteins (paralogues) and, where appropriate, transfers annotations between them. As well as accessing these data through a web interface, users can upload batches of variants in variant call format (VCF) for annotation on-the-fly. The database is freely available to download from the ftp site: ftp://ftp.nectarmutation.org.

  1. A pathway-centric approach to rare variant association analysis

    Science.gov (United States)

    Richardson, Tom G; Timpson, Nicholas J; Campbell, Colin; Gaunt, Tom R

    2017-01-01

    Current endeavours in rare variant analysis are typically underpowered when investigating association signals from individual genes. We undertook an approach to rare variant analysis which utilises biological pathway information to analyse functionally relevant genes together. Conventional filtering approaches for rare variant analysis are based on variant consequence and are therefore confined to coding regions of the genome. Therefore, we undertook a novel approach to this process by obtaining functional annotations from the Combined Annotation Dependent Depletion (CADD) tool, which allowed potentially deleterious variants from intronic regions of genes to be incorporated into analyses. This work was undertaken using whole-genome sequencing data from the UK10K project. Rare variants from the KEGG pathway for arginine and proline metabolism were collectively associated with systolic blood pressure (P=3.32x10−5) based on analyses using the optimal sequence kernel association test. Variants along this pathway also showed evidence of replication using imputed data from the Avon Longitudinal Study of Parents and Children cohort (P=0.02). Subsequent analyses found that the strength of evidence diminished when analysing genes in this pathway individually, suggesting that they would have been overlooked in a conventional gene-based analysis. Future studies that adopt similar approaches to investigate polygenic effects should yield value in better understanding the genetic architecture of complex disease. PMID:27577545

  2. Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

    Science.gov (United States)

    Dinckan, N; Du, R; Petty, L E; Coban-Akdemir, Z; Jhangiani, S N; Paine, I; Baugh, E H; Erdem, A P; Kayserili, H; Doddapaneni, H; Hu, J; Muzny, D M; Boerwinkle, E; Gibbs, R A; Lupski, J R; Uyguner, Z O; Below, J E; Letra, A

    2018-01-01

    Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

  3. Numerical calculation of spatially variant anisotropic metamaterials

    Science.gov (United States)

    Gulib, Asad Ullah Hil

    3D printing, or additive manufacturing, is rapidly evolving into a mainstream manufacturing technology that is creating new opportunities for electromagnetics and circuits. 3D printing permits circuits to fully utilize the third dimension allowing more functions in the same amount of space and allows the devices to have arbitrary form factors. 3D printing is letting us discover new physics that is not possible in standard 2D circuits and devices. However, evolving electromagnetics and circuits into three dimensions introduces some serious problems like thermal management, interference, and mutual coupling between the components which degrades performance and hurts signal integrity. Metamaterials are engineered composites that exhibit extreme electromagnetic properties and allow extraordinary control over electromagnetic fields. The EM Lab is developing spatially-variant anisotropic metamaterials (SVAMs) as a solution to mitigate mutual coupling between components. The concept of SVAMs is to electrically stretch the space between components to reduce mutual coupling. To do this, alternating layers of different dielectric must bisect adjacent components. However, the overall dielectric fill must also conform around dozens of electrical components and be smooth, continuous, and defect free. The research described here is the first prototype of an algorithm which generates a SVAM infill between all of the electrical components of a circuit in order to reduce the mutual coupling.

  4. Identification of a novel alpha1-antitrypsin variant

    Directory of Open Access Journals (Sweden)

    Camille de Seynes

    2017-01-01

    We report the identification of a novel alpha1-antitrypsin variant in a 64-year old woman presenting with dyspnea on exertion. Imaging revealed bilateral bronchiectasis associated with moderate panacinar emphysema. The pulmonary function tests (PFTs were subnormal but hypoxemia was noticed and A1AT quantitative analysis revealed a severe deficiency. DNA sequencing showed compound heterozygosity for the PIZ variant and a novel missense variant p.Phe232Leu (p.Phe208Leu. No specific treatment was proposed since PFTs were within the normal range at this stage of the disease. Close follow-up of pulmonary and hepatic parameters was recommended.

  5. De Novo Coding Variants Are Strongly Associated with Tourette Disorder

    DEFF Research Database (Denmark)

    Willsey, A Jeremy; Fernandez, Thomas V; Yu, Dongmei

    2017-01-01

    Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186...... trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably...

  6. Variante de Dandy Walker: relato de caso = Dandy Walker variant: a case report

    Directory of Open Access Journals (Sweden)

    Khan, Richard Lester et al.

    2009-01-01

    Full Text Available Objetivos: relatar o caso de um paciente com variante de Dandy Walker, chamando atenção para a importância da suspeita, investigação e manejo das repercussões clínicas. Descrição do caso: é relatado o caso de um paciente do sexo masculino, com quadro clínico e radiológico típico da Variante de Dandy Walker. Durante o pré-natal, através de ecografia obstétrica com 23 semanas e 3 dias, apresentou alterações sugestivas de Síndrome de Dandy Walker. Ao nascimento apresentou exame físico com fenda palatina, criptorquidia à direita, hexodactilia em ambos os pés. Apresentava ainda ecocardiograma com forame oval patente e persistência do canal arterial. O diagnóstico foi estabelecido através da ressonância magnética realizada após o nascimento, que evidenciava hipoplasia do vermis cerebelar, alargamento da fossa posterior e leve dilatação ventricular. Conclusões: este artigo procura caracterizar a variante de Dandy Walker, que é uma malformação congênita do sistema nervoso central e é o tipo mais comum da Síndrome de Dandy Walker. Seu fenótipo é variável, devendo-se sempre pesquisar malformações tanto intra quanto extracranianas, visto que o risco de mortalidade pós-natal aumenta quando existe esta associação. O tratamento envolve equipe multidisciplinar e o prognóstico é reservado, variando conforme o fenótipo.

  7. Evaluating the Calling Performance of a Rare Disease NGS Panel for Single Nucleotide and Copy Number Variants.

    Science.gov (United States)

    Cacheiro, P; Ordóñez-Ugalde, A; Quintáns, B; Piñeiro-Hermida, S; Amigo, J; García-Murias, M; Pascual-Pascual, S I; Grandas, F; Arpa, J; Carracedo, A; Sobrido, M J

    2017-06-01

    Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease. Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software. There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer. The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.

  8. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

    Science.gov (United States)

    LaRusch, Jessica; Jung, Jinsei; General, Ignacio J; Lewis, Michele D; Park, Hyun Woo; Brand, Randall E; Gelrud, Andres; Anderson, Michelle A; Banks, Peter A; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B; Amann, Stephen T; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L; Yadav, Dhiraj; Barmada, M Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C

    2014-07-01

    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, pbicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants

  9. Houston Methodist variant viewer: An application to support clinical laboratory interpretation of next-generation sequencing data for cancer

    Directory of Open Access Journals (Sweden)

    Paul A Christensen

    2017-01-01

    Full Text Available Introduction: Next-generation-sequencing (NGS is increasingly used in clinical and research protocols for patients with cancer. NGS assays are routinely used in clinical laboratories to detect mutations bearing on cancer diagnosis, prognosis and personalized therapy. A typical assay may interrogate 50 or more gene targets that encompass many thousands of possible gene variants. Analysis of NGS data in cancer is a labor-intensive process that can become overwhelming to the molecular pathologist or research scientist. Although commercial tools for NGS data analysis and interpretation are available, they are often costly, lack key functionality or cannot be customized by the end user. Methods: To facilitate NGS data analysis in our clinical molecular diagnostics laboratory, we created a custom bioinformatics tool termed Houston Methodist Variant Viewer (HMVV. HMVV is a Java-based solution that integrates sequencing instrument output, bioinformatics analysis, storage resources and end user interface. Results: Compared to the predicate method used in our clinical laboratory, HMVV markedly simplifies the bioinformatics workflow for the molecular technologist and facilitates the variant review by the molecular pathologist. Importantly, HMVV reduces time spent researching the biological significance of the variants detected, standardizes the online resources used to perform the variant investigation and assists generation of the annotated report for the electronic medical record. HMVV also maintains a searchable variant database, including the variant annotations generated by the pathologist, which is useful for downstream quality improvement and research projects. Conclusions: HMVV is a clinical grade, low-cost, feature-rich, highly customizable platform that we have made available for continued development by the pathology informatics community.

  10. Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

    Science.gov (United States)

    Wang, Sophie R; Agarwala, Vineeta; Flannick, Jason; Chiang, Charleston W K; Altshuler, David; Hirschhorn, Joel N

    2014-05-01

    Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  11. Hierarchical generalized linear models for multiple groups of rare and common variants: jointly estimating group and individual-variant effects.

    Directory of Open Access Journals (Sweden)

    Nengjun Yi

    2011-12-01

    Full Text Available Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/.

  12. Hierarchical generalized linear models for multiple groups of rare and common variants: jointly estimating group and individual-variant effects.

