Transformational Leadership, Transactional Contingent Reward, and Organizational Identification: The Mediating Effect of Perceived Innovation and Goal Culture Orientations

PubMed Central

Xenikou, Athena

2017-01-01

Purpose: The aim of this research was to investigate the effect of transformational leadership and transactional contingent reward as complementary, but distinct, forms of leadership on facets of organizational identification via the perception of innovation and goal organizational values. Design/Methodology/Approach: Three studies were carried out implementing either a measurement of mediation or experimental-causal-chain design to test for the hypothesized effects. Findings: The measurement of mediation study showed that transformational leadership had a positive direct and indirect effect, via innovation value orientation, on cognitive identification, whereas transactional contingent reward was more strongly related to affective, rather than cognitive, identification, and goal orientation was a mediator of their link. The findings of the two experimental-causal-chain studies further supported the hypothesized effects. Transformational leadership was found to lead subordinates to perceive the culture as more innovative compared to transactional contingent reward, whereas transactional contingent reward led employees to perceive the culture as more goal, than innovation, oriented. Finally, innovation, compared to goal, value orientation increased cognitive identification, while goal orientation facilitated affective, rather than cognitive, identification. Implications: The practical implications involve the development of strategies organizations can apply, such as leadership training programs, to strengthen their ties with their employees, which, in turn, may have a positive impact on in-role, as well as extra-role, behaviors. Originality/Value: The originality of this research concerns the identification of distinct mechanisms explaining the effect of transformational leadership and transactional contingent reward on cognitive and affective identification applying an organizational culture perspective and a combination of measurement and causal mediation designs

Outperforming whom? A multilevel study of performance-prove goal orientation, performance, and the moderating role of shared team identification.

PubMed

Dietz, Bart; van Knippenberg, Daan; Hirst, Giles; Restubog, Simon Lloyd D

2015-11-01

Performance-prove goal orientation affects performance because it drives people to try to outperform others. A proper understanding of the performance-motivating potential of performance-prove goal orientation requires, however, that we consider the question of whom people desire to outperform. In a multilevel analysis of this issue, we propose that the shared team identification of a team plays an important moderating role here, directing the performance-motivating influence of performance-prove goal orientation to either the team level or the individual level of performance. A multilevel study of salespeople nested in teams supports this proposition, showing that performance-prove goal orientation motivates team performance more with higher shared team identification, whereas performance-prove goal orientation motivates individual performance more with lower shared team identification. Establishing the robustness of these findings, a second study replicates them with individual and team performance in an educational context. (c) 2015 APA, all rights reserved).

Crystallographic Orientation Identification in Multicrystalline Silicon Wafers Using NIR Transmission Intensity

NASA Astrophysics Data System (ADS)

Skenes, Kevin; Kumar, Arkadeep; Prasath, R. G. R.; Danyluk, Steven

2018-02-01

Near-infrared (NIR) polariscopy is a technique used for the non-destructive evaluation of the in-plane stresses in photovoltaic silicon wafers. Accurate evaluation of these stresses requires correct identification of the stress-optic coefficient, a material property which relates photoelastic parameters to physical stresses. The material stress-optic coefficient of silicon varies with crystallographic orientation. This variation poses a unique problem when measuring stresses in multicrystalline silicon (mc-Si) wafers. This paper concludes that the crystallographic orientation of silicon can be estimated by measuring the transmission of NIR light through the material. The transmission of NIR light through monocrystalline wafers of known orientation were compared with the transmission of NIR light through various grains in mc-Si wafers. X-ray diffraction was then used to verify the relationship by obtaining the crystallographic orientations of these assorted mc-Si grains. Variation of transmission intensity for different crystallographic orientations is further explained by using planar atomic density. The relationship between transmission intensity and planar atomic density appears to be linear.

Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.

PubMed

Schuurs-Hoeijmakers, Janneke H M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; van de Vondervoort, Ilse I G M; van Bon, Bregje W M; de Ligt, Joep; Gilissen, Christian; Hehir-Kwa, Jayne Y; Neveling, Kornelia; del Rosario, Marisol; Hira, Gausiya; Reitano, Santina; Vitello, Aurelio; Failla, Pinella; Greco, Donatella; Fichera, Marco; Galesi, Ornella; Kleefstra, Tjitske; Greally, Marie T; Ockeloen, Charlotte W; Willemsen, Marjolein H; Bongers, Ernie M H F; Janssen, Irene M; Pfundt, Rolph; Veltman, Joris A; Romano, Corrado; Willemsen, Michèl A; van Bokhoven, Hans; Brunner, Han G; de Vries, Bert B A; de Brouwer, Arjan P M

2013-12-01

Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

Identification of Five Novel Variants in Chinese Oculocutaneous Albinism by Targeted Next-Generation Sequencing.

PubMed

Qiu, Biyuan; Ma, Tao; Peng, Chunyan; Zheng, Xiaoqin; Yang, Jiyun

2018-04-01

The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic. To develop and validate a more comprehensive, targeted, next-generation-sequencing-based diagnostic for the identification of OCA-causing variants. The genomic DNA samples from 28 OCA probands were analyzed by targeted next-generation sequencing (NGS), and the candidate variants were confirmed through Sanger sequencing. We observed mutations in the TYR, OCA2, and SLC45A2 genes in 25/28 (89%) patients with OCA. We identified 38 pathogenic variants among these three genes, including 5 novel variants: c.1970G>T (p.Gly657Val), c.1669A>C (p.Thr557Pro), c.2339-2A>C, and c.1349C>G (p.Thr450Arg) in OCA2; c.459_470delTTTTGCTGCCGA (p.Ala155_Phe158del) in SLC45A2. Our findings expand the mutational spectrum of OCA in the Chinese population, and the assay we developed should be broadly useful as a molecular diagnostic, and as an aid for genetic counseling for OCA patients.

Multi-species Identification of Polymorphic Peptide Variants via Propagation in Spectral Networks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Na, Seungjin; Payne, Samuel H.; Bandeira, Nuno

The spectral networks approach enables the detection of pairs of spectra from related peptides and thus allows for the propagation of annotations from identified peptides to unidentified spectra. Beyond allowing for unbiased discovery of unexpected post-translational modifications, spectral networks are also applicable to multi-species comparative proteomics or metaproteomics to identify numerous orthologous versions of a protein. We present algorithmic and statistical advances in spectral networks that have made it possible to rigorously assess the statistical significance of spectral pairs and accurately estimate the error rate of identifications via propagation. In the analysis of three related Cyanothece species, a model organismmore » for biohydrogen production, spectral networks identified peptides with highly divergent sequences with up to dozens of variants per peptide, including many novel peptides in species that lack a sequenced genome. Furthermore, spectral networks strongly suggested the presence of novel peptides even in genomically characterized species (i.e. missing from databases) in that a significant portion of unidentified multi-species networks included at least two polymorphic peptide variants.« less

Approach/Avoidance Orientations Affect Self-Construal and Identification with In-group

PubMed Central

Nussinson, Ravit; Häfner, Michael; Seibt, Beate; Strack, Fritz; Trope, Yaacov

2011-01-01

Approach and avoidance are two basic motivational orientations. Their activation influences cognitive and perceptive processes: Previous work suggests that an approach orientation instigates a focus on larger units as compared to avoidance. Study 1 confirms this assumption using a paradigm that more directly taps a person’s tendency to represent objects as belonging to small or large units than prior studies. It was further predicted that the self should also be represented as belonging to larger units, and hence be more interdependent under approach than under avoidance. Study 2 supports this prediction. As a consequence of this focus on belonging to larger units, it was finally predicted that approach results in a stronger identification with one’s in-group than avoidance. Studies 3 and 4 support that prediction. PMID:22844229

Simple and efficient identification of rare recessive pathologically important sequence variants from next generation exome sequence data.

PubMed

Carr, Ian M; Morgan, Joanne; Watson, Christopher; Melnik, Svitlana; Diggle, Christine P; Logan, Clare V; Harrison, Sally M; Taylor, Graham R; Pena, Sergio D J; Markham, Alexander F; Alkuraya, Fowzan S; Black, Graeme C M; Ali, Manir; Bonthron, David T

2013-07-01

Massively parallel ("next generation") DNA sequencing (NGS) has quickly become the method of choice for seeking pathogenic mutations in rare uncharacterized monogenic diseases. Typically, before DNA sequencing, protein-coding regions are enriched from patient genomic DNA, representing either the entire genome ("exome sequencing") or selected mapped candidate loci. Sequence variants, identified as differences between the patient's and the human genome reference sequences, are then filtered according to various quality parameters. Changes are screened against datasets of known polymorphisms, such as dbSNP and the 1000 Genomes Project, in the effort to narrow the list of candidate causative variants. An increasing number of commercial services now offer to both generate and align NGS data to a reference genome. This potentially allows small groups with limited computing infrastructure and informatics skills to utilize this technology. However, the capability to effectively filter and assess sequence variants is still an important bottleneck in the identification of deleterious sequence variants in both research and diagnostic settings. We have developed an approach to this problem comprising a user-friendly suite of programs that can interactively analyze, filter and screen data from enrichment-capture NGS data. These programs ("Agile Suite") are particularly suitable for small-scale gene discovery or for diagnostic analysis. © 2013 WILEY PERIODICALS, INC.

Multi-species Identification of Polymorphic Peptide Variants via Propagation in Spectral Networks*

PubMed Central

Bandeira, Nuno

2016-01-01

Peptide and protein identification remains challenging in organisms with poorly annotated or rapidly evolving genomes, as are commonly encountered in environmental or biofuels research. Such limitations render tandem mass spectrometry (MS/MS) database search algorithms ineffective as they lack corresponding sequences required for peptide-spectrum matching. We address this challenge with the spectral networks approach to (1) match spectra of orthologous peptides across multiple related species and then (2) propagate peptide annotations from identified to unidentified spectra. We here present algorithms to assess the statistical significance of spectral alignments (Align-GF), reduce the impurity in spectral networks, and accurately estimate the error rate in propagated identifications. Analyzing three related Cyanothece species, a model organism for biohydrogen production, spectral networks identified peptides from highly divergent sequences from networks with dozens of variant peptides, including thousands of peptides in species lacking a sequenced genome. Our analysis further detected the presence of many novel putative peptides even in genomically characterized species, thus suggesting the possibility of gaps in our understanding of their proteomic and genomic expression. A web-based pipeline for spectral networks analysis is available at http://proteomics.ucsd.edu/software. PMID:27609420

Search-based model identification of smart-structure damage

NASA Technical Reports Server (NTRS)

Glass, B. J.; Macalou, A.

1991-01-01

This paper describes the use of a combined model and parameter identification approach, based on modal analysis and artificial intelligence (AI) techniques, for identifying damage or flaws in a rotating truss structure incorporating embedded piezoceramic sensors. This smart structure example is representative of a class of structures commonly found in aerospace systems and next generation space structures. Artificial intelligence techniques of classification, heuristic search, and an object-oriented knowledge base are used in an AI-based model identification approach. A finite model space is classified into a search tree, over which a variant of best-first search is used to identify the model whose stored response most closely matches that of the input. Newly-encountered models can be incorporated into the model space. This adaptativeness demonstrates the potential for learning control. Following this output-error model identification, numerical parameter identification is used to further refine the identified model. Given the rotating truss example in this paper, noisy data corresponding to various damage configurations are input to both this approach and a conventional parameter identification method. The combination of the AI-based model identification with parameter identification is shown to lead to smaller parameter corrections than required by the use of parameter identification alone.

Semiconductor Whole Exome Sequencing for the Identification of Genetic Variants in Colombian Patients Clinically Diagnosed with Long QT Syndrome.

PubMed

Burgos, Mariana; Arenas, Alvaro; Cabrera, Rodrigo

2016-08-01

Inherited long QT syndrome (LQTS) is a cardiac channelopathy characterized by a prolongation of QT interval and the risk of syncope, cardiac arrest, and sudden cardiac death. Genetic diagnosis of LQTS is critical in medical practice as results can guide adequate management of patients and distinguish phenocopies such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, extensive screening of large genomic regions is required in order to reliably identify genetic causes. Semiconductor whole exome sequencing (WES) is a promising approach for the identification of variants in the coding regions of most human genes. DNA samples from 21 Colombian patients clinically diagnosed with LQTS were enriched for coding regions using multiplex polymerase chain reaction (PCR) and subjected to WES using a semiconductor sequencer. Semiconductor WES showed mean coverage of 93.6 % for all coding regions relevant to LQTS at >10× depth with high intra- and inter-assay depth heterogeneity. Fifteen variants were detected in 12 patients in genes associated with LQTS. Three variants were identified in three patients in genes associated with CPVT. Co-segregation analysis was performed when possible. All variants were analyzed with two pathogenicity prediction algorithms. The overall prevalence of LQTS and CPVT variants in our cohort was 71.4 %. All LQTS variants previously identified through commercial genetic testing were identified. Standardized WES assays can be easily implemented, often at a lower cost than sequencing panels. Our results show that WES can identify LQTS-causing mutations and permits differential diagnosis of related conditions in a real-world clinical setting. However, high heterogeneity in sequencing depth and low coverage in the most relevant genes is expected to be associated with reduced analytical sensitivity.

Team-oriented leadership: the interactive effects of leader group prototypicality, accountability, and team identification.

PubMed

Giessner, Steffen R; van Knippenberg, Daan; van Ginkel, Wendy; Sleebos, Ed

2013-07-01

We examined the interactive effects of leader group prototypicality, accountability, and team identification on team-oriented behavior of leaders, thus extending the social identity perspective on leadership to the study of leader behavior. An experimental study (N = 152) supported our hypothesis that leader accountability relates more strongly to team-oriented behavior for group nonprototypical leaders than for group prototypical leaders. A multisource field study with leaders (N = 64) and their followers (N = 209) indicated that this interactive effect is more pronounced for leaders who identify more strongly with their team. We discuss how these findings further develop the social identity analysis of leadership. PsycINFO Database Record (c) 2013 APA, all rights reserved.