    Science.gov (United States)

    Yi, Nengjun; Liu, Nianjun; Zhi, Degui; Li, Jun

    2011-12-01

    Complex diseases and traits are likely influenced by many common and rare genetic variants and environmental factors. Detecting disease susceptibility variants is a challenging task, especially when their frequencies are low and/or their effects are small or moderate. We propose here a comprehensive hierarchical generalized linear model framework for simultaneously analyzing multiple groups of rare and common variants and relevant covariates. The proposed hierarchical generalized linear models introduce a group effect and a genetic score (i.e., a linear combination of main-effect predictors for genetic variants) for each group of variants, and jointly they estimate the group effects and the weights of the genetic scores. This framework includes various previous methods as special cases, and it can effectively deal with both risk and protective variants in a group and can simultaneously estimate the cumulative contribution of multiple variants and their relative importance. Our computational strategy is based on extending the standard procedure for fitting generalized linear models in the statistical software R to the proposed hierarchical models, leading to the development of stable and flexible tools. The methods are illustrated with sequence data in gene ANGPTL4 from the Dallas Heart Study. The performance of the proposed procedures is further assessed via simulation studies. The methods are implemented in a freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/).

  13. Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

    Science.gov (United States)

    Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

    2018-01-23

    Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

  14. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features

    Science.gov (United States)

    Pijnenburg, Yolande A. L.; Perry, David C.; Cohn-Sheehy, Brendan I.; Scheltens, Nienke M. E.; Vogel, Jacob W.; Kramer, Joel H.; van der Vlies, Annelies E.; Joie, Renaud La; Rosen, Howard J.; van der Flier, Wiesje M.; Grinberg, Lea T.; Rozemuller, Annemieke J.; Huang, Eric J.; van Berckel, Bart N. M.; Miller, Bruce L.; Barkhof, Frederik; Jagust, William J.; Scheltens, Philip; Seeley, William W.; Rabinovici, Gil D.

    2015-01-01

    A ‘frontal variant of Alzheimer’s disease’ has been described in patients with predominant behavioural or dysexecutive deficits caused by Alzheimer’s disease pathology. The description of this rare Alzheimer’s disease phenotype has been limited to case reports and small series, and many clinical, neuroimaging and neuropathological characteristics are not well understood. In this retrospective study, we included 55 patients with Alzheimer’s disease with a behavioural-predominant presentation (behavioural Alzheimer’s disease) and a neuropathological diagnosis of high-likelihood Alzheimer’s disease (n = 17) and/or biomarker evidence of Alzheimer’s disease pathology (n = 44). In addition, we included 29 patients with autopsy/biomarker-defined Alzheimer’s disease with a dysexecutive-predominant syndrome (dysexecutive Alzheimer’s disease). We performed structured chart reviews to ascertain clinical features. First symptoms were more often cognitive (behavioural Alzheimer’s disease: 53%; dysexecutive Alzheimer’s disease: 83%) than behavioural (behavioural Alzheimer’s disease: 25%; dysexecutive Alzheimer’s disease: 3%). Apathy was the most common behavioural feature, while hyperorality and perseverative/compulsive behaviours were less prevalent. Fifty-two per cent of patients with behavioural Alzheimer’s disease met diagnostic criteria for possible behavioural-variant frontotemporal dementia. Overlap between behavioural and dysexecutive Alzheimer’s disease was modest (9/75 patients). Sixty per cent of patients with behavioural Alzheimer’s disease and 40% of those with the dysexecutive syndrome carried at least one APOE ε4 allele. We also compared neuropsychological test performance and brain atrophy (applying voxel-based morphometry) with matched autopsy/biomarker-defined typical (amnestic-predominant) Alzheimer’s disease (typical Alzheimer’s disease, n = 58), autopsy-confirmed/Alzheimer’s disease biomarker-negative behavioural

  15. Myostatin: genetic variants, therapy and gene doping

    Directory of Open Access Journals (Sweden)

    André Katayama Yamada

    2012-09-01

    Full Text Available Since its discovery, myostatin (MSTN has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.Desde sua descoberta, a miostatina (MSTN entrou na linha de frente em pesquisas relacionadas às terapias musculares porque mutações intrínsecas ou inibição desta proteína tanto por abordagens farmacológicas como genéticas resultam em hipertrofia muscular e hiperplasia. Além do aumento da massa muscular, a inibição de MSTN potencialmente prejudica o tecido conectivo, modula a força muscular, facilita o transplante de mioblastos, promove regeneração tecidual, induz termogênese no tecido adiposo e aumenta a oxidação na musculatura esquelética. É também sabido que os atuais avanços em terapia gênica têm uma relação com o esporte devido ao uso ilícito de tal método. Os efeitos adversos de tal abordagem, seus efeitos no desempenho de atletas e métodos para detectar doping genético s

  16. Two variants of minimum discarded fill ordering

    Energy Technology Data Exchange (ETDEWEB)

    D' Azevedo, E.F. (Oak Ridge National Lab., TN (USA)); Forsyth, P.A.; Tang, Wei-Pai (Waterloo Univ., ON (Canada). Dept. of Computer Science)

    1991-01-01

    It is well known that the ordering of the unknowns can have a significant effect on the convergence of Preconditioned Conjugate Gradient (PCG) methods. There has been considerable experimental work on the effects of ordering for regular finite difference problems. In many cases, good results have been obtained with preconditioners based on diagonal, spiral or natural row orderings. However, for finite element problems having unstructured grids or grids generated by a local refinement approach, it is difficult to define many of the orderings for more regular problems. A recently proposed Minimum Discarded Fill (MDF) ordering technique is effective in finding high quality Incomplete LU (ILU) preconditioners, especially for problems arising from unstructured finite element grids. Testing indicates this algorithm can identify a rather complicated physical structure in an anisotropic problem and orders the unknowns in the preferred'' direction. The MDF technique may be viewed as the numerical analogue of the minimum deficiency algorithm in sparse matrix technology. At any stage of the partial elimination, the MDF technique chooses the next pivot node so as to minimize the amount of discarded fill. In this work, two efficient variants of the MDF technique are explored to produce cost-effective high-order ILU preconditioners. The Threshold MDF orderings combine MDF ideas with drop tolerance techniques to identify the sparsity pattern in the ILU preconditioners. These techniques identify an ordering that encourages fast decay of the entries in the ILU factorization. The Minimum Update Matrix (MUM) ordering technique is a simplification of the MDF ordering and is closely related to the minimum degree algorithm. The MUM ordering is especially for large problems arising from Navier-Stokes problems. Some interesting pictures of the orderings are presented using a visualization tool. 22 refs., 4 figs., 7 tabs.

  17. Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

    DEFF Research Database (Denmark)

    Tvardovskiy, Andrey; Schwämmle, Veit; Kempf, Stefan J

    2017-01-01

    a causal relationship between H3 variant replacement and age-dependent changes in H3 methylation. Furthermore, the H3.3 level is drastically reduced in human hepatocarcinoma cells as compared to nontumoral hepatocytes, suggesting the potential utility of the H3.3 relative abundance as a biomarker...

  18. Population diversity of Listeria monocytogenes LO28: phenotypic and genotypic characterization of variants resistant to high hydrostatic pressure

    NARCIS (Netherlands)

    Boeijen, van K.H.; Chavaroche, A.A.E.; Valderrama, W.B.; Moezelaar, R.; Zwietering, M.H.; Abee, T.

    2010-01-01

    A comparative phenotype analysis of 24 Listeria monocytogenes LO28 stress-resistant variants obtained after high-pressure treatment was performed to assess their robustness and growth performance under a range of food-relevant conditions. In addition, genetic analysis was conducted to characterize

  19. AAV ancestral reconstruction library enables selection of broadly infectious viral variants.

    Science.gov (United States)

    Santiago-Ortiz, J; Ojala, D S; Westesson, O; Weinstein, J R; Wong, S Y; Steinsapir, A; Kumar, S; Holmes, I; Schaffer, D V

    2015-12-01

    Adeno-associated virus (AAV) vectors have achieved clinical efficacy in treating several diseases. However, enhanced vectors are required to extend these landmark successes to other indications and protein engineering approaches may provide the necessary vector improvements to address such unmet medical needs. To generate new capsid variants with potentially enhanced infectious properties and to gain insights into AAV's evolutionary history, we computationally designed and experimentally constructed a putative ancestral AAV library. Combinatorial variations at 32 amino acid sites were introduced to account for uncertainty in their identities. We then analyzed the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to iterative selection on a representative cell line panel. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes and, in general, ancestral libraries were broadly infectious across the cell line panel, indicating that they favored promiscuity over specificity. Interestingly, putative ancestral AAVs were more thermostable than modern serotypes and did not use sialic acids, galactose or heparan sulfate proteoglycans for cellular entry. Finally, variants mediated 19- to 31-fold higher gene expression in the muscle compared with AAV1, a clinically used serotype for muscle delivery, highlighting their promise for gene therapy.

  20. Segregation of distinct variants from Citrus tristeza virus isolate SY568 using aphid transmission.

    Science.gov (United States)

    Velazquez-Monreal, J J; Mathews, D M; Dodds, J A

    2009-10-01

    A well-studied severe isolate of Citrus tristeza virus (CTV) known as SY568 has previously been shown to contain multiple variants of the virus which differ in their genetic and biological characters. Aphid transmission was used in an attempt to segregate some of these variants for further characterization. Resulting infections gave symptoms which varied from asymptomatic to more severe than the inoculum source. RNase protection assays (RPAs) were used to compare nine regions of the CTV genome and determine whether unique strains could be identified. Five aphid-transmitted subcultures, with fingerprints that were different from those of the inoculum sources in at least one genomic area, were then cloned, sequenced, and compared with known isolates. An asymptomatic strain was shown to be different in every area of the CTV genome when examined by RPA and sequencing of selected regions. Mixed-infection studies using graft transmission of the asymptomatic subculture and two of the more severe aphid-transmitted subcultures showed that the mild strain was not able to compete well when in the presence of any of the severe variants tested, and its titer was significantly reduced from that seen in single infection. The mild strain and a selected severe strain were singly graft inoculated into five different citrus hosts (sweet orange, grapefruit, sour orange, lemon, and lime), where they maintained their distinct biological and genetic characteristics.

  1. Improved Variant Calling Accuracy by Merging Replicates in Whole-Exome Sequencing Studies

    Directory of Open Access Journals (Sweden)

    Yanfeng Zhang

    2014-01-01

    Full Text Available In large scale population-based whole-exome sequencing (WES studies, there are some samples occasionally sequenced two or more times due to a variety of reasons. To investigate how to efficiently utilize these duplicated sequencing data, we conducted comprehensive evaluation of variant calling strategies. 92 samples subjected to WES twice were selected from a large population study. These 92 duplicated samples were divided into two groups: group H consisting of the higher sequencing depth for each subject and group L consisting of the lower depth for each subject. The merged samples for each subject were put in a third group M. Using the GATK multisample toolkit, we compared variant calling accuracy among three strategies. Hierarchical clustering analysis indicated that the two replicates for each subject showed high homogeneity. The comparative analyses on the basis of heterozygous-homozygous ratio (Hete/Homo, transition-transversion ratio (Ti/Tv, and overlapping rate with the 1000 Genomes Project consistently showed that the data quality of the SNPs detected from the M group was more accurate than that of SNPs detected from the H and L groups. These results suggested that merging homogeneous duplicated exomes instead of using one of them could improve variant calling accuracy.

  2. Prothrombotic gene variants as risk factors of acute myocardial infarction in young women

    Directory of Open Access Journals (Sweden)

    Tomaiuolo Rossella

    2012-11-01

    Full Text Available Abstract Background Acute myocardial infarction (AMI in young women represent an extreme phenotype associated with a higher mortality compared with similarly aged men. Prothrombotic gene variants could play a role as risk factors for AMI at young age. Methods We studied Factor V Leiden, FII G20210A, MTHFR C677T and beta-fibrinogen -455G>A variants by real-time PCR in 955 young AMI (362 females and in 698 AMI (245 females patients. The data were compared to those obtained in 909 unrelated subjects (458 females from the general population of the same geographical area (southern Italy. Results In young AMI females, the allelic frequency of either FV Leiden and of FII G20210A was significantly higher versus the general population (O.R.: 3.67 for FV Leiden and O.R.: 3.84 for FII G20210A; p Discussion and conclusion Our data confirm that young AMI in females is a peculiar phenotype with specific risk factors as the increased plasma procoagulant activity of FV and FII. On the contrary, the homozygous state for the 677T MTHFR variant may cause increased levels of homocysteine and/or an altered folate status and thus an increased risk for AMI, particularly in males. The knowledge of such risk factors (that may be easily identified by molecular analysis may help to improve prevention strategies for acute coronary diseases in specific risk-group subjects.

  3. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications.

    Science.gov (United States)

    Rimmer, Andy; Phan, Hang; Mathieson, Iain; Iqbal, Zamin; Twigg, Stephen R F; Wilkie, Andrew O M; McVean, Gil; Lunter, Gerton

    2014-08-01

    High-throughput DNA sequencing technology has transformed genetic research and is starting to make an impact on clinical practice. However, analyzing high-throughput sequencing data remains challenging, particularly in clinical settings where accuracy and turnaround times are critical. We present a new approach to this problem, implemented in a software package called Platypus. Platypus achieves high sensitivity and specificity for SNPs, indels and complex polymorphisms by using local de novo assembly to generate candidate variants, followed by local realignment and probabilistic haplotype estimation. It is an order of magnitude faster than existing tools and generates calls from raw aligned read data without preprocessing. We demonstrate the performance of Platypus in clinically relevant experimental designs by comparing with SAMtools and GATK on whole-genome and exome-capture data, by identifying de novo variation in 15 parent-offspring trios with high sensitivity and specificity, and by estimating human leukocyte antigen genotypes directly from variant calls.

  4. Histone H3 variants and their chaperones during development and disease: contributing to epigenetic control.

    Science.gov (United States)

    Filipescu, Dan; Müller, Sebastian; Almouzni, Geneviève

    2014-01-01

    Within the nucleus, the interplay between lineage-specific transcription factors and chromatin dynamics defines cellular identity. Control of this interplay is necessary to properly balance stability and plasticity during the development and entire life span of multicellular organisms. Here, we present our current knowledge of the contribution of histone H3 variants to chromatin dynamics during development. We review the network of histone chaperones that governs their deposition timing and sites of incorporation and highlight how their distinct distribution impacts genome organization and function. We integrate the importance of H3 variants in the context of nuclear reprogramming and cell differentiation, and, using the centromere as a paradigm, we describe a case in which the identity of a given genomic locus is propagated across different cell types. Finally, we compare development to changes in stress and disease. Both physiological and pathological settings underline the importance of H3 dynamics for genome and chromatin integrity.

  5. Common Gene Variants Account for Most Genetic Risk for Autism

    Science.gov (United States)

    ... gene variants account for most genetic risk for autism Roles of heritability, mutations, environment estimated – NIH-funded study. The bulk of risk, or liability, for autism spectrum disorders (ASD) was traced to inherited variations ...

  6. Infectious Bronchitis Virus Variants: Molecular Analysis and Pathogenicity Investigation

    Directory of Open Access Journals (Sweden)

    Shu-Yi Lin

    2017-09-01

    Full Text Available Infectious bronchitis virus (IBV variants constantly emerge and pose economic threats to poultry farms worldwide. Numerous studies on the molecular and pathogenic characterization of IBV variants have been performed between 2007 and 2017, which we have reviewed herein. We noted that viral genetic mutations and recombination events commonly gave rise to distinct IBV genotypes, serotypes and pathotypes. In addition to characterizing the S1 genes, full viral genomic sequencing, comprehensive antigenicity, and pathogenicity studies on emerging variants have advanced our understanding of IBV infections, which is valuable for developing countermeasures against IBV field outbreaks. This review of IBV variants provides practical value for understanding their phylogenetic relationships and epidemiology from both regional and worldwide viewpoints.

  7. cyvcf2: fast, flexible variant analysis with Python.

    Science.gov (United States)

    Pedersen, Brent S; Quinlan, Aaron R

    2017-06-15

    Variant call format (VCF) files document the genetic variation observed after DNA sequencing, alignment and variant calling of a sample cohort. Given the complexity of the VCF format as well as the diverse variant annotations and genotype metadata, there is a need for fast, flexible methods enabling intuitive analysis of the variant data within VCF and BCF files. We introduce cyvcf2 , a Python library and software package for fast parsing and querying of VCF and BCF files and illustrate its speed, simplicity and utility. bpederse@gmail.com or aaronquinlan@gmail.com. cyvcf2 is available from https://github.com/brentp/cyvcf2 under the MIT license and from common python package managers. Detailed documentation is available at http://brentp.github.io/cyvcf2/.

  8. Genotype and phenotype spectrum of NRAS germline variants

    NARCIS (Netherlands)

    Altmuller, F.; Lissewski, C.; Bertola, D.; Flex, E.; Stark, Z.; Spranger, S.; Baynam, G.; Buscarilli, M.; Dyack, S.; Gillis, J.; Yntema, H.G.; Pantaleoni, F.; Loon, R.L. van; MacKay, S.; Mina, K.; Schanze, I.; Tan, T.Y.; Walsh, M.; White, S.M.; Niewisch, M.R.; Garcia-Minaur, S.; Plaza, D.; Ahmadian, M.R.; Cave, H.; Tartaglia, M.; Zenker, M.