HapFABIA: Identification of very short segments of identity by descent characterized by rare variants in large sequencing data

PubMed Central

Hochreiter, Sepp

2013-01-01

Identity by descent (IBD) can be reliably detected for long shared DNA segments, which are found in related individuals. However, many studies contain cohorts of unrelated individuals that share only short IBD segments. New sequencing technologies facilitate identification of short IBD segments through rare variants, which convey more information on IBD than common variants. Current IBD detection methods, however, are not designed to use rare variants for the detection of short IBD segments. Short IBD segments reveal genetic structures at high resolution. Therefore, they can help to improve imputation and phasing, to increase genotyping accuracy for low-coverage sequencing and to increase the power of association studies. Since short IBD segments are further assumed to be old, they can shed light on the evolutionary history of humans. We propose HapFABIA, a computational method that applies biclustering to identify very short IBD segments characterized by rare variants. HapFABIA is designed to detect short IBD segments in genotype data that were obtained from next-generation sequencing, but can also be applied to DNA microarray data. Especially in next-generation sequencing data, HapFABIA exploits rare variants for IBD detection. HapFABIA significantly outperformed competing algorithms at detecting short IBD segments on artificial and simulated data with rare variants. HapFABIA identified 160 588 different short IBD segments characterized by rare variants with a median length of 23 kb (mean 24 kb) in data for chromosome 1 of the 1000 Genomes Project. These short IBD segments contain 752 000 single nucleotide variants (SNVs), which account for 39% of the rare variants and 23.5% of all variants. The vast majority—152 000 IBD segments—are shared by Africans, while only 19 000 and 11 000 are shared by Europeans and Asians, respectively. IBD segments that match the Denisova or the Neandertal genome are found significantly more often in Asians and Europeans but also

Protein-based forensic identification using genetically variant peptides in human bone.

PubMed

Mason, Katelyn Elizabeth; Anex, Deon; Grey, Todd; Hart, Bradley; Parker, Glendon

2018-04-22

Bone tissue contains organic material that is useful for forensic investigations and may contain preserved endogenous protein that can persist in the environment for extended periods of time over a range of conditions. Single amino acid polymorphisms in these proteins reflect genetic information since they result from non-synonymous single nucleotide polymorphisms (SNPs) in DNA. Detection of genetically variant peptides (GVPs) - those peptides that contain amino acid polymorphisms - in digests of bone proteins allows for the corresponding SNP alleles to be inferred. Resulting genetic profiles can be used to calculate statistical measures of association between a bone sample and an individual. In this study proteomic analysis on rib cortical bone samples from 10 recently deceased individuals demonstrates this concept. A straight-forward acidic demineralization protocol yielded proteins that were digested with trypsin. Tryptic digests were analyzed by liquid chromatography mass spectrometry. A total of 1736 different proteins were identified across all resulting datasets. On average, individual samples contained 454±121 (x¯±σ) proteins. Thirty-five genetically variant peptides were identified from 15 observed proteins. Overall, 134 SNP inferences were made based on proteomically detected GVPs, which were confirmed by sequencing of subject DNA. Inferred individual SNP genetic profiles ranged in random match probability (RMP) from 1/6 to 1/42,472 when calculated with European population frequencies in the 1000 Genomes Project, Phase 3. Similarly, RMPs based on African population frequencies were calculated for each SNP genetic profile and likelihood ratios (LR) were obtained by dividing each European RMP by the corresponding African RMP. Resulting LR values ranged from 1.4 to 825 with a median value of 16. GVP markers offer a basis for the identification of compromised skeletal remains independent of the presence of DNA template. Published by Elsevier B.V.

Identification of a new variant of Chlamydia trachomatis in Mexico.

PubMed

Escobedo-Guerra, Marcos R; Katoku-Herrera, Mitzuko; Lopez-Hurtado, Marcela; Villagrana-Zesati, Jesus Roberto; de Haro-Cruz, María de J; Guerra-Infante, Fernando M

2018-04-07

Chlamydia trachomatis is one of the main etiological agents of sexually transmitted infections worldwide. In 2006, a Swedish variant of C. trachomatis (Swedish-nvCT), which has a deletion of 377bp in the plasmid, was reported. In Latin America, Swedish-nvCT infections have not been reported. We investigated the presence of Swedish-nvCT in women with infertility in Mexico. Swedish-nvCT was searched in 69C. trachomatis positive samples from 2339 endocervical specimens. We designed PCR primers to identify the deletion in the plasmid in the ORF1, and the presence of a repeated 44bp in the ORF3. The sample with the deletion was genotyped with the genes of the major outer membrane protein A (ompA) and the polymorphic membrane protein (pmpH). The deletion was detected in one of the 69 samples positive C. trachomatis of 2339 endocervical exudates. The nucleotide sequence analysis of the ompA shows a high degree of similarity with the Swedish nvCT (98%), however the variant found belongs to serovar D. The nucleotide sequence of the pmpH gene associates to the variant found in the genitourinary pathotype of the Swedish-nvCT but in different clusters. Our results revealed the presence of a new variant of C. trachomatis in Mexican patients. This variant found in Mexico belongs to serovar D based on the in silico analysis of the ompA and pmpH genes and differs to the Swedish-nvCT (serovars E). For these variants of C. trachomatis that have been found it is necessary to carry out a more detailed analysis, although the role of this mutation has not been demonstrated in the pathogenesis. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia

PubMed Central

Brenner, Darren R.; Amos, Christopher I.; Brhane, Yonathan; Timofeeva, Maria N.; Caporaso, Neil; Wang, Yufei; Christiani, David C.; Bickeböller, Heike; Yang, Ping; Albanes, Demetrius; Stevens, Victoria L.; Gapstur, Susan; McKay, James; Boffetta, Paolo; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E.; Skorpen, Frank; Gabrielsen, Maiken E.; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Broderick, Peter; Eisen, Timothy; Wu, Xifeng; Zhang, Di; Chen, Wei; Spitz, Margaret R.; Wei, Yongyue; Su, Li; Xie, Dong; She, Jun; Matsuo, Keitaro; Matsuda, Fumihiko; Ito, Hidemi; Risch, Angela; Heinrich, Joachim; Rosenberger, Albert; Muley, Thomas; Dienemann, Hendrik; Field, John K.; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P.A.; Marcus, Michael; McLaughlin, John; Orlow, Irene; Han, Younghun; Li, Yafang; Zong, Xuchen; Johansson, Mattias; Liu, Geoffrey; Tworoger, Shelley S.; Le Marchand, Loic; Henderson, Brian E.; Wilkens, Lynne R.; Dai, Juncheng; Shen, Hongbing; Houlston, Richard S.; Landi, Maria T.; Brennan, Paul; Hung, Rayjean J.

2015-01-01

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. PMID:26363033

Fraction-variant beam orientation optimization for non-coplanar IMRT

NASA Astrophysics Data System (ADS)

O'Connor, Daniel; Yu, Victoria; Nguyen, Dan; Ruan, Dan; Sheng, Ke

2018-02-01

Conventional beam orientation optimization (BOO) algorithms for IMRT assume that the same set of beam angles is used for all treatment fractions. In this paper we present a BOO formulation based on group sparsity that simultaneously optimizes non-coplanar beam angles for all fractions, yielding a fraction-variant (FV) treatment plan. Beam angles are selected by solving a multi-fraction fluence map optimization problem involving 500-700 candidate beams per fraction, with an additional group sparsity term that encourages most candidate beams to be inactive. The optimization problem is solved using the fast iterative shrinkage-thresholding algorithm. Our FV BOO algorithm is used to create five-fraction treatment plans for digital phantom, prostate, and lung cases as well as a 30-fraction plan for a head and neck case. A homogeneous PTV dose coverage is maintained in all fractions. The treatment plans are compared with fraction-invariant plans that use a fixed set of beam angles for all fractions. The FV plans reduced OAR mean dose and D 2 values on average by 3.3% and 3.8% of the prescription dose, respectively. Notably, mean OAR dose was reduced by 14.3% of prescription dose (rectum), 11.6% (penile bulb), 10.7% (seminal vesicle), 5.5% (right femur), 3.5% (bladder), 4.0% (normal left lung), 15.5% (cochleas), and 5.2% (chiasm). D 2 was reduced by 14.9% of prescription dose (right femur), 8.2% (penile bulb), 12.7% (proximal bronchus), 4.1% (normal left lung), 15.2% (cochleas), 10.1% (orbits), 9.1% (chiasm), 8.7% (brainstem), and 7.1% (parotids). Meanwhile, PTV homogeneity defined as D 95/D 5 improved from .92 to .95 (digital phantom), from .95 to .98 (prostate case), and from .94 to .97 (lung case), and remained constant for the head and neck case. Moreover, the FV plans are dosimetrically similar to conventional plans that use twice as many beams per fraction. Thus, FV BOO offers the potential to reduce delivery time for non-coplanar IMRT.

Identification of pathogen genomic variants through an integrated pipeline

PubMed Central

2014-01-01

Background Whole-genome sequencing represents a powerful experimental tool for pathogen research. We present methods for the analysis of small eukaryotic genomes, including a streamlined system (called Platypus) for finding single nucleotide and copy number variants as well as recombination events. Results We have validated our pipeline using four sets of Plasmodium falciparum drug resistant data containing 26 clones from 3D7 and Dd2 background strains, identifying an average of 11 single nucleotide variants per clone. We also identify 8 copy number variants with contributions to resistance, and report for the first time that all analyzed amplification events are in tandem. Conclusions The Platypus pipeline provides malaria researchers with a powerful tool to analyze short read sequencing data. It provides an accurate way to detect SNVs using known software packages, and a novel methodology for detection of CNVs, though it does not currently support detection of small indels. We have validated that the pipeline detects known SNVs in a variety of samples while filtering out spurious data. We bundle the methods into a freely available package. PMID:24589256

Identification of POMC exonic variants associated with substance dependence and body mass index.

PubMed

Wang, Fan; Gelernter, Joel; Kranzler, Henry R; Zhang, Huiping

2012-01-01

Risk of substance dependence (SD) and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC). POMC exons were Sanger sequenced in 280 African Americans (AAs) and 308 European Americans (EAs). Among them, 311 (167 AAs and 114 EAs) were affected with substance (alcohol, cocaine, opioid and/or marijuana) dependence and 277 (113 AAs and164 EAs) were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571) and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI), with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj) = 0.005; Obese: P(adj) = 0.018; Overweight+Obese: P(adj) = 0.002) but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df) = 0.026; alcohol dependence: P(FET,1df) = 0.027; cocaine dependence: P(FET,1df) = 0.007; marijuana dependence: P(FET,1df) = 0.050) (the P-value from cocaine dependence analysis survived Bonferroni correction). There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD. These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert

Germline contamination and leakage in whole genome somatic single nucleotide variant detection.

PubMed

Sendorek, Dorota H; Caloian, Cristian; Ellrott, Kyle; Bare, J Christopher; Yamaguchi, Takafumi N; Ewing, Adam D; Houlahan, Kathleen E; Norman, Thea C; Margolin, Adam A; Stuart, Joshua M; Boutros, Paul C

2018-01-31

The clinical sequencing of cancer genomes to personalize therapy is becoming routine across the world. However, concerns over patient re-identification from these data lead to questions about how tightly access should be controlled. It is not thought to be possible to re-identify patients from somatic variant data. However, somatic variant detection pipelines can mistakenly identify germline variants as somatic ones, a process called "germline leakage". The rate of germline leakage across different somatic variant detection pipelines is not well-understood, and it is uncertain whether or not somatic variant calls should be considered re-identifiable. To fill this gap, we quantified germline leakage across 259 sets of whole-genome somatic single nucleotide variant (SNVs) predictions made by 21 teams as part of the ICGC-TCGA DREAM Somatic Mutation Calling Challenge. The median somatic SNV prediction set contained 4325 somatic SNVs and leaked one germline polymorphism. The level of germline leakage was inversely correlated with somatic SNV prediction accuracy and positively correlated with the amount of infiltrating normal cells. The specific germline variants leaked differed by tumour and algorithm. To aid in quantitation and correction of leakage, we created a tool, called GermlineFilter, for use in public-facing somatic SNV databases. The potential for patient re-identification from leaked germline variants in somatic SNV predictions has led to divergent open data access policies, based on different assessments of the risks. Indeed, a single, well-publicized re-identification event could reshape public perceptions of the values of genomic data sharing. We find that modern somatic SNV prediction pipelines have low germline-leakage rates, which can be further reduced, especially for cloud-sharing, using pre-filtering software.

Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.

PubMed

Brenner, Darren R; Amos, Christopher I; Brhane, Yonathan; Timofeeva, Maria N; Caporaso, Neil; Wang, Yufei; Christiani, David C; Bickeböller, Heike; Yang, Ping; Albanes, Demetrius; Stevens, Victoria L; Gapstur, Susan; McKay, James; Boffetta, Paolo; Zaridze, David; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Krokan, Hans E; Skorpen, Frank; Gabrielsen, Maiken E; Vatten, Lars; Njølstad, Inger; Chen, Chu; Goodman, Gary; Lathrop, Mark; Vooder, Tõnu; Välk, Kristjan; Nelis, Mari; Metspalu, Andres; Broderick, Peter; Eisen, Timothy; Wu, Xifeng; Zhang, Di; Chen, Wei; Spitz, Margaret R; Wei, Yongyue; Su, Li; Xie, Dong; She, Jun; Matsuo, Keitaro; Matsuda, Fumihiko; Ito, Hidemi; Risch, Angela; Heinrich, Joachim; Rosenberger, Albert; Muley, Thomas; Dienemann, Hendrik; Field, John K; Raji, Olaide; Chen, Ying; Gosney, John; Liloglou, Triantafillos; Davies, Michael P A; Marcus, Michael; McLaughlin, John; Orlow, Irene; Han, Younghun; Li, Yafang; Zong, Xuchen; Johansson, Mattias; Liu, Geoffrey; Tworoger, Shelley S; Le Marchand, Loic; Henderson, Brian E; Wilkens, Lynne R; Dai, Juncheng; Shen, Hongbing; Houlston, Richard S; Landi, Maria T; Brennan, Paul; Hung, Rayjean J

2015-11-01

Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits.

PubMed

Cirera, S; Clop, A; Jacobsen, M J; Guerin, M; Lesnik, P; Jørgensen, C B; Fredholm, M; Karlskov-Mortensen, P

2018-04-01

Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. © 2018 Stichting International Foundation for Animal Genetics.

Identification and validation of loss of function variants in clinical contexts.