    2017-01-01

    RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly

  9. Genotype and phenotype spectrum of NRAS germline variants

    National Research Council Canada - National Science Library

    Altmuller, F; Lissewski, C; Bertola, D; Flex, E; Stark, Z; Spranger, S; Baynam, G; Buscarilli, M; Dyack, S; Gillis, J; Yntema, H.G; Pantaleoni, F; Loon, R.L. van; MacKay, S; Mina, K; Schanze, I; Tan, T.Y; Walsh, M; White, S.M; Niewisch, M.R; Garcia-Minaur, S; Plaza, D; Ahmadian, M.R; Cave, H; Tartaglia, M; Zenker, M

    2017-01-01

    .... Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants...

  10. variant formula for predicting peak expiratory flow rate in pregnant ...

    African Journals Online (AJOL)

    DR. AMINU

    Accepted: November, 2009. VARIANT FORMULA FOR PREDICTING PEAK EXPIRATORY FLOW RATE IN. PREGNANT WOMEN IN KURA LOCAL GOVERNMENT AREA, KANO STATE,. NIGERIA. A. I. Salisu. Department of Human Physiology, Faculty of Medicine, Bayero University, Kano salisahmedibrahim@yahoo.co.uk;.

  11. Leapfrog variants of iterative methods for linear algebra equations

    Science.gov (United States)

    Saylor, Paul E.

    1988-01-01

    Two iterative methods are considered, Richardson's method and a general second order method. For both methods, a variant of the method is derived for which only even numbered iterates are computed. The variant is called a leapfrog method. Comparisons between the conventional form of the methods and the leapfrog form are made under the assumption that the number of unknowns is large. In the case of Richardson's method, it is possible to express the final iterate in terms of only the initial approximation, a variant of the iteration called the grand-leap method. In the case of the grand-leap variant, a set of parameters is required. An algorithm is presented to compute these parameters that is related to algorithms to compute the weights and abscissas for Gaussian quadrature. General algorithms to implement the leapfrog and grand-leap methods are presented. Algorithms for the important special case of the Chebyshev method are also given.

  12. HD-CNV: hotspot detector for copy number variants

    National Research Council Canada - National Science Library

    Butler, Jenna L; Osborne Locke, Marjorie Elizabeth; Hill, Kathleen A; Daley, Mark

    2013-01-01

    ... (hotspot detector for copy number variants) is a tool for downstream analysis of previously identified CNV regions from multiple samples, and it detects recurrent regions by finding cliques in an interval graph generated from the input...

  13. vipR: variant identification in pooled DNA using R

    National Research Council Canada - National Science Library

    Altmann, Andre; Weber, Peter; Quast, Carina; Rex-Haffner, Monika; Binder, Elisabeth B; Müller-Myhsok, Bertram

    2011-01-01

    .... Thus, recently, screens for rare sequence variants were carried out in samples of pooled DNA, in which equimolar amounts of DNA from multiple individuals are mixed prior to sequencing with HTS...

  14. Method of generating ploynucleotides encoding enhanced folding variants

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M.; Kiss, Csaba; Waldo, Geoffrey S.

    2017-05-02

    The invention provides directed evolution methods for improving the folding, solubility and stability (including thermostability) characteristics of polypeptides. In one aspect, the invention provides a method for generating folding and stability-enhanced variants of proteins, including but not limited to fluorescent proteins, chromophoric proteins and enzymes. In another aspect, the invention provides methods for generating thermostable variants of a target protein or polypeptide via an internal destabilization baiting strategy. Internally destabilization a protein of interest is achieved by inserting a heterologous, folding-destabilizing sequence (folding interference domain) within DNA encoding the protein of interest, evolving the protein sequences adjacent to the heterologous insertion to overcome the destabilization (using any number of mutagenesis methods), thereby creating a library of variants. The variants in the library are expressed, and those with enhanced folding characteristics selected.

  15. Anatomic variant of the median nerve in the carpal tunnel.

    Science.gov (United States)

    Steinberg, E L; Luger, E; Taitz, C; Arensburg, B

    1998-07-01

    Forty-six hands of 23 cadavers (15 female and 8 male) were dissected to observe the patterns of distribution of the median nerve. The findings showed that in 33 hands the median nerve had a normal distribution of its branches. Also identified was the commonly recognized transligamentous variant, where the recurrent branch pierces the carpal ligament 2 to 4 mm proximal to the distal end of the carpal tunel. This latter variant occurred in 13 hands. The current study focused on the presence of an additional variant, not previously identified, that occurred in 10 hands. This branch, considered sensory, was approximately 1 mm wide and pierced the lateral carpal ligament 3 to 6 mm distal to the proximal edge of the tunnel. The importance of recognition of variants of median nerve distribution in surgery of the carpal tunnel is emphasized.

  16. Pharyngeal-Cervical-Brachial Variant of Guillain-Barre Syndrome

    OpenAIRE

    J Gordon Millichap; John J Millichap

    2014-01-01

    Investigators from National University Hospital, Singapore, review the clinical features of 13 cases of pharyngeal-cervical-brachial (PCB) variant of Guillain-Barre syndrome (GBS) and outline new diagnostic criteria.

  17. Disintegrating perineal disease: A variant of watering-can perineum

    OpenAIRE

    N. Abrol; Devasia, A.

    2014-01-01

    Watering-can perineum is a known complication of inflammatory urethral stricture disease. We report a case of disintegrating perineal disease, a fulminant variant of watering-can perineum, in an immunocompetent patient.

  18. Genetic variant as a marker for bladder cancer therapy

    Science.gov (United States)

    Patients who have inherited a specific common genetic variant develop bladder cancer tumors that strongly express a protein known as prostate stem cell antigen (PSCA), which is also expressed in many pancreatic and prostate tumors, according to research a

  19. Association of Genetic Variants of Milk Proteins with Milk Production ...

    African Journals Online (AJOL)

    Administrator

    Aschaffenburg & Drewry,. 1955; 1957) researchers have become interested in the genetic polymorphism of milk proteins. It is known today that there are at least 39 genetic variants of six milk protein fractions (Eigel et al., 1984; Bouniol et al.,.

  20. Detection of combined genomic variants in a Jordanian family with ...

    Indian Academy of Sciences (India)

    TSHR) gene was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of all family members. The sequence analysis of all TSHR gene exons and intron borders revealed two genomic variants. The first ...

  1. Variant Plasmodium ovale isolated from a patient infected in Ghana

    Directory of Open Access Journals (Sweden)

    Petersen Eskild

    2011-01-01

    Full Text Available Abstract Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago.

  2. Analysis of NPM1 splice variants reveals differential expression patterns of prognostic value in acute myeloid leukemia

    Science.gov (United States)

    Stasiak, Grazyna; Zaleska, Joanna; Kielbus, Michal; Czapinski, Jakub; Schunn, Matthias; Correa, Stephany C.; Glodkowska-Mrowka, Eliza; Sundaram, Reddy Chakkarappan; Jankowska-Lecka, Olga; Schlenk, Richard F.; Döhner, Hartmut; Döhner, Konstanze; Stepulak, Andrzej; Bullinger, Lars; Giannopoulos, Krzysztof

    2017-01-01

    Mutations of the nucleophosmin-1 (NPM1) gene in cytogenetically normal (CN) acute myeloid leukemia (AML) identify a group of patients with more favorable prognosis. NPM1 encodes three main alternatively spliced isoforms R1(B23.1), R2(B23.2), and R3(B23.3). The expression of splice variants R1, R2 and R3 were higher in AML patients compared to normal cells of healthy volunteers (HVs), although RNA-seq analysis revealed enhanced R2 expression also in less differentiated cells of HVs as well as in AML cells. The variant R2, which lacks exons 11 and 12 coding for the nucleolar localization domain, might behave similar to the mutant form of NPM1 (NPM1mut). In accordance, in CN-AML high R2 expression was associated with favorable impact on outcome. Moreover, functional studies showed nucleolar localization of the eGFP-NPM1 wildtype and cytoplasmic localization of the eGFP-NPM1 mut protein. While the eGFP-NPM1 R2 splice variant localized predominantly in the nucleoplasm, we also could detect cytoplasmic expression for the R2 variant. These results support a unique biological consequence of R2 overexpression and in part explain our clinical observation, where that high R2 variant expression was associated with a better prognosis in CN-AML patients. PMID:29221119

  3. Expression of a Splice Variant of CYP26B1 in Betel Quid-Related Oral Cancer

    Directory of Open Access Journals (Sweden)

    Ping-Ho Chen

    2014-01-01

    Full Text Available Betel quid (BQ is a psychostimulant, an addictive substance, and a group 1 carcinogen that exhibits the potential to induce adverse health effects. Approximately, 600 million users chew a variety of BQ. Areca nut (AN is a necessary ingredient in BQ products. Arecoline is the primary alkaloid in the AN and can be metabolized through the cytochrome P450 (CYP superfamily by inducing reactive oxygen species (ROS production. Full-length CYP26B1 is related to the development of oral pharyngeal cancers. We investigated whether a splice variant of CYP26B1 is associated with the occurrence of ROS related oral and pharyngeal cancer. Cytotoxicity assays were used to measure the effects of arecoline on cell viability in a dose-dependent manner. In vitro and in vivo studies were conducted to evaluate the expression of the CYP26B1 splice variant. The CYP26B1 splice variant exhibited lower expression than did full-length CYP26B1 in the human gingival fibroblast-1 and Ca9-22 cell models. Increased expression of the CYP26B1 splice variant was observed in human oral cancer tissue compared with adjacent normal tissue, and increased expression was observed in patients at a late tumor stage. Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer.

  4. Outcomes of Technical Variant Liver Transplantation versus Whole Liver Transplantation for Pediatric Patients: A Meta-Analysis.

    Science.gov (United States)

    Ye, Hui; Zhao, Qiang; Wang, Yufang; Wang, Dongping; Zheng, Zhouying; Schroder, Paul Michael; Lu, Yao; Kong, Yuan; Liang, Wenhua; Shang, Yushu; Guo, Zhiyong; He, Xiaoshun

    2015-01-01

    To overcome the shortage of appropriate-sized whole liver grafts for children, technical variant liver transplantation has been practiced for decades. We perform a meta-analysis to compare the survival rates and incidence of surgical complications between pediatric whole liver transplantation and technical variant liver transplantation. To identify relevant studies up to January 2014, we searched PubMed/Medline, Embase, and Cochrane library databases. The primary outcomes measured were patient and graft survival rates, and the secondary outcomes were the incidence of surgical complications. The outcomes were pooled using a fixed-effects model or random-effects model. The one-year, three-year, five-year patient survival rates and one-year, three-year graft survival rates were significantly higher in whole liver transplantation than technical variant liver transplantation (OR = 1.62, 1.90, 1.65, 1.78, and 1.62, respectively, ptechnical variant liver transplantation. Continuing efforts should be made to minimize surgical complications to improve the outcomes of technical variant liver transplantation.

  5. Assessments of pulmonary vein and left atrial anatomical variants in atrial fibrillation patients for catheter ablation with cardiac CT

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jing; Yang, Zhi-Gang; Xu, Hua-Yan; Shi, Ke; Long, Qi-Hua [Sichuan University, Department of Radiology, West China Hospital, Chengdu, Sichuan (China); Guo, Ying-Kun [Sichuan University, Department of Radiology, West China Second University Hospital, Chengdu (China)

    2017-02-15

    To provide a road map of pulmonary vein (PV) and left atrial (LA) variants in patients with atrial fibrillation (AF) before catheter ablation procedure using cardiac CT. Cardiac CT was performed in 1420 subjects for accurate anatomical information, including 710 patients with AF and 710 matched controls without AF. PV variants, PV ostia and spatial orientation, LA enlargement, and left atrial diverticulum (LAD) were measured, respectively. Differences between these two groups were also respectively compared. Some risk factors for the occurrence of LAD were analyzed. In total, PV variants were observed in 202 (28.5 %) patients with AF patients and 206 (29.0 %) controls without AF (p = 0.8153). The ostial sizes of all accessory veins were generally smaller than those of the typical four PVs (p = 0.0153 to 0.3958). There was a significant difference of LA enlargement between the AF and control groups (36.3 % vs. 12.5 %, p < 0.0001), while the prevalence of LAD was similar in these two groups (43.2 % vs. 41.9 %, p = 0.6293). PV variants are common. Detailed knowledge of PVs and LA variants are helpful for providing anatomical road map to determine ablation strategy. (orig.)

  6. Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.

    Science.gov (United States)

    Machuca, Eduardo; Hummel, Aurélie; Nevo, Fabien; Dantal, Jacques; Martinez, Frank; Al-Sabban, Essam; Baudouin, Véronique; Abel, Laurent; Grünfeld, Jean-Pierre; Antignac, Corinne

    2009-04-01

    Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant.

  7. Identifying novel sequence variants of RNA 3D motifs

    Science.gov (United States)

    Zirbel, Craig L.; Roll, James; Sweeney, Blake A.; Petrov, Anton I.; Pirrung, Meg; Leontis, Neocles B.

    2015-01-01

    Predicting RNA 3D structure from sequence is a major challenge in biophysics. An important sub-goal is accurately identifying recurrent 3D motifs from RNA internal and hairpin loop sequences extracted from secondary structure (2D) diagrams. We have developed and validated new probabilistic models for 3D motif sequences based on hybrid Stochastic Context-Free Grammars and Markov Random Fields (SCFG/MRF). The SCFG/MRF models are constructed using atomic-resolution RNA 3D structures. To parameterize each model, we use all instances of each motif found in the RNA 3D Motif Atlas and annotations of pairwise nucleotide interactions generated by the FR3D software. Isostericity relations between non-Watson–Crick basepairs are used in scoring sequence variants. SCFG techniques model nested pairs and insertions, while MRF ideas handle crossing interactions and base triples. We use test sets of randomly-generated sequences to set acceptance and rejection thresholds for each motif group and thus control the false positive rate. Validation was carried out by comparing results for four motif groups to RMDetect. The software developed for sequence scoring (JAR3D) is structured to automatically incorporate new motifs as they accumulate in the RNA 3D Motif Atlas when new structures are solved and is available free for download. PMID:26130723

  8. Multicriteria analysis in selecting the optimal variant of solar system

    Directory of Open Access Journals (Sweden)

    Radziejowska Aleksandra

    2016-01-01

    Full Text Available Alternative energy sources are becoming more serious competition to traditional ways of generating energy. It becomes real integration of eco-energy with ecology, as well as the innovative technologies with low-energy construction. Apart from the cost an important issue are technical parameters of the equipment, durability, ease of installation, etc. The investor therefore is facing with the problem of decision-making to choose the best solution from the point of view of many criteria. In the article, the authors present the proposal to apply the methods of multi-criteria analysis to select the most beneficial variant of the solar system solutions. In this purpose will be use among other method: multivariate analysis of Saaty’s AHP, the taxonomic method of weighting factors and, belonging to a group of methods using outranking relations, the Promethee II method. Proposed comparative analysis can be used as a method for decision support during the selection of the most beneficial technological solution of solar installation and to evaluate operational efficiency existing buildings which will have implemented new systems.

  9. Consistency of the Babinski reflex and its variants.

    Science.gov (United States)

    Singerman, J; Lee, L

    2008-09-01

    The Babinski Reflex, first described in 1896, is still an integral part of the neurological examination. Many have studied the consistency of this reflex, but none have compared the inter- and intra-observer consistency of the Babinski reflex and its variants. Thirty-four subjects were examined by six neurologists. The Babinski, Gordon, Chaddock, and Oppenheim reflexes were tested, and each neurologist concluded if the plantar response was flexor or extensor. Six subjects were re-tested 1 week later to determine intra-observer consistency. The Babinski reflex had the highest interobserver consistency with a kappa value of 0.5491. The Chaddock, Oppenheim, and Gordon reflexes had kappa values of 0.4065, 0.3739, and 0.3515, respectively. For intra-observer consistency, Gordon was the most consistent with a kappa value of 0.6731. When reflexes were combined in pairs, the Babinski and Chaddock reflexes together were the most reliable. The Babinski reflex was shown to be the most consistent between examiners. The Gordon reflex had the highest intra-observer consistency; however, the small sample size should limit conclusions drawn from this calculation. Clinicians often utilize more than one reflex to examine the plantar response; the combination of the Babinski and Chaddock reflexes was the most reliable.

  10. Hospital Compare

    Data.gov (United States)

    U.S. Department of Health & Human Services — Hospital Compare has information about the quality of care at over 4,000 Medicare-certified hospitals across the country. You can use Hospital Compare to find...

  11. An analysis of correspondence between unique rabies virus variants and divergent big brown bat (Eptesicus fuscus) mitochondrial DNA lineages

    Science.gov (United States)

    Neubaum, M.A.; Shankar, V.; Douglas, M.R.; Douglas, M.E.; O'Shea, T.J.; Rupprecht, C.E.

    2008-01-01

    The literature supports that unique rabies virus (RABV) variants are often compartmentalized in different species of bats. In Colorado, two divergent mtDNA lineages of big brown bats (Eptesicus fuscus) co-occur. RABV associated with this species also segregates into two clades. We hypothesized that unique RABV variants might be associated with mtDNA lineages of Colorado big brown bats. DNA was extracted from brain tissue of rabid big brown bats, the ND2 gene was amplified to determine mtDNA lineage, and the lineage was compared to a previously derived phylogenetic analysis of the RABV N gene. No correspondence was found between host bat lineage and RABV variant. ?? 2008 Springer-Verlag.