PubMed

Lescai, Francesco; Marasco, Elena; Bacchelli, Chiara; Stanier, Philip; Mantovani, Vilma; Beales, Philip

2014-01-01

The choice of an appropriate variant calling pipeline for exome sequencing data is becoming increasingly more important in translational medicine projects and clinical contexts. Within GOSgene, which facilitates genetic analysis as part of a joint effort of the University College London and the Great Ormond Street Hospital, we aimed to optimize a variant calling pipeline suitable for our clinical context. We implemented the GATK/Queue framework and evaluated the performance of its two callers: the classical UnifiedGenotyper and the new variant discovery tool HaplotypeCaller. We performed an experimental validation of the loss-of-function (LoF) variants called by the two methods using Sequenom technology. UnifiedGenotyper showed a total validation rate of 97.6% for LoF single-nucleotide polymorphisms (SNPs) and 92.0% for insertions or deletions (INDELs), whereas HaplotypeCaller was 91.7% for SNPs and 55.9% for INDELs. We confirm that GATK/Queue is a reliable pipeline in translational medicine and clinical context. We conclude that in our working environment, UnifiedGenotyper is the caller of choice, being an accurate method, with a high validation rate of error-prone calls like LoF variants. We finally highlight the importance of experimental validation, especially for INDELs, as part of a standard pipeline in clinical environments.

Identification of Two Novel Mycobacterium avium Allelic Variants in Pig and Human Isolates from Brazil by PCR-Restriction Enzyme Analysis

PubMed Central

Leão, Sylvia Cardoso; Briones, Marcelo R. S.; Sircili, Marcelo Palma; Balian, Simone Carvalho; Mores, Nelson; Ferreira-Neto, José Soares

1999-01-01

Mycobacterium avium complex (MAC) is composed of environmental mycobacteria found widely in soil, water, and aerosols that can cause disease in animals and humans, especially disseminated infections in AIDS patients. MAC consists of two closely related species, M. avium and M. intracellulare, and may also include other, less-defined groups. The precise differentiation of MAC species is a fundamental step in epidemiological studies and for the evaluation of possible reservoirs for MAC infection in humans and animals. In this study, which included 111 pig and 26 clinical MAC isolates, two novel allelic M. avium PCR-restriction enzyme analysis (PRA) variants were identified, differing from the M. avium PRA prototype in the HaeIII digestion pattern. Mutations in HaeIII sites were confirmed by DNA sequencing. Identification of these isolates as M. avium was confirmed by PCR with DT1-DT6 and IS1245 primers, nucleic acid hybridization with the AccuProbe system, 16S ribosomal DNA sequencing, and biochemical tests. The characterization of M. avium PRA variants can be useful in the elucidation of factors involved in mycobacterial virulence and routes of infection and also has diagnostic significance, since they can be misidentified as M. simiae II and M. kansasii I if the PRA method is used in the clinical laboratory for identification of mycobacteria. PMID:10405407

A survey of tools for variant analysis of next-generation genome sequencing data

PubMed Central

Pabinger, Stephan; Dander, Andreas; Fischer, Maria; Snajder, Rene; Sperk, Michael; Efremova, Mirjana; Krabichler, Birgit; Speicher, Michael R.; Zschocke, Johannes

2014-01-01

Recent advances in genome sequencing technologies provide unprecedented opportunities to characterize individual genomic landscapes and identify mutations relevant for diagnosis and therapy. Specifically, whole-exome sequencing using next-generation sequencing (NGS) technologies is gaining popularity in the human genetics community due to the moderate costs, manageable data amounts and straightforward interpretation of analysis results. While whole-exome and, in the near future, whole-genome sequencing are becoming commodities, data analysis still poses significant challenges and led to the development of a plethora of tools supporting specific parts of the analysis workflow or providing a complete solution. Here, we surveyed 205 tools for whole-genome/whole-exome sequencing data analysis supporting five distinct analytical steps: quality assessment, alignment, variant identification, variant annotation and visualization. We report an overview of the functionality, features and specific requirements of the individual tools. We then selected 32 programs for variant identification, variant annotation and visualization, which were subjected to hands-on evaluation using four data sets: one set of exome data from two patients with a rare disease for testing identification of germline mutations, two cancer data sets for testing variant callers for somatic mutations, copy number variations and structural variations, and one semi-synthetic data set for testing identification of copy number variations. Our comprehensive survey and evaluation of NGS tools provides a valuable guideline for human geneticists working on Mendelian disorders, complex diseases and cancers. PMID:23341494

Antagonistic lactic acid bacteria isolated from goat milk and identification of a novel nisin variant Lactococcus lactis

PubMed Central

2014-01-01

Background The raw goat milk microbiota is considered a good source of novel bacteriocinogenic lactic acid bacteria (LAB) strains that can be exploited as an alternative for use as biopreservatives in foods. The constant demand for such alternative tools justifies studies that investigate the antimicrobial potential of such strains. Results The obtained data identified a predominance of Lactococcus and Enterococcus strains in raw goat milk microbiota with antimicrobial activity against Listeria monocytogenes ATCC 7644. Enzymatic assays confirmed the bacteriocinogenic nature of the antimicrobial substances produced by the isolated strains, and PCR reactions detected a variety of bacteriocin-related genes in their genomes. Rep-PCR identified broad genetic variability among the Enterococcus isolates, and close relations between the Lactococcus strains. The sequencing of PCR products from nis-positive Lactococcus allowed the identification of a predicted nisin variant not previously described and possessing a wide inhibitory spectrum. Conclusions Raw goat milk was confirmed as a good source of novel bacteriocinogenic LAB strains, having identified Lactococcus isolates possessing variations in their genomes that suggest the production of a nisin variant not yet described and with potential for use as biopreservatives in food due to its broad spectrum of action. PMID:24521354

Identification of copy number variants in whole-genome data using Reference Coverage Profiles

PubMed Central

Glusman, Gustavo; Severson, Alissa; Dhankani, Varsha; Robinson, Max; Farrah, Terry; Mauldin, Denise E.; Stittrich, Anna B.; Ament, Seth A.; Roach, Jared C.; Brunkow, Mary E.; Bodian, Dale L.; Vockley, Joseph G.; Shmulevich, Ilya; Niederhuber, John E.; Hood, Leroy

2015-01-01

The identification of DNA copy numbers from short-read sequencing data remains a challenge for both technical and algorithmic reasons. The raw data for these analyses are measured in tens to hundreds of gigabytes per genome; transmitting, storing, and analyzing such large files is cumbersome, particularly for methods that analyze several samples simultaneously. We developed a very efficient representation of depth of coverage (150–1000× compression) that enables such analyses. Current methods for analyzing variants in whole-genome sequencing (WGS) data frequently miss copy number variants (CNVs), particularly hemizygous deletions in the 1–100 kb range. To fill this gap, we developed a method to identify CNVs in individual genomes, based on comparison to joint profiles pre-computed from a large set of genomes. We analyzed depth of coverage in over 6000 high quality (>40×) genomes. The depth of coverage has strong sequence-specific fluctuations only partially explained by global parameters like %GC. To account for these fluctuations, we constructed multi-genome profiles representing the observed or inferred diploid depth of coverage at each position along the genome. These Reference Coverage Profiles (RCPs) take into account the diverse technologies and pipeline versions used. Normalization of the scaled coverage to the RCP followed by hidden Markov model (HMM) segmentation enables efficient detection of CNVs and large deletions in individual genomes. Use of pre-computed multi-genome coverage profiles improves our ability to analyze each individual genome. We make available RCPs and tools for performing these analyses on personal genomes. We expect the increased sensitivity and specificity for individual genome analysis to be critical for achieving clinical-grade genome interpretation. PMID:25741365

Flavour identification in frontotemporal lobar degeneration.

PubMed

Omar, Rohani; Mahoney, Colin J; Buckley, Aisling H; Warren, Jason D

2013-01-01

Deficits of flavour processing may be clinically important in frontotemporal lobar degeneration (FTLD). To examine flavour processing in FTLD. We studied flavour identification prospectively in 25 patients with FTLD (12 with behavioural variant frontotemporal dementia (bvFTD), eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures. All subjects completed a general neuropsychological assessment, and odour identification was also assessed using a modified University of Pennsylvania Smell Identification Test. Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification. Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant (p<0.05) deficits of flavour identification and all three FTLD subgroups showed deficits of odour identification. Flavour identification performance did not differ significantly between the FTLD syndromic subgroups. Flavour identification performance in the combined FTLD cohort was significantly (p<0.05 after multiple comparisons correction) associated with grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole. Certain FTLD syndromes are associated with impaired flavour identification and this is underpinned by grey matter atrophy in an anteromedial temporal lobe network. These findings may have implications for our understanding of abnormal eating behaviour in these diseases.

Identification of genomic variants putatively targeted by selection during dog domestication.

PubMed

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

mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications.

PubMed

Li, Zhongshan; Liu, Zhenwei; Jiang, Yi; Chen, Denghui; Ran, Xia; Sun, Zhong Sheng; Wu, Jinyu

2017-01-01

Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic sequence variants prioritizations from clinical exome sequencing (CES) variant data of single individual or family. The mirVAFC is able to comprehensively annotate sequence variants, filter out most irrelevant variants using custom criteria, classify variants into different categories as for estimated pathogenicity, and lastly provide pathogenic variants prioritizations based on classifications and mutation effects. Case studies using different types of datasets for different diseases from publication and our in-house data have revealed that mirVAFC can efficiently identify the right pathogenic candidates as in original work in each case. Overall, the Web server mirVAFC is specifically developed for pathogenic sequence variant identifications from family-based CES variants using classification-based prioritizations. The mirVAFC Web server is freely accessible at https://www.wzgenomics.cn/mirVAFC/. © 2016 WILEY PERIODICALS, INC.

Mapping of Epitopes Occurring in Bovine α(s1)-Casein Variants by Peptide Microarray Immunoassay.

PubMed

Lisson, Maria; Erhardt, Georg

2016-01-01

Immunoglobulin E epitope mapping of milk proteins reveals important information about their immunologic properties. Genetic variants of αS1-casein, one of the major allergens in bovine milk, are until now not considered when discussing the allergenic potential. Here we describe the complete procedure to assess the allergenicity of αS1-casein variants B and C, which are frequent in most breeds, starting from milk with identification and purification of casein variants by isoelectric focusing (IEF) and anion-exchange chromatography, followed by in vitro gastrointestinal digestion of the casein variants, identification of the resulting peptides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), in silico analysis of the variant-specific peptides as allergenic epitopes, and determination of their IgE-binding properties by microarray immunoassay with cow's milk allergic human sera.

A Bioinformatics Workflow for Variant Peptide Detection in Shotgun Proteomics*

PubMed Central

Li, Jing; Su, Zengliu; Ma, Ze-Qiang; Slebos, Robbert J. C.; Halvey, Patrick; Tabb, David L.; Liebler, Daniel C.; Pao, William; Zhang, Bing

2011-01-01

Shotgun proteomics data analysis usually relies on database search. However, commonly used protein sequence databases do not contain information on protein variants and thus prevent variant peptides and proteins from been identified. Including known coding variations into protein sequence databases could help alleviate this problem. Based on our recently published human Cancer Proteome Variation Database, we have created a protein sequence database that comprehensively annotates thousands of cancer-related coding variants collected in the Cancer Proteome Variation Database as well as noncancer-specific ones from the Single Nucleotide Polymorphism Database (dbSNP). Using this database, we then developed a data analysis workflow for variant peptide identification in shotgun proteomics. The high risk of false positive variant identifications was addressed by a modified false discovery rate estimation method. Analysis of colorectal cancer cell lines SW480, RKO, and HCT-116 revealed a total of 81 peptides that contain either noncancer-specific or cancer-related variations. Twenty-three out of 26 variants randomly selected from the 81 were confirmed by genomic sequencing. We further applied the workflow on data sets from three individual colorectal tumor specimens. A total of 204 distinct variant peptides were detected, and five carried known cancer-related mutations. Each individual showed a specific pattern of cancer-related mutations, suggesting potential use of this type of information for personalized medicine. Compatibility of the workflow has been tested with four popular database search engines including Sequest, Mascot, X!Tandem, and MyriMatch. In summary, we have developed a workflow that effectively uses existing genomic data to enable variant peptide detection in proteomics. PMID:21389108

Functional identification of a novel 14-3-3 epsilon splicing variant suggests dimerization is not necessary for 14-3-3 epsilon to inhibit UV-induced apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Dingding; Ye, Guangming; Liu, Tingting

2010-05-28

14-3-3 proteins function as a dimer and have been identified to involve in diverse signaling pathways. Here we reported the identification of a novel splicing variant of human 14-3-3 epsilon (14-3-3 epsilon sv), which is derived from a novel exon 1' insertion. The insertion contains a stop codon and leads to a truncated splicing variant of 14-3-3 epsilon. The splicing variant is translated from the exon 2 and results in the deletion of an N-terminal {alpha}-helix which is crucial for the dimerization. Therefore, the 14-3-3 epsilon sv could not form a dimer with 14-3-3 zeta. However, after UV irradiation 14-3-3more » epsilon sv could also support cell survival, suggesting monomer of 14-3-3 epsilon is sufficient to protect cell from apoptosis.« less

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.

PubMed

Shim, Ye Jee; Kim, Jung Eun; Hwang, Su-Kyeong; Choi, Bong Seok; Choi, Byung Ho; Cho, Eun-Mi; Jang, Kyoung Mi; Ko, Cheol Woo

2015-01-01

To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells. © 2015 S. Karger AG, Basel.

Base Excision Repair Variants in Cancer

PubMed Central

Marsden, Carolyn G.; Dragon, Julie A.; Wallace, Susan S.; Sweasy, Joann B.

2018-01-01

Base excision repair (BER) is a key genome maintenance pathway that removes endogenously damaged DNA bases that arise in cells at very high levels on a daily basis. Failure to remove these damaged DNA bases leads to increased levels of mutagenesis and chromosomal instability, which have the potential to drive carcinogenesis. Next Generation sequencing efforts of the germline and tumors genomes of thousands of individuals has uncovered many rare mutations in BER genes. Given that BER is critical for genome maintenance, it is important to determine whether BER genomic variants have functional phenotypes. In this chapter we present our in silico methods for the identification and prioritization of BER variants for further study. We also provide detailed instructions and commentary on the initial cellular assays we employ to dissect potentially important phenotypes of human BER variants and highlight the strengths and weaknesses of our approaches. BER variants possessing interesting functional phenotypes can then be studied in more detail to provide important mechanistic insights regarding the role of aberrant BER in carcinogenesis. PMID:28645367

Systematic RH genotyping and variant identification in French donors of African origin

PubMed Central

Kappler-Gratias, Sandrine; Auxerre, Carine; Dubeaux, Isabelle; Beolet, Marylise; Ripaux, Maryline; Le Pennec, Pierre-Yves; Pham, Bach-Nga

2014-01-01

Background RH molecular analysis has enabled the documentation of numerous variants of RHD and RHCE alleles, especially in individuals of African origin. The aim of the present study was to determine the type and frequency of D and/or RhCE variants among blood donors of African origin in France, by performing a systematic RH molecular analysis, in order to evaluate the implications for blood transfusion of patients of African origin. Materials and methods Samples from 316 African blood donors, whose origin was established by their Fy(a−b−) phenotype, were first analysed using the RHD and RHCE BeadChips Kit (BioArray Solutions, Immucor, Warren, NJ, USA). Sequencing was performed when necessary. Results RHD molecular analysis showed that 26.2% of donors had a variant RHD allele. It allowed the prediction of a partial D in 11% of cases. RHCE molecular analysis showed that 14.2% of donors had a variant RHCE allele or RH [RN or (C)ces] haplotype. A rare Rh phenotype associated with the loss of a high-prevalence antigen or partial RhCE antigens were predicted from RHCE molecular analysis in 1 (0.3%) and 17 (5%) cases, respectively. Discussion Systematic RHD and RHCE molecular analysis performed in blood donors of African origin provides transfusion-relevant information for individuals of African origin because of the frequency of variant RH alleles. RH molecular analysis may improve transfusion therapy of patients by allowing better donor and recipient matching, based not only on phenotypically matched red blood cell units, but also on units that are genetically matched with regards to RhCE variants. PMID:23867180

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

PubMed Central

Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

2018-01-01

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer. PMID:29058716

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

PubMed

Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Alnæs, Grethe I Grenaker; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-Ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

2017-12-01

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Sequencing Structural Variants in Cancer for Precision Therapeutics.

PubMed

Macintyre, Geoff; Ylstra, Bauke; Brenton, James D

2016-09-01

The identification of mutations that guide therapy selection for patients with cancer is now routine in many clinical centres. The majority of assays used for solid tumour profiling use DNA sequencing to interrogate somatic point mutations because they are relatively easy to identify and interpret. Many cancers, however, including high-grade serous ovarian, oesophageal, and small-cell lung cancer, are driven by somatic structural variants that are not measured by these assays. Therefore, there is currently an unmet need for clinical assays that can cheaply and rapidly profile structural variants in solid tumours. In this review we survey the landscape of 'actionable' structural variants in cancer and identify promising detection strategies based on massively-parallel sequencing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea.

PubMed

Jang, Mi-Ae; Lee, Taeheon; Lee, Junnam; Cho, Eun-Hae; Ki, Chang-Seok

2015-05-01

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea.

Identification of a Novel De Novo Variant in the PAX3 Gene in Waardenburg Syndrome by Diagnostic Exome Sequencing: The First Molecular Diagnosis in Korea

PubMed Central

Jang, Mi-Ae; Lee, Taeheon; Lee, Junnam

2015-01-01

Waardenburg syndrome (WS) is a clinically and genetically heterogeneous hereditary auditory pigmentary disorder characterized by congenital sensorineural hearing loss and iris discoloration. Many genes have been linked to WS, including PAX3, MITF, SNAI2, EDNRB, EDN3, and SOX10, and many additional genes have been associated with disorders with phenotypic overlap with WS. To screen all possible genes associated with WS and congenital deafness simultaneously, we performed diagnostic exome sequencing (DES) in a male patient with clinical features consistent with WS. Using DES, we identified a novel missense variant (c.220C>G; p.Arg74Gly) in exon 2 of the PAX3 gene in the patient. Further analysis by Sanger sequencing of the patient and his parents revealed a de novo occurrence of the variant. Our findings show that DES can be a useful tool for the identification of pathogenic gene variants in WS patients and for differentiation between WS and similar disorders. To the best of our knowledge, this is the first report of genetically confirmed WS in Korea. PMID:25932447

Scripps Genome ADVISER: Annotation and Distributed Variant Interpretation SERver

PubMed Central

Pham, Phillip H.; Shipman, William J.; Erikson, Galina A.; Schork, Nicholas J.; Torkamani, Ali

2015-01-01

Interpretation of human genomes is a major challenge. We present the Scripps Genome ADVISER (SG-ADVISER) suite, which aims to fill the gap between data generation and genome interpretation by performing holistic, in-depth, annotations and functional predictions on all variant types and effects. The SG-ADVISER suite includes a de-identification tool, a variant annotation web-server, and a user interface for inheritance and annotation-based filtration. SG-ADVISER allows users with no bioinformatics expertise to manipulate large volumes of variant data with ease – without the need to download large reference databases, install software, or use a command line interface. SG-ADVISER is freely available at genomics.scripps.edu/ADVISER. PMID:25706643

Vecuum: identification and filtration of false somatic variants caused by recombinant vector contamination.

PubMed

Kim, Junho; Maeng, Ju Heon; Lim, Jae Seok; Son, Hyeonju; Lee, Junehawk; Lee, Jeong Ho; Kim, Sangwoo

2016-10-15

Advances in sequencing technologies have remarkably lowered the detection limit of somatic variants to a low frequency. However, calling mutations at this range is still confounded by many factors including environmental contamination. Vector contamination is a continuously occurring issue and is especially problematic since vector inserts are hardly distinguishable from the sample sequences. Such inserts, which may harbor polymorphisms and engineered functional mutations, can result in calling false variants at corresponding sites. Numerous vector-screening methods have been developed, but none could handle contamination from inserts because they are focusing on vector backbone sequences alone. We developed a novel method-Vecuum-that identifies vector-originated reads and resultant false variants. Since vector inserts are generally constructed from intron-less cDNAs, Vecuum identifies vector-originated reads by inspecting the clipping patterns at exon junctions. False variant calls are further detected based on the biased distribution of mutant alleles to vector-originated reads. Tests on simulated and spike-in experimental data validated that Vecuum could detect 93% of vector contaminants and could remove up to 87% of variant-like false calls with 100% precision. Application to public sequence datasets demonstrated the utility of Vecuum in detecting false variants resulting from various types of external contamination. Java-based implementation of the method is available at http://vecuum.sourceforge.net/ CONTACT: swkim@yuhs.acSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The impact of professional and organizational identification on the relationship between hospital-physician exchange and customer-oriented behaviour of physicians.

PubMed

Trybou, Jeroen; De Caluwé, Gaelle; Verleye, Katrien; Gemmel, Paul; Annemans, Lieven

2015-02-17

Hospitals face increasingly competitive market conditions. In this challenging environment, hospitals have been struggling to build high-quality hospital-physician relationships. In the literature, two types of managerial strategies for optimizing relationships have been identified. The first focuses on optimizing the economic relationship; the second focuses on the noneconomic dimension and emphasizes the cooperative structure and collaborative nature of the hospital-physician relationship. We investigate potential spillover effects between the perceptions of physicians of organizational exchange and their customer-oriented behaviors. A cross-sectional study was conducted on 130 self-employed physicians practicing at six Belgian hospitals. Economic exchange was measured using the concept of distributive justice (DJ); noneconomic exchange was measured by the concept of perceived organizational support (POS). Our outcomes consist of three types of customer-oriented behaviours: internal influence (II), external representation (ER), and service delivery (SD). Our results show a positive relationship between DJ and II (adjusted R(2) = 0.038, t = 2.35; p = 0.028) and ER (adjusted R(2) = 0.15, t = 4.59; p < 0.001) and a positive relationship between POS and II (adjusted R(2) = 0.032, t = 2.26; p = 0.026) and ER (adjusted R(2) = 0.22, t = 5.81; p < 0.001). No relationship was present between DJ (p = 0.54) or POS (p = 0.57) and SD. Organizational identification positively moderates the relationship between POS and ER (p = 0.045) and between DJ and ER (p = 0.056). The relationships between POS and II (p = 0.54) and between DJ and II (p = 0.99) were not moderated by OI. Professional identification did not moderate the studied relationships. Our results demonstrate that both perceptions of economic and noneconomic exchange are important to self-employed physicians' customer-oriented behaviours. Fostering organizational identification could enhance this reciprocity

Identification of a novel 16S rRNA gene variant of Actinomyces funkei from six patients with purulent infections.

PubMed

Hinić, V; Straub, C; Schultheiss, E; Kaempfer, P; Frei, R; Goldenberger, D

2013-07-01

Little is known about the clinical significance and laboratory diagnosis of Actinomyces funkei. In this report we describe six clinical cases where A. funkei was isolated from purulent, polymicrobial infections. Conventional identification procedures were compared with molecular methods including matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. Analysis of the full 16S rRNA gene sequence of the six investigated strains revealed differences from the A. funkei type strain. DNA-DNA hybridization showed that the clinical strains represent a novel 16S rRNA gene variant within the species of A. funkei. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Orientation to Machine Shop. Safety, Machine Identification, Metal Identification.

ERIC Educational Resources Information Center

Engelbrecht, Nancy; And Others

These instructional materials provide an orientation to the machine shop for use at the postsecondary level. The first of three sections discusses four important areas of safety: (1) personal safety; (2) safety procedures; (3) safe work practices; and (4) fire prevention. The second section identifies and describes the general purposes of 12…

Identification of Low-Level Product-Related Variants in Filgrastim Products Presently Available in Highly Regulated Markets.

PubMed

Hausberger, Anna; Lamanna, William C; Hartinger, Martin; Seidl, Andreas; Toll, Hansjoerg; Holzmann, Johann

2016-06-01

Filgrastim is a recombinant, non-glycosylated form of human granulocyte colony-stimulating factor, used to stimulate leukocyte proliferation in patients suffering from neutropenia. Since the expiration of patents associated with Amgen's filgrastim biopharmaceutical, Neupogen(®), in 2006, a number of filgrastim products have been marketed; however, a detailed characterization and comparison of variants associated with these products have not been publically reported. The objective of this study was to identify and quantify product-related variants in filgrastim reference products and biosimilars thereof that are presently available in highly regulated markets. In this study, we used intact and top-down mass spectrometry to identify and quantify product-related variants in filgrastim products. Mass spectrometry has become the method of choice for physicochemical characterization of biopharmaceuticals, allowing accurate and sensitive characterization of product-related variants. In addition to modifications ubiquitously present in biopharmaceuticals, such as methionine oxidation and asparagine/glutamine deamidation, we identified six different low-level, product-related variants present in some, but not all, of the tested products. Two variants, an acetylated filgrastim variant and a filgrastim variant containing an additional C-terminal tryptophan extension, are newly identified variants. This study demonstrates that filgrastim products already in widespread clinical use in highly regulated markets differ in low-level, product-related variants present at levels mostly below 1 % relative abundance. This study provides a comprehensive catalog of minor differences between filgrastim products and suggests that the filgrastim product-related variants described here are not clinically relevant when present at low abundance.

A low density microarray method for the identification of human papillomavirus type 18 variants.

PubMed

Meza-Menchaca, Thuluz; Williams, John; Rodríguez-Estrada, Rocío B; García-Bravo, Aracely; Ramos-Ligonio, Ángel; López-Monteon, Aracely; Zepeda, Rossana C

2013-09-26

We describe a novel microarray based-method for the screening of oncogenic human papillomavirus 18 (HPV-18) molecular variants. Due to the fact that sequencing methodology may underestimate samples containing more than one variant we designed a specific and sensitive stacking DNA hybridization assay. This technology can be used to discriminate between three possible phylogenetic branches of HPV-18. Probes were attached covalently on glass slides and hybridized with single-stranded DNA targets. Prior to hybridization with the probes, the target strands were pre-annealed with the three auxiliary contiguous oligonucleotides flanking the target sequences. Screening HPV-18 positive cell lines and cervical samples were used to evaluate the performance of this HPV DNA microarray. Our results demonstrate that the HPV-18's variants hybridized specifically to probes, with no detection of unspecific signals. Specific probes successfully reveal detectable point mutations in these variants. The present DNA oligoarray system can be used as a reliable, sensitive and specific method for HPV-18 variant screening. Furthermore, this simple assay allows the use of inexpensive equipment, making it accessible in resource-poor settings.

A Low Density Microarray Method for the Identification of Human Papillomavirus Type 18 Variants

PubMed Central

Meza-Menchaca, Thuluz; Williams, John; Rodríguez-Estrada, Rocío B.; García-Bravo, Aracely; Ramos-Ligonio, Ángel; López-Monteon, Aracely; Zepeda, Rossana C.

2013-01-01

We describe a novel microarray based-method for the screening of oncogenic human papillomavirus 18 (HPV-18) molecular variants. Due to the fact that sequencing methodology may underestimate samples containing more than one variant we designed a specific and sensitive stacking DNA hybridization assay. This technology can be used to discriminate between three possible phylogenetic branches of HPV-18. Probes were attached covalently on glass slides and hybridized with single-stranded DNA targets. Prior to hybridization with the probes, the target strands were pre-annealed with the three auxiliary contiguous oligonucleotides flanking the target sequences. Screening HPV-18 positive cell lines and cervical samples were used to evaluate the performance of this HPV DNA microarray. Our results demonstrate that the HPV-18's variants hybridized specifically to probes, with no detection of unspecific signals. Specific probes successfully reveal detectable point mutations in these variants. The present DNA oligoarray system can be used as a reliable, sensitive and specific method for HPV-18 variant screening. Furthermore, this simple assay allows the use of inexpensive equipment, making it accessible in resource-poor settings. PMID:24077317

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

PubMed

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.

Automated Dispersion and Orientation Analysis for Carbon Nanotube Reinforced Polymer Composites

PubMed Central

Gao, Yi; Li, Zhuo; Lin, Ziyin; Zhu, Liangjia; Tannenbaum, Allen; Bouix, Sylvain; Wong, C.P.

2012-01-01

The properties of carbon nanotube (CNT)/polymer composites are strongly dependent on the dispersion and orientation of CNTs in the host matrix. Quantification of the dispersion and orientation of CNTs by microstructure observation and image analysis has been demonstrated as a useful way to understand the structure-property relationship of CNT/polymer composites. However, due to the various morphologies and large amount of CNTs in one image, automatic and accurate identification of CNTs has become the bottleneck for dispersion/orientation analysis. To solve this problem, shape identification is performed for each pixel in the filler identification step, so that individual CNT can be exacted from images automatically. The improved filler identification enables more accurate analysis of CNT dispersion and orientation. The obtained dispersion index and orientation index of both synthetic and real images from model compounds correspond well with the observations. Moreover, these indices help to explain the electrical properties of CNT/Silicone composite, which is used as a model compound. This method can also be extended to other polymer composites with high aspect ratio fillers. PMID:23060008

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

PubMed

Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

2014-03-01

The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case-control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.