  12. Linc-ROR and its spliced variants 2 and 4 are significantly up-regulated in esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Reza Sahebi

    2016-10-01

    Results: The quantitative real-time RT-PCR results revealed a significant up-regulation of linc-ROR (P=0.0098 and its variants 2 (P=0.0250 and 4 (P=0.0002 in tumor samples of ESCC, compared to their matched non-tumor tissues obtained from the margin of same tumors. Our data also demonstrated a significant up-regulation of variant 4 in high-grade tumor samples, in comparison to the low-grade ones (P=0.04. Moreover, the ROC curve analysis demonstrated that the variant 4 of ROR has a potential to discriminate between tumor and non-tumor samples (AUC=0.66, P

  13. Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity

    DEFF Research Database (Denmark)

    Larsen, Lesli H; Echwald, Søren Morgenthaler; Sørensen, Thorkild I A

    2005-01-01

    )) for mutations in MC4R. A total of 14 different mutations were identified of which two, Ala219Val and Leu325Phe, were novel variants. The variant receptor, Leu325Phe, was unable to bind [Nle4,d-Phe7]-alphaMSH, whereas the Ala219Val variant showed a significantly impaired melanotan II induction of cAMP, compared......Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 +/- 2.4 kg/m(2)) and 706 control subjects (body mass index 21.4 +/- 2.1 kg/m(2...

  14. Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0480 TITLE: Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy PRINCIPAL INVESTIGATOR...Splice Variants and Resistance to Taxane Chemotherapy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0480 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...During this reporting period, we have obtained approval for a no-cost extension of this award and change of research focus in the final year. This

  15. HIV-1 genetic variants in the Russian Far East.

    Science.gov (United States)

    Kazennova, Elena; Laga, Vita; Lapovok, Ilya; Glushchenko, Nataliya; Neshumaev, Dmitry; Vasilyev, Alexander; Bobkova, Marina

    2014-08-01

    A molecular analysis of HIV-1 subtypes and recombinants circulating in cities in the Russian Far East was performed. The study included samples from 201 outpatients from Vladivostok, Khabarovsk, and Blagoveshchensk. In most parts of Russia, patients are infected with HIV-1 subtype A, known as the IDU-A variant. Subtype B, including the IDU-B variant, is rare in Russia but widespread in the Ukraine, and the CRF02_AG is prevalent in Central Asian countries and Siberia, Russia. One of the challenges of this study in the Far East was to determine whether the molecular landscape of HIV infection in this region is influenced by the bordering countries, including China and Japan, where a distinct set of HIV subtypes is circulating, such as B', C, and CRF01_AE. The distribution of HIV-1 genetic variants in the cities studied was as follows: subtype A (IDU-A), 55.7%; subtype B, 25.3% (IDU-B variant-24.3%); subtype C, 10.0%; CRF02_AG, 1.5%; and CRF63_02A1, 7.5%. A phylogenetic analysis confirmed the relationship of subtype A viruses with the IDU-A variant predominating in Ukraine, Russia and other former Soviet Union (FSU) countries, of subtype B viruses with IDU-B in the Ukraine and of CRF02_AG variants with variants in Uzbekistan, Russia, and other former USSR countries. Subtype C sequences were not uniform, and most clustered between each other and HIV-1 sequences originating from Africa; there was only one sample possibly related to Chinese variants. Thus, despite close cultural and commercial relationships among Russia, China, and Japan, the distribution of HIV-1 subtypes in the Russian Far East is still primarily influenced by contacts with the countries of the former USSR.

  16. Histone variant innovation in a rapidly evolving chordate lineage

    Directory of Open Access Journals (Sweden)

    Jansen Pascal WTC

    2011-07-01

    Full Text Available Abstract Background Histone variants alter the composition of nucleosomes and play crucial roles in transcription, chromosome segregation, DNA repair, and sperm compaction. Modification of metazoan histone variant lineages occurs on a background of genome architecture that shows global similarities from sponges to vertebrates, but the urochordate, Oikopleura dioica, a member of the sister group to vertebrates, exhibits profound modification of this ancestral architecture. Results We show that a histone complement of 47 gene loci encodes 31 histone variants, grouped in distinct sets of developmental expression profiles throughout the life cycle. A particularly diverse array of 15 male-specific histone variants was uncovered, including a testes-specific H4t, the first metazoan H4 sequence variant reported. Universal histone variants H3.3, CenH3, and H2A.Z are present but O. dioica lacks homologs of macroH2A and H2AX. The genome encodes many H2A and H2B variants and the repertoire of H2A.Z isoforms is expanded through alternative splicing, incrementally regulating the number of acetylatable lysine residues in the functionally important N-terminal "charge patch". Mass spectrometry identified 40 acetylation, methylation and ubiquitylation posttranslational modifications (PTMs and showed that hallmark PTMs of "active" and "repressive" chromatin were present in O. dioica. No obvious reduction in silent heterochromatic marks was observed despite high gene density in this extraordinarily compacted chordate genome. Conclusions These results show that histone gene complements and their organization differ considerably even over modest phylogenetic distances. Substantial innovation among all core and linker histone variants has evolved in concert with adaptation of specific life history traits in this rapidly evolving chordate lineage.

  17. Stress Induced Cardiomyopathy with Midventricular Ballooning: A Rare Variant

    OpenAIRE

    Muhammad Umer Siddiqui; Michael C. Desiderio; Nicholas Ricculli; Arthur Rusovici

    2015-01-01

    Stress cardiomyopathy (SCM) also referred to as the ?broken heart syndrome? is a condition in which intense emotional or physical stress can cause fulminant and reversible cardiac muscle weakness. SCM most commonly involves the apical segment of left ventricle but newer and rare variants have recently been seen reported. We here report a case of rare midventricular variant of stress related cardiomyopathy. A 72-year-old female with past medical history, only significant for SVT, presented wit...

  18. Structural insights into methanol-stable variants of lipase T6 from Geobacillus stearothermophilus.

    Science.gov (United States)

    Dror, Adi; Kanteev, Margarita; Kagan, Irit; Gihaz, Shalev; Shahar, Anat; Fishman, Ayelet

    2015-11-01

    Enzymatic production of biodiesel by transesterification of triglycerides and alcohol, catalyzed by lipases, offers an environmentally friendly and efficient alternative to the chemically catalyzed process while using low-grade feedstocks. Methanol is utilized frequently as the alcohol in the reaction due to its reactivity and low cost. However, one of the major drawbacks of the enzymatic system is the presence of high methanol concentrations which leads to methanol-induced unfolding and inactivation of the biocatalyst. Therefore, a methanol-stable lipase is of great interest for the biodiesel industry. In this study, protein engineering was applied to substitute charged surface residues with hydrophobic ones to enhance the stability in methanol of a lipase from Geobacillus stearothermophilus T6. We identified a methanol-stable variant, R374W, and combined it with a variant found previously, H86Y/A269T. The triple mutant, H86Y/A269T/R374W, had a half-life value at 70 % methanol of 324 min which reflects an 87-fold enhanced stability compared to the wild type together with elevated thermostability in buffer and in 50 % methanol. This variant also exhibited an improved biodiesel yield from waste chicken oil compared to commercial Lipolase 100L® and Novozyme® CALB. Crystal structures of the wild type and the methanol-stable variants provided insights regarding structure-stability correlations. The most prominent features were the extensive formation of new hydrogen bonds between surface residues directly or mediated by structural water molecules and the stabilization of Zn and Ca binding sites. Mutation sites were also characterized by lower B-factor values calculated from the X-ray structures indicating improved rigidity.

  19. Variants affecting exon skipping contribute to complex traits.

    Directory of Open Access Journals (Sweden)

    Younghee Lee

    Full Text Available DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1 experimentally validate our in silico predictions of skipped exons and 2 characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits.

  20. Prebiotic Competition between Information Variants, With Low Error Catastrophe Risks

    Directory of Open Access Journals (Sweden)

    Radu Popa

    2015-07-01

    Full Text Available During competition for resources in primitive networks increased fitness of an information variant does not necessarily equate with successful elimination of its competitors. If variability is added fast to a system, speedy replacement of pre-existing and less-efficient forms of order is required as novel information variants arrive. Otherwise, the information capacity of the system fills up with information variants (an effect referred as “error catastrophe”. As the cost for managing the system’s exceeding complexity increases, the correlation between performance capabilities of information variants and their competitive success decreases, and evolution of such systems toward increased efficiency slows down. This impasse impedes the understanding of evolution in prebiotic networks. We used the simulation platform Biotic Abstract Dual Automata (BiADA to analyze how information variants compete in a resource-limited space. We analyzed the effect of energy-related features (differences in autocatalytic efficiency, energy cost of order, energy availability, transformation rates and stability of order on this competition. We discuss circumstances and controllers allowing primitive networks acquire novel information with minimal “error catastrophe” risks. We present a primitive mechanism for maximization of energy flux in dynamic networks. This work helps evaluate controllers of evolution in prebiotic networks and other systems where information variants compete.

  1. Update on lichen planus and its clinical variants.

    Science.gov (United States)

    Weston, Gillian; Payette, Michael

    2015-08-01

    Lichen planus (LP) is an inflammatory skin condition with characteristic clinical and histopathological findings. Classic LP typically presents as pruritic, polygonal, violaceous flat-topped papules and plaques; many variants in morphology and location also exist, including oral, nail, linear, annular, atrophic, hypertrophic, inverse, eruptive, bullous, ulcerative, lichen planus pigmentosus, lichen planopilaris, vulvovaginal, actinic, lichen planus-lupus erythematosus overlap syndrome, and lichen planus pemphigoides. Clinical presentation of the rarer variant lesions may be largely dissimilar to classic LP and therefore difficult to diagnose based solely on clinical examination. However, histopathological examination of LP and LP-variant lesions reveal similar features, aiding in the proper diagnosis of the disease. Management of LP and LP variants aims to control symptoms and to decrease time from onset to resolution; it often involves topical corticosteroids, but varies depending on the severity and location of the lesion. The literature contains an array of reports on the variations in presentation and successful management of LP and its variants. A familiarity with LP and its variants is important in achieving timely recognition and management of the disease.

  2. [Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies].

    Science.gov (United States)

    Romero-Sánchez, Consuelo; Gómez Gutiérrez, Alberto; Duarte, Yurani; Amazo, Constanza; Manosalva, Clara; Chila M, Lorena; Casas-Gómez, María Consuelo; Briceño Balcázar, Ignacio

    2015-10-01

    Oxygen transport is altered in hemoglobinopathies. To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

  3. Lightning-fast genome variant detection with GROM.

    Science.gov (United States)

    Smith, Sean D; Kawash, Joseph K; Grigoriev, Andrey

    2017-10-01

    Current human whole genome sequencing projects produce massive amounts of data, often creating significant computational challenges. Different approaches have been developed for each type of genome variant and method of its detection, necessitating users to run multiple algorithms to find variants. We present Genome Rearrangement OmniMapper (GROM), a novel comprehensive variant detection algorithm accepting aligned read files as input and finding SNVs, indels, structural variants (SVs), and copy number variants (CNVs). We show that GROM outperforms state-of-the-art methods on 7 validated benchmarks using 2 whole genome sequencing (WGS) data sets. Additionally, GROM boasts lightning-fast run times, analyzing a 50× WGS human data set (NA12878) on commonly available computer hardware in 11 minutes, more than an order of magnitude (up to 72 times) faster than tools detecting a similar range of variants. Addressing the needs of big data analysis, GROM combines in 1 algorithm SNV, indel, SV, and CNV detection, providing superior speed, sensitivity, and precision. GROM is also able to detect CNVs, SNVs, and indels in non-paired-read WGS libraries, as well as SNVs and indels in whole exome or RNA sequencing data sets. © The Authors 2017. Published by Oxford University Press.

  4. An Efficient Multiple Variants Coordination Framework for Differential Evolution.

    Science.gov (United States)

    Zhang, Sheng Xin; Zheng, Shao Yong; Zheng, Li Ming

    2017-09-01

    Differential evolution (DE) is recognized as a simple but powerful algorithm in the family of evolutionary algorithms. Over the past two decades, many advanced DE variants with significantly improved performance have been proposed. However, the variants may only achieve the best performance on a certain type of functions. Moreover, a specific optimizer may not always be suitable for the whole optimization process. To overcome these weaknesses, this paper proposes a multiple variants coordination (MVC) framework with two mechanisms, namely, the multiple variants adaptive selecting mechanism and the multiple variants adaptive solutions preserving mechanisms (MV-APM). In MVC, the evolution process is divided into nonoverlap segments with equal numbers of generations. Each segment includes the learning generations (LGs) and executing generations (EGs). In LG, all the candidate DE optimizers are utilized independently. The best performing optimizer is determined and then utilized in EG in the same segment. Furthermore, MV-APM maintains the population by adaptively preserving promising solutions generated by multiple optimizers. Numerical experiments on the CEC2014 benchmark suit show that the proposed MVC framework can significantly improve the performance of the baseline algorithms and the resulted algorithm significantly outperform the start-of-the-art and up-to-date DEs. Moreover, as a general framework, MVC can also be applied to coordinate multiple improved DE variants to further enhance their performance.

  5. The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response.

    Science.gov (United States)

    Ooi, Teik Chye; Krysa, Jacqueline A; Chaker, Seham; Abujrad, Hussein; Mayne, Janice; Henry, Kathy; Cousins, Marion; Raymond, Angela; Favreau, Colette; Taljaard, Monica; Chrétien, Michel; Mbikay, Majambu; Proctor, Spencer D; Vine, Donna F

    2017-09-01

    Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low-density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR. We hypothesized that PCSK9-LOF carriers would have lower fasting and postprandial remnant lipoproteins on top of lower LDL-C. To compare fasting and postprandial concentrations of triglycerides (TGs), total apoB, and apoB48 as indicators of remnant lipoprotein metabolism in PCSK9-LOF carriers with those with no PCSK9 variants. Case-control, metabolic study. Clinical Research Center of The Ottawa Hospital. Persons with one or more copies of the L10ins/A53V and/or I474V and/or R46L PCSK9 variant and persons with no PCSK9 variants. Oral fat tolerance test. Fasting and postprandial plasma TG, apoB48, total apoB, total cholesterol, and PCSK9 were measured at 0, 2, 4, and 6 hours after an oral fat load. Participants with PCSK9-LOF variants (n = 22) had reduced fasting LDL-C (-14%) as well as lower fasting TG (-21%) compared with noncarrier controls (n = 23). LOF variants also had reduced postprandial total apoB (-17%), apoB48 (-23%), and TG (-18%). Postprandial PCSK9 declined in both groups (-24% vs -16%, respectively). Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.

  6. Identification of Novel Variant of EML4-ALK Fusion Gene in NSCLC: Potential Benefits of the RT-PCR Method

    Science.gov (United States)

    Maus, Martin K. H.; Stephens, Craig; Zeger, Gary; Grimminger, Peter P.; Huang, Eric

    2012-01-01

    Background: The discovery of the transforming fusion gene of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) as an oncogene in 2007 has led to its validation as a clinical target in NSCLC patients in a short period of time. The inhibition of the anaplastic lymphoma receptor tyrosine kinase has demonstrated to prolong progression-free survival compared to the standard of care chemotherapy in patients with advanced NSCLC that are ALK positive. However, the clinical implications of the 15 different variants of the EML4-ALK transforming gene described so far are currently not defined. Here we present a novel variant of the EML4-ALK fusion gene which we named variant 3c. Methods: RNA extracted from formalin fixed paraffin embedded (FFPE) specimens from patients with advanced and metastatic NSCLC was amplified, using primers and probes designed to detect specific EML4-ALK fusion gene fragments. Gel electrophoresis showed a different band for the new variant 3c compared to the known bands of positive cell lines for variant 3a and 3b. These findings were further investigated by dye-terminator Sequencing and FISH. Results: The novel variant, detected in two NSCLC specimens, is longer than v3a and shorter than v3b, representing an 18 base pair insertion of intron 19 of ALK between exon 6 of EML4 and exon 20 of ALK. All of the two samples showed exactly the same sequencing result. One of the samples was negative for FISH break apart testing and the other one showed a positive result, defined by ≥15% split nuclei as indicative of an ALK rearrangement. Conclusions: Compared to FISH technology, RT-PCR enables the detection of different isoforms of the EML4-ALK transforming gene, which can be validated by sequencing. Only one out of two samples that were positive for the new variant by RT-PCR could be confirmed by FISH. The clinical significance of the different variants, notably to resistance and response to ALK

  7. Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1.

    Science.gov (United States)

    Liu, Wen; Poole, Elizabeth M; Ulrich, Cornelia M; Kulmacz, Richard J

    2012-07-01

    Aspirin (ASA), a major antiplatelet and cancer-preventing drug, irreversibly blocks the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (PGHS-1). Considerable differences in ASA effectiveness are observed between individuals, and some of this variability may be due to PGHS-1 protein variants. Our overall aim is to determine which, if any, of the known variants in the mature PGHS-1 protein lead to functional alterations in COX catalysis or inhibition by ASA. The present study targeted four PGHS-1 variants: R53H, R108Q, L237M, and V481I. Wild-type human PGHS-1 and the four polymorphic variants were expressed as histidine-tagged, homodimeric proteins in insect cells using baculovirus vectors, solubilized with a detergent, and purified by affinity chromatography. The purified proteins were characterized in vitro to evaluate COX and peroxidase (POX) catalytic parameters and the kinetics of COX inhibition by ASA and NS-398. Compared with the wild type, several variants showed a higher COX/POX ratio (up to 1.5-fold, for R108Q), an elevated arachidonate Km (up to 1.9-fold, for R108Q), and/or a lower ASA reactivity (up to 60% less, for R108Q). The decreased ASA reactivity in R108Q reflected both a 70% increase in the Ki for ASA and a 30% decrease in the rate constant for acetyl group transfer to the protein. Computational modeling of the brief ASA pulses experienced by PGHS-1 in circulating platelets during daily ASA dosing predicted that the 60% lower ASA reactivity in R108Q yields a 15-fold increase in surviving COX activity; smaller, approximately two-fold increases in surviving COX activity were predicted for L237M and V481I. NS-398 competitively inhibited COX catalysis of the wild type (Ki=6 µmol/l) and inhibited COX inactivation by 1.0 mmol/l ASA in both the wild type (IC50=0.8 µmol/l) and R108Q (IC50=2.1 µmol/l). Of the four PGHS-1 variants examined, R108Q exerts the largest functional effects, with evidence for impaired interactions with a COX