The Spectrum of Pedagogical Orientations of Malawian and South African Physical Science Teachers towards Inquiry

ERIC Educational Resources Information Center

Ramnarain, Umesh; Nampota, Dorothy; Schuster, David

2016-01-01

This study investigated and compared the pedagogical orientations of physical sciences teachers in Malawi and South Africa towards inquiry or direct methods of science teaching. Pedagogical orientation has been theorized as a component of pedagogical content knowledge. Orientations were characterized along a spectrum of two variants of inquiry and…

Identification and functional characterization of genetic variants of human organic cation transporters in a Korean population.

PubMed

Kang, Ho-Jin; Song, Im-Sook; Shin, Ho Jung; Kim, Woo-Young; Lee, Choong-Hee; Shim, Joo-Cheol; Zhou, Hong-Hao; Lee, Sang Seop; Shin, Jae-Gook

2007-04-01

Genetic variants of three human organic cation transporter genes (hOCTs) were extensively explored in a Korean population. The functional changes of hOCT2 variants were evaluated in vitro, and those genetic polymorphisms of hOCTs were compared among different ethnic populations. From direct DNA sequencing, 7 of 13 coding variants were nonsynonymous single-nucleotide polymorphisms (SNPs), including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), whereas 6 were synonymous SNPs. The linkage disequilibrium analysis presented for three independent LD blocks for each hOCT gene showed no significant linkage among all three hOCT genes. The transporter activities of MDCK cells that overexpress the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of [(3)H]methyl-4-phenylpyridinium acetate (MPP(+)) or [(14)C]tetraethylammonium compared with those cells that overexpress wild-type hOCT2, and the estimated kinetic parameters of these variants for [(3)H]MPP(+) uptake in oocytes showed a 2- to 5-fold increase in K(m) values and a 10- to 20-fold decrease in V(max) values. The allele frequencies of the five functional variants hOCT1-P283L, -P341L, and hOCT2-T199I, -T201M, and -A270S were 1.3, 17, 0.7, 0.7, and 11%, respectively, in a Korean population; the frequency distributions of these variants were not significantly different from those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among three genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared with the wild type, although the clinical relevance of these variants remains to be evaluated.

Identification of Putative Olfactory Genes from the Oriental Fruit Moth Grapholita molesta via an Antennal Transcriptome Analysis

PubMed Central

Li, Yiping; Wu, Junxiang

2015-01-01

Background The oriental fruit moth, Grapholita molesta, is an extremely important oligophagous pest species of stone and pome fruits throughout the world. As a host-switching species, adult moths, especially females, depend on olfactory cues to a large extent in locating host plants, finding mates, and selecting oviposition sites. The identification of olfactory genes can facilitate investigation on mechanisms for chemical communications. Methodology/Principal Finding We generated transcriptome of female antennae of G.molesta using the next-generation sequencing technique, and assembled transcripts from RNA-seq reads using Trinity, SOAPdenovo-trans and Abyss-trans assemblers. We identified 124 putative olfactory genes. Among the identified olfactory genes, 118 were novel to this species, including 28 transcripts encoding for odorant binding proteins, 17 chemosensory proteins, 48 odorant receptors, four gustatory receptors, 24 ionotropic receptors, two sensory neuron membrane proteins, and one odor degrading enzyme. The identified genes were further confirmed through semi-quantitative reverse transcription PCR for transcripts coding for 26 OBPs and 17 CSPs. OBP transcripts showed an obvious antenna bias, whereas CSP transcripts were detected in different tissues. Conclusion Antennal transcriptome data derived from the oriental fruit moth constituted an abundant molecular resource for the identification of genes potentially involved in the olfaction process of the species. This study provides a foundation for future research on the molecules involved in olfactory recognition of this insect pest, and in particular, the feasibility of using semiochemicals to control this pest. PMID:26540284

Identification of Blastocystis Subtype 1 Variants in the Home for Girls, Bangkok, Thailand

PubMed Central

Thathaisong, Umaporn; Siripattanapipong, Suradej; Mungthin, Mathirut; Pipatsatitpong, Duangnate; Tan-ariya, Peerapan; Naaglor, Tawee; Leelayoova, Saovanee

2013-01-01

A cross-sectional study of Blastocystis infection was conducted to evaluate the prevalence, risk factors, and subtypes of Blastocystis at the Home for Girls, Bangkok, Thailand in November 2008. Of 370 stool samples, 118 (31.9%) were infected with Blastocystis. Genotypic characterization of Blastocystis was performed by polymerase chain reaction and sequence analysis of the partial small subunit ribosomal RNA (SSU rRNA) gene. Subtype 1 was the most predominant (94.8%), followed by subtype 6 (3.5%) and subtype 2 (1.7%). Sequence analyses revealed nucleotide polymorphisms for Blastocystis subtype 1, which were described as subtype 1/variant 1, subtype 1/variant 2. Blastocystis subtype 1/variant 1 was the most predominant infection occurring in almost every house. The results showed that subtype analysis of Blastocystis was useful for molecular epidemiological study. PMID:23166199

Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

PubMed

Lovelock, Paul K; Spurdle, Amanda B; Mok, Myth T S; Farrugia, Daniel J; Lakhani, Sunil R; Healey, Sue; Arnold, Stephen; Buchanan, Daniel; Couch, Fergus J; Henderson, Beric R; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia; Brown, Melissa A

2007-01-01

Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. These data highlight the need for a range of

Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

PubMed Central

Lovelock, Paul K; Spurdle, Amanda B; Mok, Myth TS; Farrugia, Daniel J; Lakhani, Sunil R; Healey, Sue; Arnold, Stephen; Buchanan, Daniel; Investigators, kConFab; Couch, Fergus J; Henderson, Beric R; Goldgar, David E; Tavtigian, Sean V; Chenevix-Trench, Georgia; Brown, Melissa A

2007-01-01

Introduction Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion

A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.

PubMed

Wang, Li; Feng, Yong; Yan, Denise; Qin, Litao; Grati, M'hamed; Mittal, Rahul; Li, Tao; Sundhari, Abhiraami Kannan; Liu, Yalan; Chapagain, Prem; Blanton, Susan H; Liao, Shixiu; Liu, Xuezhong

2018-06-02

Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca 2+ homeostasis.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

PubMed

Tong, J H S; Hawi, Z; Dark, C; Cummins, T D R; Johnson, B P; Newman, D P; Lau, R; Vance, A; Heussler, H S; Matthews, N; Bellgrove, M A; Pang, K C

2016-11-01

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

Human AZU-1 gene, variants thereof and expressed gene products

DOEpatents

Chen, Huei-Mei; Bissell, Mina

2004-06-22

A human AZU-1 gene, mutants, variants and fragments thereof. Protein products encoded by the AZU-1 gene and homologs encoded by the variants of AZU-1 gene acting as tumor suppressors or markers of malignancy progression and tumorigenicity reversion. Identification, isolation and characterization of AZU-1 and AZU-2 genes localized to a tumor suppressive locus at chromosome 10q26, highly expressed in nonmalignant and premalignant cells derived from a human breast tumor progression model. A recombinant full length protein sequences encoded by the AZU-1 gene and nucleotide sequences of AZU-1 and AZU-2 genes and variant and fragments thereof. Monoclonal or polyclonal antibodies specific to AZU-1, AZU-2 encoded protein and to AZU-1, or AZU-2 encoded protein homologs.

Chromosomal microarray analysis as the first-tier test for the identification of pathogenic copy number variants in chromosome 9 pericentric regions and its challenge.

PubMed

Wang, Jia-Chi; Boyar, Fatih Z

2016-01-01

Chromosomal microarray analysis (CMA) has been recommended and practiced routinely in the large reference laboratories of U.S.A. as the first-tier test for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Using CMA as a diagnostic tool and without a routine setting of fluorescence in situ hybridization with labeled bacterial artificial chromosome probes (BAC-FISH) in the large reference laboratories becomes a challenge in the characterization of chromosome 9 pericentric region. This region has a very complex genomic structure and contains a variety of heterochromatic and euchromatic polymorphic variants. These variants were usually studied by G-banding, C-banding and BAC-FISH analysis. Chromosomal microarray analysis (CMA) was not recommended since it may lead to false positive results. Here, we presented a cohort of four cases, in which high-resolution CMA was used as the first-tier test or simultaneously with G-banding analysis on the proband to identify pathogenic copy number variants (CNVs) in the whole genome. CMA revealed large pathogenic CNVs from chromosome 9 in 3 cases which also revealed different G-banding patterns between the two chromosome 9 homologues. Although we demonstrated that high-resolution CMA played an important role in the identification of pathogenic copy number variants in chromosome 9 pericentric regions, the lack of BAC-FISH analysis or other useful tools renders significant challenges in the characterization of chromosome 9 pericentric regions. None; it is not a clinical trial, and the cases were retrospectively collected and analyzed.

Characterization of an Enterococcus faecium small-colony variant isolated from blood culture.

PubMed

Gröbner, Sabine; Beck, Julia; Schaller, Martin; Autenrieth, Ingo B; Schulte, Berit

2012-01-01

Small-colony variants (SCVs) of bacteria are slow-growing subpopulations which can cause latent or recurrent infections due to better intracellular survival compared to their wild-type counterparts. Atypical colony morphology and altered biochemical profile may lead to failure in identification of SCV strains. We here report for the first time the isolation of an Enterococcus faecium SCV phenotype. The case of a 65-year-old woman with acute myeloid leukaemia who developed symptoms of sepsis during induction chemotherapy is presented. E. faecium with normal and SCV phenotype was isolated from blood cultures. At the same time urine culture was positive with E. faecium suggesting that bacteraemia originated from the urinary tract. The SCV phenotype was characterized by atypical growth behaviour. Electron microscopic analyses revealed perturbation of the separation of daughter cells and the accumulation of cell wall material. Accordingly, the SCV variant showed a dysfunction or lack of spontaneous autolysis whereas the normal phenotype did not. In contrast to conventional identification systems based on biochemical characteristics, the E. faecium SCV was precisely identified by MALDI-TOF MS analysis implemented in our laboratory. Hence, the increasing use of MALDI-TOF MS analysis for the identification of bacteria might be an appropriate tool for the detection of SCV variants, the diagnosis of which is of importance for the clinical outcome and the antibiotic treatment. Copyright © 2011. Published by Elsevier GmbH.

Whole exome sequencing for familial bicuspid aortic valve identifies putative variants.

PubMed

Martin, Lisa J; Pilipenko, Valentina; Kaufman, Kenneth M; Cripe, Linda; Kottyan, Leah C; Keddache, Mehdi; Dexheimer, Phillip; Weirauch, Matthew T; Benson, D Woodrow

2014-10-01

Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation. Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing a multiplex BAV kindred. Whole exome sequencing was performed on 17 individuals from a single family (BAV=3; other cardiovascular malformation, 3). Postvariant calling error control metrics were established after examining the relationship between Mendelian inheritance error rate and coverage, quality score, and call rate. To determine the most effective approach to identifying susceptibility variants from among 54 674 variants passing error control metrics, we evaluated 3 variant selection strategies frequently used in whole exome sequencing studies plus extended family linkage. No putative rare, high-effect variants were identified in all affected but no unaffected individuals. Eight high-effect variants were identified by ≥2 of the commonly used selection strategies; however, these were either common in the general population (>10%) or present in the majority of the unaffected family members. However, using extended family linkage, 3 synonymous variants were identified; all 3 variants were identified by at least one other strategy. These results suggest that traditional whole exome sequencing approaches, which assume causal variants alter coding sense, may be insufficient for BAV and other complex traits. Identification of disease-associated variants is facilitated by the use of segregation within families. © 2014 American Heart Association, Inc.

Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis

PubMed Central

Alcina, Antonio; Fedetz, Maria; Fernández, Óscar; Saiz, Albert; Izquierdo, Guillermo; Lucas, Miguel; Leyva, Laura; García-León, Juan-Antonio; Abad-Grau, María del Mar; Alloza, Iraide; Antigüedad, Alfredo; Garcia-Barcina, María J; Vandenbroeck, Koen; Varadé, Jezabel; de la Hera, Belén; Arroyo, Rafael; Comabella, Manuel; Montalban, Xavier; Petit-Marty, Natalia; Navarro, Arcadi; Otaegui, David; Olascoaga, Javier; Blanco, Yolanda; Urcelay, Elena; Matesanz, Fuencisla

2013-01-01

Background and aim Several studies have highlighted the association of the 12q13.3–12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS. Methods Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses. Results rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously. Conclusions This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3–12q14.1 region with MS. PMID:23160276

Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action.

PubMed

Xu, Jin; Xu, Ming; Brown, Taylor; Rossi, Grace C; Hurd, Yasmin L; Inturrisi, Charles E; Pasternak, Gavril W; Pan, Ying-Xian

2013-07-19

The μ-opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, as illustrated by the identification of an array of splice variants generated by both 5' and 3' alternative splicing. The current study reports the identification of another set of splice variants conserved across species that are generated through exon skipping or insertion that encodes proteins containing only a single transmembrane (TM) domain. Using a Tet-Off system, we demonstrated that the truncated single TM variants can dimerize with the full-length 7-TM μ-opioid receptor (MOR-1) in the endoplasmic reticulum, leading to increased expression of MOR-1 at the protein level by a chaperone-like function that minimizes endoplasmic reticulum-associated degradation. In vivo antisense studies suggested that the single TM variants play an important role in morphine analgesia, presumably through modulation of receptor expression levels. Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families.

Congenital anatomic variants of the kidney and ureter: a pictorial essay.

PubMed

Srinivas, M R; Adarsh, K M; Jeeson, Riya; Ashwini, C; Nagaraj, B R

2016-03-01

Congenital renal parenchymal and pelvicalyceal abnormalities have a wide spectrum. Most of them are asymptomatic, like that of ectopia, cross fused kidney, horseshoe kidney, etc., while a few of them become complicated, leading to renal failure and death. It is very important for the radiologist to identify these anatomic variants and guide the clinicians for surgical and therapeutic procedures. Cross-sectional imaging with a volume rendered technique/maximum intensity projection has overcome ultrasonography and IVU for identification and interpretation of some of these variants.

Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.

PubMed

Steinberg, Karyn Meltz; Ramachandran, Dhanya; Patel, Viren C; Shetty, Amol C; Cutler, David J; Zwick, Michael E

2012-09-28

Autism spectrum disorder (ASD) is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3' UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects.

Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder

PubMed Central

2012-01-01

Background Autism spectrum disorder (ASD) is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. Methods We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. Results We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3’ UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. Conclusions These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects. PMID:23020841

TIAM1 variants improve clinical outcome in neuroblastoma.

PubMed

Sanmartín, Elena; Yáñez, Yania; Fornés-Ferrer, Victoria; Zugaza, José L; Cañete, Adela; Castel, Victoria; Font de Mora, Jaime

2017-07-11

Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease. The detected variants are located within the different domains of TIAM1 that signal to the upstream regulator RAS and downstream effector molecules MYC and RAC, which are all implicated in neuroblastoma etiology and progression. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification. Given the function of these signaling molecules in cell survival, proliferation, differentiation and neurite outgrowth, our data suggest that the TIAM1-mediated network is essential to neuroblastoma and thus, inhibiting TIAM1 reflects a rational strategy for improving therapy efficacy in neuroblastoma.

Microstructural development inside the stress induced martensite variant in a Ti-Ni-Nb shape memory alloy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, Y.F.; Cai, W.; Zhang, J.X.

2000-04-03

The microstructural development inside the stress induced martensite (SIM) variants in Ti-Ni-Nb alloy with various degrees of deformation have been revealed by electron microscopic observations. The orientation relationship between the SIM and the parent phase has been found: [1{bar 1}0]{sub M}{parallel}[11{bar 1}]{sub B2}, (001){sub M} 5{degree} away from (101){sub B2}. The lattice invariant shear of the SIM variants at the slightly deformed stage is dominantly (11{bar 1}) Type I twin. Besides the ordinary slip, the adjustment and development of the internal secondary twinning from (11{bar 1}) Type I twin to {l_angle}011{r_angle} Type II/ or (011) Type I twin, (001)compound twinmore » and (111) Type I twin happen concurrently or in combination inside the SIM variants with the further deformation. The corresponding deformation mechanisms include stress induced reorientation of SIM substructural bands by the most favorably oriented twin system, stress induced migration of the SIM substructural boundary through internal twinning and stress induced injection of foreign SIM variant to the preexisting substructural bands.« less

Ankle fracture spur sign is pathognomonic for a variant ankle fracture.

PubMed

Hinds, Richard M; Garner, Matthew R; Lazaro, Lionel E; Warner, Stephen J; Loftus, Michael L; Birnbaum, Jacqueline F; Burket, Jayme C; Lorich, Dean G

2015-02-01

The hyperplantarflexion variant ankle fracture is composed of a posterior tibial lip fracture with posterolateral and posteromedial fracture fragments separated by a vertical fracture line. This infrequently reported injury pattern often includes an associated "spur sign" or double cortical density at the inferomedial tibial metaphysis. The objective of this study was to quantitatively establish the association of the ankle fracture spur sign with the hyperplantarflexion variant ankle fracture. Our clinical database of operative ankle fractures was retrospectively reviewed for the incidence of hyperplantarflexion variant and nonvariant ankle fractures as determined by assessment of injury radiographs, preoperative advanced imaging, and intraoperative observation. Injury radiographs were then evaluated for the presence of the spur sign, and association between the spur sign and variant fractures was analyzed. The incidence of the hyperplantarflexion variant fracture among all ankle fractures was 6.7% (43/640). The spur sign was present in 79% (34/43) of variant fractures and absent in all nonvariant fractures, conferring a specificity of 100% in identifying variant fractures. Positive predictive value and negative predictive value were 100% and 99%, respectively. The ankle fracture spur sign was pathognomonic for the hyperplantarflexion variant ankle fracture. It is important to identify variant fractures preoperatively as patient positioning, operative approach, and fixation construct of variant fractures often differ from those employed for osteosynthesis of nonvariant fractures. Identification of the spur sign should prompt acquisition of advanced imaging to formulate an appropriate operative plan to address the variant fracture pattern. Level III, retrospective comparative study. © The Author(s) 2014.

Identification and replication of the interplay of four genetic high-risk variants for urinary bladder cancer

PubMed Central

Selinski, Silvia; Blaszkewicz, Meinolf; Ickstadt, Katja; Gerullis, Holger; Otto, Thomas; Roth, Emanuel; Volkert, Frank; Ovsiannikov, Daniel; Moormann, Oliver; Banfi, Gergely; Nyirady, Peter; Vermeulen, Sita H; Garcia-Closas, Montserrat; Figueroa, Jonine D; Johnson, Alison; Karagas, Margaret R; Kogevinas, Manolis; Malats, Nuria; Schwenn, Molly; Silverman, Debra T; Koutros, Stella; Rothman, Nathaniel; Kiemeney, Lambertus A; Hengstler, Jan G; Golka, Klaus

2017-01-01

Abstract Little is known whether genetic variants identified in genome-wide association studies interact to increase bladder cancer risk. Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case–control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case–control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered. The strongest four-variant combination was obtained in never smokers. The combination of rs1014971[AA] near apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and chromobox homolog 6 (CBX6), solute carrier family 1s4 (urea transporter), member 1 (Kidd blood group) (SLC14A1) exon single nucleotide polymorphism (SNP) rs1058396[AG, GG], UDP glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A) intron SNP rs11892031[AA] and rs8102137[CC, CT] near cyclin E1 (CCNE1) resulted in an unadjusted odds ratio (OR) of 2.59 (95% CI = 1.93–3.47; P = 1.87 × 10−10), while the individual variant ORs ranged only between 1.11 and 1.30. The combination replicated in the New England and Spanish Bladder Cancer Studies (ORunadjusted = 1.60, 95% CI = 1.10–2.33; P = 0.013). The four-variant combination is relatively frequent, with 25% in never smoking cases and 11% in never smoking controls (total study group: 19% cases, 14% controls). In conclusion, we show that four high-risk variants can statistically

Using whole-exome sequencing to identify variants inherited from mosaic parents

PubMed Central

Rios, Jonathan J; Delgado, Mauricio R

2015-01-01

Whole-exome sequencing (WES) has allowed the discovery of genes and variants causing rare human disease. This is often achieved by comparing nonsynonymous variants between unrelated patients, and particularly for sporadic or recessive disease, often identifies a single or few candidate genes for further consideration. However, despite the potential for this approach to elucidate the genetic cause of rare human disease, a majority of patients fail to realize a genetic diagnosis using standard exome analysis methods. Although genetic heterogeneity contributes to the difficulty of exome sequence analysis between patients, it remains plausible that rare human disease is not caused by de novo or recessive variants. Multiple human disorders have been described for which the variant was inherited from a phenotypically normal mosaic parent. Here we highlight the potential for exome sequencing to identify a reasonable number of candidate genes when dominant disease variants are inherited from a mosaic parent. We show the power of WES to identify a limited number of candidate genes using this disease model and how sequence coverage affects identification of mosaic variants by WES. We propose this analysis as an alternative to discover genetic causes of rare human disorders for which typical WES approaches fail to identify likely pathogenic variants. PMID:24986828

RAPTR-SV: a hybrid method for the detection of structural variants

USDA-ARS?s Scientific Manuscript database

Motivation: Identification of Structural Variants (SV) in sequence data results in a large number of false positive calls using existing software, which overburdens subsequent validation. Results: Simulations using RAPTR-SV and another software package that uses a similar algorithm for SV detection...

Identification of variant-specific surface proteins in Giardia muris trophozoites.

PubMed

Ropolo, Andrea S; Saura, Alicia; Carranza, Pedro G; Lujan, Hugo D

2005-08-01

Giardia lamblia undergoes antigenic variation, a process that might allow the parasite to evade the host's immune response and adapt to different environments. Here we show that Giardia muris, a related species that naturally infects rodents, possesses multiple variant-specific surface proteins (VSPs) and expresses VSPs on its surface, suggesting that it undergoes antigenic variation similar to that of G. lamblia.

Identification of Variant-Specific Surface Proteins in Giardia muris Trophozoites

PubMed Central

Ropolo, Andrea S.; Saura, Alicia; Carranza, Pedro G.; Lujan, Hugo D.

2005-01-01

Giardia lamblia undergoes antigenic variation, a process that might allow the parasite to evade the host's immune response and adapt to different environments. Here we show that Giardia muris, a related species that naturally infects rodents, possesses multiple variant-specific surface proteins (VSPs) and expresses VSPs on its surface, suggesting that it undergoes antigenic variation similar to that of G. lamblia. PMID:16041041

Common genetic variants influence human subcortical brain structures.

PubMed

Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

2015-04-09

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Common genetic variants influence human subcortical brain structures

PubMed Central

Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

2015-01-01

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

Probing the Orientation of Surface-Immobilized Protein G B1 Using ToF-SIMS Sum Frequency Generation and NEXAFS Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

L Baugh; T Weidner; J Baio

2011-12-31

The ability to orient active proteins on surfaces is a critical aspect of many medical technologies. An important related challenge is characterizing protein orientation in these surface films. This study uses a combination of time-of-flight secondary ion mass spectrometry (ToF-SIMS), sum frequency generation (SFG) vibrational spectroscopy, and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy to characterize the orientation of surface-immobilized Protein G B1, a rigid 6 kDa domain that binds the Fc fragment of IgG. Two Protein G B1 variants with a single cysteine introduced at either end were immobilized via the cysteine thiol onto maleimide-oligo(ethylene glycol)-functionalized gold and baremore » gold substrates. X-ray photoelectron spectroscopy was used to measure the amount of immobilized protein, and ToF-SIMS was used to measure the amino acid composition of the exposed surface of the protein films and to confirm covalent attachment of protein thiol to the substrate maleimide groups. SFG and NEXAFS were used to characterize the ordering and orientation of peptide or side chain bonds. On both substrates and for both cysteine positions, ToF-SIMS data showed enrichment of mass peaks from amino acids located at the end of the protein opposite to the cysteine surface position as compared with nonspecifically immobilized protein, indicating end-on protein orientations. Orientation on the maleimide substrate was enhanced by increasing pH (7.0-9.5) and salt concentration (0-1.5 M NaCl). SFG spectral peaks characteristic of ordered {alpha}-helix and {beta}-sheet elements were observed for both variants but not for cysteine-free wild type protein on the maleimide surface. The phase of the {alpha}-helix and {beta}-sheet peaks indicated a predominantly upright orientation for both variants, consistent with an end-on protein binding configuration. Polarization dependence of the NEXAFS signal from the N 1s to {pi}* transition of {beta}-sheet peptide bonds

The Role of Constitutional Copy Number Variants in Breast Cancer

PubMed Central

Walker, Logan C.; Wiggins, George A.R.; Pearson, John F.

2015-01-01

Constitutional copy number variants (CNVs) include inherited and de novo deviations from a diploid state at a defined genomic region. These variants contribute significantly to genetic variation and disease in humans, including breast cancer susceptibility. Identification of genetic risk factors for breast cancer in recent years has been dominated by the use of genome-wide technologies, such as single nucleotide polymorphism (SNP)-arrays, with a significant focus on single nucleotide variants. To date, these large datasets have been underutilised for generating genome-wide CNV profiles despite offering a massive resource for assessing the contribution of these structural variants to breast cancer risk. Technical challenges remain in determining the location and distribution of CNVs across the human genome due to the accuracy of computational prediction algorithms and resolution of the array data. Moreover, better methods are required for interpreting the functional effect of newly discovered CNVs. In this review, we explore current and future application of SNP array technology to assess rare and common CNVs in association with breast cancer risk in humans. PMID:27600231

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

PubMed

Lohoff, F W; Hodge, R; Narasimhan, S; Nall, A; Ferraro, T N; Mickey, B J; Heitzeg, M M; Langenecker, S A; Zubieta, J-K; Bogdan, R; Nikolova, Y S; Drabant, E; Hariri, A R; Bevilacqua, L; Goldman, D; Doyle, G A

2014-01-01

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Mutation Update for GNE Gene Variants Associated with GNE Myopathy

PubMed Central

Celeste, Frank V.; Vilboux, Thierry; Ciccone, Carla; de Dios, John Karl; Malicdan, May Christine V.; Leoyklang, Petcharat; McKew, John C.; Gahl, William A.; Carrillo-Carrasco, Nuria; Huizing, Marjan

2014-01-01

The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions and 7 intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants as well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ~ 4–21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder’s pathomechanism and for the success of ongoing treatment trials. PMID:24796702

fMRI orientation decoding in V1 does not require global maps or globally coherent orientation stimuli.

PubMed

Alink, Arjen; Krugliak, Alexandra; Walther, Alexander; Kriegeskorte, Nikolaus

2013-01-01

The orientation of a large grating can be decoded from V1 functional magnetic resonance imaging (fMRI) data, even at low resolution (3-mm isotropic voxels). This finding has suggested that columnar-level neuronal information might be accessible to fMRI at 3T. However, orientation decodability might alternatively arise from global orientation-preference maps. Such global maps across V1 could result from bottom-up processing, if the preferences of V1 neurons were biased toward particular orientations (e.g., radial from fixation, or cardinal, i.e., vertical or horizontal). Global maps could also arise from local recurrent or top-down processing, reflecting pre-attentive perceptual grouping, attention spreading, or predictive coding of global form. Here we investigate whether fMRI orientation decoding with 2-mm voxels requires (a) globally coherent orientation stimuli and/or (b) global-scale patterns of V1 activity. We used opposite-orientation gratings (balanced about the cardinal orientations) and spirals (balanced about the radial orientation), along with novel patch-swapped variants of these stimuli. The two stimuli of a patch-swapped pair have opposite orientations everywhere (like their globally coherent parent stimuli). However, the two stimuli appear globally similar, a patchwork of opposite orientations. We find that all stimulus pairs are robustly decodable, demonstrating that fMRI orientation decoding does not require globally coherent orientation stimuli. Furthermore, decoding remained robust after spatial high-pass filtering for all stimuli, showing that fine-grained components of the fMRI patterns reflect visual orientations. Consistent with previous studies, we found evidence for global radial and vertical preference maps in V1. However, these were weak or absent for patch-swapped stimuli, suggesting that global preference maps depend on globally coherent orientations and might arise through recurrent or top-down processes related to the perception of

Assigning Main Orientation to an EOH Descriptor on Multispectral Images.