  8. KinMutRF: a random forest classifier of sequence variants in the human protein kinase superfamily.

    Science.gov (United States)

    Pons, Tirso; Vazquez, Miguel; Matey-Hernandez, María Luisa; Brunak, Søren; Valencia, Alfonso; Izarzugaza, Jose Mg

    2016-06-23

    The association between aberrant signal processing by protein kinases and human diseases such as cancer was established long time ago. However, understanding the link between sequence variants in the protein kinase superfamily and the mechanistic complex traits at the molecular level remains challenging: cells tolerate most genomic alterations and only a minor fraction disrupt molecular function sufficiently and drive disease. KinMutRF is a novel random-forest method to automatically identify pathogenic variants in human kinases. Twenty six decision trees implemented as a random forest ponder a battery of features that characterize the variants: a) at the gene level, including membership to a Kinbase group and Gene Ontology terms; b) at the PFAM domain level; and c) at the residue level, the types of amino acids involved, changes in biochemical properties, functional annotations from UniProt, Phospho.ELM and FireDB. KinMutRF identifies disease-associated variants satisfactorily (Acc: 0.88, Prec:0.82, Rec:0.75, F-score:0.78, MCC:0.68) when trained and cross-validated with the 3689 human kinase variants from UniProt that have been annotated as neutral or pathogenic. All unclassified variants were excluded from the training set. Furthermore, KinMutRF is discussed with respect to two independent kinase-specific sets of mutations no included in the training and testing, Kin-Driver (643 variants) and Pon-BTK (1495 variants). Moreover, we provide predictions for the 848 protein kinase variants in UniProt that remained unclassified. A public implementation of KinMutRF, including documentation and examples, is available online ( http://kinmut2.bioinfo.cnio.es ). The source code for local installation is released under a GPL version 3 license, and can be downloaded from https://github.com/Rbbt-Workflows/KinMut2 . KinMutRF is capable of classifying kinase variation with good performance. Predictions by KinMutRF compare favorably in a benchmark with other state

  9. Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A.

    Science.gov (United States)

    Nguyen, G N; George, L A; Siner, J I; Davidson, R J; Zander, C B; Zheng, X L; Arruda, V R; Camire, R M; Sabatino, D E

    2017-01-01

    Essentials Factor (F) VIII is an inefficiently expressed protein. Furin deletion FVIII variants were purified and characterized using in vitro and in vivo assays. These minimally modified novel FVIII variants have enhanced function. These variants provide a strategy for increasing FVIII expression in hemophilia A gene therapy. Background The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a paired basic amino acid cleaving enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain-deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function. Objective We hypothesized that deletion(s) of the furin site modulates FVIII biology and may enhance its function. Methods A series of recombinant hFVIII-furin deletion variants were introduced into hFVIII-BDD [Δ1645, 1645-46(Δ2), 1645-47(Δ3), 1645-48(Δ4), or Δ1648] and characterized. Results In vitro, recombinant purified Δ3 and Δ4 were primarily SC and, interestingly, had 2-fold higher procoagulant activity compared with FVIII-BDD. In vivo, the variants also have improved hemostatic function. After adeno-associated viral (AAV) vector delivery, the expression of these variants is 2-4-fold higher than hFVIII-BDD. Protein challenges of each variant in mice tolerant to hFVIII-BDD showed no anti-FVIII immune response. Conclusions These data suggest that the furin deletion hFVIII variants are superior to hFVIII-BDD without increased immunogenicity. In the setting of gene-based therapeutics, these novel variants provide a unique strategy to increase FVIII expression, thus lowering the vector dose, a

  10. Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

    Science.gov (United States)

    Mabuchi, Fumihiko; Mabuchi, Nakako; Sakurada, Yoichi; Yoneyama, Seigo; Kashiwagi, Kenji; Iijima, Hiroyuki; Yamagata, Zentaro; Takamoto, Mitsuko; Aihara, Makoto; Iwata, Takeshi; Kawase, Kazuhide; Shiga, Yukihiro; Nishiguchi, Koji M; Nakazawa, Toru; Ozaki, Mineo; Araie, Makoto

    2017-01-01

    To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1±1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7±1.8) in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP≥22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

  11. Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

    Directory of Open Access Journals (Sweden)

    Fumihiko Mabuchi

    Full Text Available To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP and IOP, vertical cup-to-disc ratio (VCDR, and high tension glaucoma (HTG or normal tension glaucoma (NTG as phenotypic features of primary open-angle glaucoma (POAG, and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255 and NTG (n = 261 and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS, and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012 and VCDR (P = 0.010 significantly increased. The GRS (9.1±1.9 in patients with HTG was significantly higher (P = 0.011 than that (8.7±1.8 in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085 risk on HTG (maximum IOP≥22mmHg compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

  12. Functional non-synonymous variants of ABCG2 and gout risk.

    Science.gov (United States)

    Stiburkova, Blanka; Pavelcova, Katerina; Zavada, Jakub; Petru, Lenka; Simek, Pavel; Cepek, Pavel; Pavlikova, Marketa; Matsuo, Hirotaka; Merriman, Tony R; Pavelka, Karel

    2017-11-01

    Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout.

  13. Genetic risk variants for social anxiety.

    Science.gov (United States)

    Stein, Murray B; Chen, Chia-Yen; Jain, Sonia; Jensen, Kevin P; He, Feng; Heeringa, Steven G; Kessler, Ronald C; Maihofer, Adam; Nock, Matthew K; Ripke, Stephan; Sun, Xiaoying; Thomas, Michael L; Ursano, Robert J; Smoller, Jordan W; Gelernter, Joel

    2017-03-01

    Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h2g  = 0.12, P = 2.17 × 10-4 in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10-8 ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10-8 ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (rg  = -0.52, se = 0.22, P = 0.02) but not with neuroticism (rg  = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (rg  = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. Psychosis in behavioral variant frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Gossink FT

    2017-04-01

    Full Text Available Flora T Gossink,1,2 Everard GB Vijverberg,2,3 Welmoed Krudop,2 Philip Scheltens,2 Max L Stek,1 Yolande AL Pijnenburg,1,2 Annemiek Dols1,2 1Department of Old Age Psychiatry, GGZinGeest, 2Alzheimer Center & Department of Neurology, VU University Medical Center, Amsterdam, 3Department of Neurology, HagaZiekenhuis, The Hague, the Netherlands Background: Dementia is generally characterized by cognitive impairment that can be accompanied by psychotic symptoms; for example, visual hallucinations are a core feature of dementia with Lewy bodies, and delusions are often seen in Alzheimer’s disease. However, for behavioral variant of frontotemporal dementia (bvFTD, studies on the broad spectrum of psychotic symptoms are still lacking. The aim of this study was to systematically and prospectively subtype the wide spectrum of psychotic symptoms in probable and definite bvFTD.Methods: In this study, a commonly used and validated clinical scale that quantifies the broad spectrum of psychotic symptoms (Positive and Negative Symptom Scale was used in patients with probable and definite bvFTD (n=22 and with a primary psychiatric disorder (n=35 in a late-onset frontal lobe cohort. Median symptom duration was 2.8 years, and the patients were prospectively followed for 2 years.Results: In total, 22.7% of bvFTD patients suffered from delusions, hallucinatory behavior, and suspiciousness, although the majority of the patients exhibited negative psychotic symptoms such as social and emotional withdrawal and blunted affect (95.5% and formal thought disorders (81.8%. “Difficulty in abstract thinking” and “stereotypical thinking” (formal thought disorders differentiated bvFTD from psychiatric disorders. The combined predictors difficulty in abstract thinking, stereotypical thinking, “anxiety”, “guilt feelings,” and “tension” explained 75.4% of variance in the diagnosis of bvFTD versus psychiatric diagnoses (P<0.001.Conclusion: Delusions

  15. Alternative Technical Summary Report: Electrometallurgical Treatment Variant

    Energy Technology Data Exchange (ETDEWEB)

    Gray, L.W.

    1995-11-30

    Immobilization is the fixation of the surplus fissile materials in an acceptable matrix such as glass or ceramics to create an environmentally benign form for disposal in a repository. In addition to the traditional characteristics required of an immobilization form to achieve isolation of the fissile material from the biosphere over geologic times, the immobilization form for the Fissile Materials Disposition Program (FMDP) must also possess the property that it is inherently as unattractive and inaccessible as the fissile material from commercial spent fuel. This latter requirement is similar to the wording of the ''spent fuel standard'' invoked in the National Academy of Sciences (NAS) study on plutonium disposition. High-level wastes (HLW) or separated cesium ({sup 137}Cs), can be added with the fissile material into the waste form to create a radiation field that increases the proliferation resistance