PubMed

Li, Yong; Shi, Xiang; Wei, Lijun; Zou, Junwei; Chen, Fang

2015-07-01

This paper proposes an approach to compute an EOH (edge-oriented histogram) descriptor with main orientation. EOH has a better matching ability than SIFT (scale-invariant feature transform) on multispectral images, but does not assign a main orientation to keypoints. Alternatively, it tends to assign the same main orientation to every keypoint, e.g., zero degrees. This limits EOH to matching keypoints between images of translation misalignment only. Observing this limitation, we propose assigning to keypoints the main orientation that is computed with PIIFD (partial intensity invariant feature descriptor). In the proposed method, SIFT keypoints are detected from images as the extrema of difference of Gaussians, and every keypoint is assigned to the main orientation computed with PIIFD. Then, EOH is computed for every keypoint with respect to its main orientation. In addition, an implementation variant is proposed for fast computation of the EOH descriptor. Experimental results show that the proposed approach performs more robustly than the original EOH on image pairs that have a rotation misalignment.

REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants.

PubMed

Ioannidis, Nilah M; Rothstein, Joseph H; Pejaver, Vikas; Middha, Sumit; McDonnell, Shannon K; Baheti, Saurabh; Musolf, Anthony; Li, Qing; Holzinger, Emily; Karyadi, Danielle; Cannon-Albright, Lisa A; Teerlink, Craig C; Stanford, Janet L; Isaacs, William B; Xu, Jianfeng; Cooney, Kathleen A; Lange, Ethan M; Schleutker, Johanna; Carpten, John D; Powell, Isaac J; Cussenot, Olivier; Cancel-Tassin, Geraldine; Giles, Graham G; MacInnis, Robert J; Maier, Christiane; Hsieh, Chih-Lin; Wiklund, Fredrik; Catalona, William J; Foulkes, William D; Mandal, Diptasri; Eeles, Rosalind A; Kote-Jarai, Zsofia; Bustamante, Carlos D; Schaid, Daniel J; Hastie, Trevor; Ostrander, Elaine A; Bailey-Wilson, Joan E; Radivojac, Predrag; Thibodeau, Stephen N; Whittemore, Alice S; Sieh, Weiva

2016-10-06

The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10 -12 ) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale. Copyright © 2016 American Society of Human Genetics. All rights reserved.

New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies.

PubMed

Gamonet, Clémentine; Bole-Richard, Elodie; Delherme, Aurélia; Aubin, François; Toussirot, Eric; Garnache-Ottou, Francine; Godet, Yann; Ysebaert, Loïc; Tournilhac, Olivier; Caroline, Dartigeas; Larosa, Fabrice; Deconinck, Eric; Saas, Philippe; Borg, Christophe; Deschamps, Marina; Ferrand, Christophe

2015-01-01

CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors. Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL. The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cell malignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies.

Identification of a rare coding variant in TREM2 in a Chinese individual with Alzheimer's disease.

PubMed

Bonham, Luke W; Sirkis, Daniel W; Fan, Jia; Aparicio, Renan E; Tse, Marian; Ramos, Eliana Marisa; Wang, Qing; Coppola, Giovanni; Rosen, Howard J; Miller, Bruce L; Yokoyama, Jennifer S

2017-02-01

Rare variation in the TREM2 gene is associated with a broad spectrum of neurodegenerative disorders including Alzheimer's disease (AD). TREM2 encodes a receptor expressed in microglia which is thought to influence neurodegeneration by sensing damage signals and regulating neuroinflammation. Many of the variants reported to be associated with AD, including the rare R47H variant, were discovered in populations of European ancestry and have not replicated in diverse populations from other genetic backgrounds. We utilized a cohort of elderly Chinese individuals diagnosed as cognitively normal, or with mild cognitive impairment or AD to identify a rare variant, A192T, present in a single patient diagnosed with AD. We characterized this variant using biochemical cell surface expression assays and found that it significantly altered cell surface expression of the TREM2 protein. Together these data provide evidence that the A192T variant in TREM2 could contribute risk for AD. This study underscores the increasingly recognized role of immune-related processes in AD and highlights the importance of including diverse populations in research to identify genetic variation that contributes risk for AD and other neurodegenerative disorders.

Childhood Abuse Experiences and the COMT and MTHFR Genetic Variants Associated With Male Sexual Orientation in the Han Chinese Populations: A Case-Control Study.

PubMed

Qin, Jia-Bi; Zhao, Guang-Lu; Wang, Feng; Cai, Yu-Mao; Lan, Li-Na; Yang, Lin; Feng, Tie-Jian

2018-01-01

variants could be positively associated with the development of homosexuality. However, it remains unknown how these factors jointly play a role in the development of homosexuality, and more studies in different ethnic populations and with a larger sample and a prospective design are required to confirm our findings. Qin J-B, Zhao G-L, Wang F, et al. Childhood Abuse Experiences and the COMT and MTHFR Genetic Variants Associated With Male Sexual Orientation in the Han Chinese Populations: A Case-Control Study. J Sex Med 2018;15:29-42. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization

PubMed Central

2012-01-01

Introduction In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling. Methods To identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay. Results None of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility. Conclusions Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population. PMID:22513239

Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs.

PubMed

Ionita-Laza, Iuliana; Ottman, Ruth

2011-11-01

The recent progress in sequencing technologies makes possible large-scale medical sequencing efforts to assess the importance of rare variants in complex diseases. The results of such efforts depend heavily on the use of efficient study designs and analytical methods. We introduce here a unified framework for association testing of rare variants in family-based designs or designs based on unselected affected individuals. This framework allows us to quantify the enrichment in rare disease variants in families containing multiple affected individuals and to investigate the optimal design of studies aiming to identify rare disease variants in complex traits. We show that for many complex diseases with small values for the overall sibling recurrence risk ratio, such as Alzheimer's disease and most cancers, sequencing affected individuals with a positive family history of the disease can be extremely advantageous for identifying rare disease variants. In contrast, for complex diseases with large values of the sibling recurrence risk ratio, sequencing unselected affected individuals may be preferable.

Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling.

PubMed

Petersen, Annabeth Høgh; Aagaard, Mads Malik; Nielsen, Henriette Roed; Steffensen, Karina Dahl; Waldstrøm, Marianne; Bojesen, Anders

2016-08-01

Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible.

Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling

PubMed Central

Petersen, Annabeth Høgh; Aagaard, Mads Malik; Nielsen, Henriette Roed; Steffensen, Karina Dahl; Waldstrøm, Marianne; Bojesen, Anders

2016-01-01

Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1–14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0–43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0–38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible. PMID:26733283

Cancer-Related Analysis of Variants Toolkit (CRAVAT) | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

CRAVAT is an easy to use web-based tool for analysis of cancer variants (missense, nonsense, in-frame indel, frameshift indel, splice site). CRAVAT provides scores and a variety of annotations that assist in identification of important variants. Results are provided in an interactive, highly graphical webpage and include annotated 3D structure visualization. CRAVAT is also available for local or cloud-based installation as a Docker container. MuPIT provides 3D visualization of mutation clusters and functional annotation and is now integrated with CRAVAT.

Synthesis of spatially variant lattices.

PubMed

Rumpf, Raymond C; Pazos, Javier

2012-07-02

It is often desired to functionally grade and/or spatially vary a periodic structure like a photonic crystal or metamaterial, yet no general method for doing this has been offered in the literature. A straightforward procedure is described here that allows many properties of the lattice to be spatially varied at the same time while producing a final lattice that is still smooth and continuous. Properties include unit cell orientation, lattice spacing, fill fraction, and more. This adds many degrees of freedom to a design such as spatially varying the orientation to exploit directional phenomena. The method is not a coordinate transformation technique so it can more easily produce complicated and arbitrary spatial variance. To demonstrate, the algorithm is used to synthesize a spatially variant self-collimating photonic crystal to flow a Gaussian beam around a 90° bend. The performance of the structure was confirmed through simulation and it showed virtually no scattering around the bend that would have arisen if the lattice had defects or discontinuities.

The Clock Is Ticking: Library Orientation as Puzzle Room

ERIC Educational Resources Information Center

Reade, Tripp

2017-01-01

Tripp Reade is the school librarian at Cardinal Gibbons High School in Raleigh, North Carolina. This article describes how he redesigned his school's library orientation program after learning about escape rooms and a variant known as puzzle rooms. Puzzle rooms present players with a set of challenges to solve; they require "teamwork,…

Transhomosexuality, or the dissociation of sexual orientation and sex object choice.

PubMed

Clare, D; Tully, B

1989-12-01

Subjects whose sexual orientation and identification is with homosexual persons of the opposite biological sex were studied. "Transhomosexual" has been coined to describe such persons. Forms of transhomosexual expression vary with different emphases found in regard to orientation to, idealization of, and wish to participate in activities of homosexuals of the opposite biological sex. Where identification is strong or overriding, such persons become "transsexual." However, there are important differences between these and conventionally diagnosed transsexuals. Sexual orientation then is not defined entirely or always by the sex of the sexual object choice, but sometimes additionally by references to preferred heterosexual or homosexual styles of relationship.

Identification of cultivated land using remote sensing images based on object-oriented artificial bee colony algorithm

NASA Astrophysics Data System (ADS)

Li, Nan; Zhu, Xiufang

2017-04-01

Cultivated land resources is the key to ensure food security. Timely and accurate access to cultivated land information is conducive to a scientific planning of food production and management policies. The GaoFen 1 (GF-1) images have high spatial resolution and abundant texture information and thus can be used to identify fragmentized cultivated land. In this paper, an object-oriented artificial bee colony algorithm was proposed for extracting cultivated land from GF-1 images. Firstly, the GF-1 image was segmented by eCognition software and some samples from the segments were manually identified into 2 types (cultivated land and non-cultivated land). Secondly, the artificial bee colony (ABC) algorithm was used to search for classification rules based on the spectral and texture information extracted from the image objects. Finally, the extracted classification rules were used to identify the cultivated land area on the image. The experiment was carried out in Hongze area, Jiangsu Province using wide field-of-view sensor on the GF-1 satellite image. The total precision of classification result was 94.95%, and the precision of cultivated land was 92.85%. The results show that the object-oriented ABC algorithm can overcome the defect of insufficient spectral information in GF-1 images and obtain high precision in cultivated identification.

Personal Factors in Organizational Identification

ERIC Educational Resources Information Center

Hall, Douglas T.; And Others

1970-01-01

Results of a study suggested possibility of a process whereby (1) service-oriented individuals are attracted to and recruited by the Forest Service, (2) service-oriented members are likely to identify strongly with the Service, and (3) this identification results in intrinsic need satisfactions. (Author/KJ)

Perceptual-cognitive skills and performance in orienteering.

PubMed

Guzmán, José F; Pablos, Ana M; Pablos, Carlos

2008-08-01

The goal was analysis of the perceptual-cognitive skills associated with sport performance in orienteering in a sample of 22 elite and 17 nonelite runners. Variables considered were memory, basic orienteering techniques, map reading, symbol knowledge, map-terrain-map identification, and spatial organisation. A computerised questionnaire was developed to measure the variables. The reliability of the test (agreement between experts) was 90%. Findings suggested that competence in performing basic orienteering techniques efficiently was a key variable differentiating between the elite and the nonelite athletes. The results are discussed in comparison with previous studies.

Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting.

PubMed

Zilbermintz, Leeor; Leonardi, William; Jeong, Sun-Young; Sjodt, Megan; McComb, Ryan; Ho, Chi-Lee C; Retterer, Cary; Gharaibeh, Dima; Zamani, Rouzbeh; Soloveva, Veronica; Bavari, Sina; Levitin, Anastasia; West, Joel; Bradley, Kenneth A; Clubb, Robert T; Cohen, Stanley N; Gupta, Vivek; Martchenko, Mikhail

2015-08-27

A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.

Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants.

PubMed

Berger, Seth I; Ciccone, Carla; Simon, Karen L; Malicdan, May Christine; Vilboux, Thierry; Billington, Charles; Fischer, Roxanne; Introne, Wendy J; Gropman, Andrea; Blancato, Jan K; Mullikin, James C; Gahl, William A; Huizing, Marjan; Smith, Ann C M

2017-04-01

Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.

[Genetic variants in miRNAs and its association with breast cancer].

PubMed

Méndez-Gómez, Susana; Ruiz Esparza-Garrido, Ruth; Velázquez-Flores, Miguel; Dolores-Vergara, Maria; Salamanca-Gómez, Fabio; Arenas-Aranda, Diego Julio

2014-01-01

In Mexico, breast cancer represents the first cause of cancer death in females. At the molecular level, non-coding RNAs and especially microRNAs have played an important role in the origin and development of this neoplasm In the Anglo-Saxon population, diverse genetic variants in microRNA genes and in their targets are associated with the development of this disease. In the Mexican population it is not known if these or other variants exist. Identification of these or new variants in our population is fundamental in order to have a better understanding of cancer development and to help establish a better diagnostic strategy. DNA was isolated from mammary tumors, adjacent tissue and peripheral blood of Mexican females with or without cancer. From DNA, five microRNA genes and three of their targets were amplified and sequenced. Genetic variants associated with breast cancer in an Anglo- Saxon population have been previously identified in these sequences. In the samples studied we identified seven single nucleotide polymorphisms (SNPs). Two had not been previously described and were identified only in women with cancer. The new variants may be genetic predisposition factors for the development of breast cancer in our population. Further experiments are needed to determine the involvement of these variants in the development, establishment and progression of breast cancer.

Behavioral and language variants of frontotemporal dementia: a review of key symptoms.

PubMed

Laforce, Robert

2013-12-01

While recent advances in the development of neuroimaging and molecular biomarkers for studying neurodegenerative conditions have revolutionized the field, dementia remains a clinical diagnosis. No component of the diagnostic process is more crucial than obtaining a good history. Getting to know the first manifestations of the disease, tracking their evolution and functional impact, combined with a targeted neurological examination, further guides differential diagnosis. This paper summarizes the key symptoms of the behavioral and language variants of frontotemporal dementia. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by severe changes in behavior and personality such as disinhibition, apathy, loss of empathy, or stereotypic behavior, leading to a loss of social competence. Executive functions are impaired, while memory and visuospatial skills are relatively better preserved. By contrast, the language variants or primary progressive aphasias (PPAs) are marked by prominent language disturbances that can be subclassified into a non-fluent/agrammatic variant (naPPA), a semantic variant (svPPA), and a logopenic variant (lvPPA). Although combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis of such heterogeneous conditions, the author emphasizes the importance of accurate recognition of key symptoms that can lead to better identification of underlying neuropathology and appropriate treatment approaches.

Molecular identification of Gd A- and Gd B- G6PD deficient variants by ARMS-PCR in a Tunisian population.

PubMed

Haloui, Sabrine; Laouini, Naouel; Sahli, Chaima Abdelhafidh; Daboubi, Rim; Becher, Mariem; Jouini, Latifa; Kazdaghli, Kalthoum; Tinsa, Faten; Cherif, Semia; Khemiri, Monia; Fredj, Sondess Hadj; Othmani, Rim; Ouali, Faida; Siala, Hajer; Toumi, Nour El Houda; Barsaoui, Sihem; Bibi, Amina; Messaoud, Taieb

2016-01-01

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy. More than 200 mutations in the G6PD gene have been described. In Tunisia, the A-African and the B-Mediterranean mutations predominate the mutational spectrum. The purpose of this study was to apply the amplification refractory mutation system (ARMS-PCR) to the identification of Gd A+, Gd A- and Gd B- variants in a cohort of deficient individuals and to establish a phenotype/genotype association. 90 subjects were screened for enzymatic deficiency by spectrophotometric assay. The molecular analyses were performed in a group of 50 unrelated patients. Of the 54 altered chromosomes examined, 60% had the Gd A- mutation, 18% showed the Gd B- mutation and in 20% of cases, no mutations have been identified. The ARMS-PCR showed complete concordance with the endonuclease cleavage reference method and agreed perfectly with previous Tunisian studies where Gd A- and Gd B- were the most encountered. Also, similarities in spectrum mutations with North African and Mediterranean countries suggest gene migration from Africa to Europe through Spain. In conclusion, ARMS has been introduced in this study for common G6PD alleles identification in Tunisia. It gives some advantages compared to the traditional endonuclease digestion method since it is more convenient and timesaving and also offers the possibility to be applied in mass screening surveys.

Identification of common variants associated with human hippocampal and intracranial volumes.

PubMed

Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias; Hibar, Derrek P; Senstad, Rudy E; Winkler, Anderson M; Toro, Roberto; Appel, Katja; Bartecek, Richard; Bergmann, Ørjan; Bernard, Manon; Brown, Andrew A; Cannon, Dara M; Chakravarty, M Mallar; Christoforou, Andrea; Domin, Martin; Grimm, Oliver; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hottenga, Jouke-Jan; Langan, Camilla; Lopez, Lorna M; Hansell, Narelle K; Hwang, Kristy S; Kim, Sungeun; Laje, Gonzalo; Lee, Phil H; Liu, Xinmin; Loth, Eva; Lourdusamy, Anbarasu; Mattingsdal, Morten; Mohnke, Sebastian; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; O'Brien, Carol; Papmeyer, Martina; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rijpkema, Mark; Risacher, Shannon L; Roddey, J Cooper; Rose, Emma J; Ryten, Mina; Shen, Li; Sprooten, Emma; Strengman, Eric; Teumer, Alexander; Trabzuni, Daniah; Turner, Jessica; van Eijk, Kristel; van Erp, Theo G M; van Tol, Marie-Jose; Wittfeld, Katharina; Wolf, Christiane; Woudstra, Saskia; Aleman, Andre; Alhusaini, Saud; Almasy, Laura; Binder, Elisabeth B; Brohawn, David G; Cantor, Rita M; Carless, Melanie A; Corvin, Aiden; Czisch, Michael; Curran, Joanne E; Davies, Gail; de Almeida, Marcio A A; Delanty, Norman; Depondt, Chantal; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fagerness, Jesen; Fox, Peter T; Freimer, Nelson B; Gill, Michael; Göring, Harald H H; Hagler, Donald J; Hoehn, David; Holsboer, Florian; Hoogman, Martine; Hosten, Norbert; Jahanshad, Neda; Johnson, Matthew P; Kasperaviciute, Dalia; Kent, Jack W; Kochunov, Peter; Lancaster, Jack L; Lawrie, Stephen M; Liewald, David C; Mandl, René; Matarin, Mar; Mattheisen, Manuel; Meisenzahl, Eva; Melle, Ingrid; Moses, Eric K; Mühleisen, Thomas W; Nauck, Matthias; Nöthen, Markus M; Olvera, Rene L; Pandolfo, Massimo; Pike, G Bruce; Puls, Ralf; Reinvang, Ivar; Rentería, Miguel E; Rietschel, Marcella; Roffman, Joshua L; Royle, Natalie A; Rujescu, Dan; Savitz, Jonathan; Schnack, Hugo G; Schnell, Knut; Seiferth, Nina; Smith, Colin; Steen, Vidar M; Valdés Hernández, Maria C; Van den Heuvel, Martijn; van der Wee, Nic J; Van Haren, Neeltje E M; Veltman, Joris A; Völzke, Henry; Walker, Robert; Westlye, Lars T; Whelan, Christopher D; Agartz, Ingrid; Boomsma, Dorret I; Cavalleri, Gianpiero L; Dale, Anders M; Djurovic, Srdjan; Drevets, Wayne C; Hagoort, Peter; Hall, Jeremy; Heinz, Andreas; Jack, Clifford R; Foroud, Tatiana M; Le Hellard, Stephanie; Macciardi, Fabio; Montgomery, Grant W; Poline, Jean Baptiste; Porteous, David J; Sisodiya, Sanjay M; Starr, John M; Sussmann, Jessika; Toga, Arthur W; Veltman, Dick J; Walter, Henrik; Weiner, Michael W; Bis, Joshua C; Ikram, M Arfan; Smith, Albert V; Gudnason, Vilmundur; Tzourio, Christophe; Vernooij, Meike W; Launer, Lenore J; DeCarli, Charles; Seshadri, Sudha; Andreassen, Ole A; Apostolova, Liana G; Bastin, Mark E; Blangero, John; Brunner, Han G; Buckner, Randy L; Cichon, Sven; Coppola, Giovanni; de Zubicaray, Greig I; Deary, Ian J; Donohoe, Gary; de Geus, Eco J C; Espeseth, Thomas; Fernández, Guillén; Glahn, David C; Grabe, Hans J; Hardy, John; Hulshoff Pol, Hilleke E; Jenkinson, Mark; Kahn, René S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meyer-Lindenberg, Andreas; Morris, Derek W; Müller-Myhsok, Bertram; Nichols, Thomas E; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W; Potkin, Steven G; Sämann, Philipp G; Saykin, Andrew J; Schumann, Gunter; Smoller, Jordan W; Wardlaw, Joanna M; Weale, Michael E; Martin, Nicholas G; Franke, Barbara; Wright, Margaret J; Thompson, Paul M

2012-04-15

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Identifying Mendelian disease genes with the Variant Effect Scoring Tool

PubMed Central

2013-01-01

Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is

Trends in Sexual Orientation Missing Data Over a Decade of the California Health Interview Survey

PubMed Central

Viana, Joseph; Grant, David; Cochran, Susan D.; Lee, Annie C.; Ponce, Ninez A.

2015-01-01

Objectives. We explored changes in sexual orientation question item completion in a large statewide health survey. Methods. We used 2003 to 2011 California Health Interview Survey data to investigate sexual orientation item nonresponse and sexual minority self-identification trends in a cross-sectional sample representing the noninstitutionalized California household population aged 18 to 70 years (n = 182 812 adults). Results. Asians, Hispanics, limited-English-proficient respondents, and those interviewed in non-English languages showed the greatest declines in sexual orientation item nonresponse. Asian women, regardless of English-proficiency status, had the highest odds of item nonresponse. Spanish interviews produced more nonresponse than English interviews and Asian-language interviews produced less nonresponse when we controlled for demographic factors and survey cycle. Sexual minority self-identification increased in concert with the item nonresponse decline. Conclusions. Sexual orientation nonresponse declines and the increase in sexual minority identification suggest greater acceptability of sexual orientation assessment in surveys. Item nonresponse rate convergence among races/ethnicities, language proficiency groups, and interview languages shows that sexual orientation can be measured in surveys of diverse populations. PMID:25790399

m6ASNP: a tool for annotating genetic variants by m6A function.

PubMed

Jiang, Shuai; Xie, Yubin; He, Zhihao; Zhang, Ya; Zhao, Yuli; Chen, Li; Zheng, Yueyuan; Miao, Yanyan; Zuo, Zhixiang; Ren, Jian

2018-05-01

Large-scale genome sequencing projects have identified many genetic variants for diverse diseases. A major goal of these projects is to characterize these genetic variants to provide insight into their function and roles in diseases. N6-methyladenosine (m6A) is one of the most abundant RNA modifications in eukaryotes. Recent studies have revealed that aberrant m6A modifications are involved in many diseases. In this study, we present a user-friendly web server called "m6ASNP" that is dedicated to the identification of genetic variants that target m6A modification sites. A random forest model was implemented in m6ASNP to predict whether the methylation status of an m6A site is altered by the variants that surround the site. In m6ASNP, genetic variants in a standard variant call format (VCF) are accepted as the input data, and the output includes an interactive table that contains the genetic variants annotated by m6A function. In addition, statistical diagrams and a genome browser are provided to visualize the characteristics and to annotate the genetic variants. We believe that m6ASNP is a very convenient tool that can be used to boost further functional studies investigating genetic variants. The web server "m6ASNP" is implemented in JAVA and PHP and is freely available at [60].

Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer.

PubMed

Mitsui, Jun; Fukuda, Yoko; Azuma, Kyo; Tozaki, Hirokazu; Ishiura, Hiroyuki; Takahashi, Yuji; Goto, Jun; Tsuji, Shoji

2010-07-01

We have recently found that multiple rare variants of the glucocerebrosidase gene (GBA) confer a robust risk for Parkinson disease, supporting the 'common disease-multiple rare variants' hypothesis. To develop an efficient method of identifying rare variants in a large number of samples, we applied multiplexed resequencing using a next-generation sequencer to identification of rare variants of GBA. Sixteen sets of pooled DNAs from six pooled DNA samples were prepared. Each set of pooled DNAs was subjected to polymerase chain reaction to amplify the target gene (GBA) covering 6.5 kb, pooled into one tube with barcode indexing, and then subjected to extensive sequence analysis using the SOLiD System. Individual samples were also subjected to direct nucleotide sequence analysis. With the optimization of data processing, we were able to extract all the variants from 96 samples with acceptable rates of false-positive single-nucleotide variants.

Genetic epidemiology of motor neuron disease-associated variants in the Scottish population.

PubMed

Black, Holly A; Leighton, Danielle J; Cleary, Elaine M; Rose, Elaine; Stephenson, Laura; Colville, Shuna; Ross, David; Warner, Jon; Porteous, Mary; Gorrie, George H; Swingler, Robert; Goldstein, David; Harms, Matthew B; Connick, Peter; Pal, Suvankar; Aitman, Timothy J; Chandran, Siddharthan

2017-03-01

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Identification of Rare Variants in TNNI3 with Atrial Fibrillation in a Chinese GeneID Population

PubMed Central

Wang, Chuchu; Wu, Manman; Qian, Jin; Li, Bin; Tu, Xin; Xu, Chengqi; Li, Sisi; Chen, Shanshan; Zhao, Yuanyuan; Huang, Yufeng; Shi, Lisong; Cheng, Xiang; Liao, Yuhua; Chen, Qiuyun; Xia, Yunlong; Yao, Wei; Wu, Gang; Cheng, Mian; Wang, Qing K.

2015-01-01

Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as ‘missing heritability’. One potential cause for ‘missing heritability’ is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by 5-fold and doubles risk of heart failure and sudden death. Here we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1,583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1,127 unrelated AF patients and 1,583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1,583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggests that rare TNNI3 variants are associated with AF (P=0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability. PMID:26169204

Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities).

PubMed

Pankow, James S; Tang, Weihong; Pankratz, Nathan; Guan, Weihua; Weng, Lu-Chen; Cushman, Mary; Boerwinkle, Eric; Folsom, Aaron R

2017-03-01

Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 15% of the variance in circulating levels of protein C. To further characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low-frequency and rare variants, and searched for new associations in genes known to influence protein C. Genetic associations with protein C antigen level were evaluated in ≤10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low-frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip. Genome-wide significant associations ( P <5×10 -8 ) were found for common variants in the GCKR , PROC , BAZ1B , and PROCR-EDEM2 regions in whites and PROC and PROCR-EDEM2 regions in blacks, confirming earlier findings. In a novel finding, the low-density lipoprotein cholesterol-lowering allele of rs12740374, located in the CELSR2-PSRC1-SORT1 region, was associated with lower protein C level in both whites and blacks, reaching genome-wide significance in a meta-analysis combining results from both groups ( P =1.4×10 -9 ). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly low-density lipoprotein cholesterol, influence protein C levels. Discovery of variants influencing circulating protein C levels in the CELSR2-PSRC1-SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis. © 2017 American Heart Association, Inc.

Accuracy of next-generation sequencing for the identification of clinically relevant variants in cytology smears in lung adenocarcinoma.

PubMed

Baum, Jordan E; Zhang, Pan; Hoda, Rana S; Geraghty, Brian; Rennert, Hanna; Narula, Navneet; Fernandes, Helen D

2017-06-01

Minimally invasive diagnostic procedures such as needle-core biopsy and fine-needle aspiration provide adequate material for molecular analyses. Advances in precision oncology are trending toward the interrogation of limited amounts of genomic material to guide clinical and therapeutic decisions. The aim of this study was to investigate the minimum cellularity needed on cytologic smears for the identification of clinically relevant variants with next-generation sequencing (NGS). Thirty cases of cytologically diagnosed, resection-proven primary lung adenocarcinoma were identified. Nineteen of the 30 cases were known to harbor actionable variants. One Diff-Quik (DQ)-stained slide and 1 Papanicolaou (Pap)-stained slide were selected from each case. Cases were categorized as containing fewer than 100 tumor cells, 100 to 500 tumor cells, or more than 500 tumor cells. NGS was performed on the Ion Torrent platform. NGS was successfully performed on all cell blocks and on 90% of the smears. Paired DQ and Pap smears showed similar cellularity, and cases that differed in cellularity were within 1 category of each other. The cases with more than 100 tumor cells had a 93% success rate; this was significantly different from the situation for cases with fewer than 100 tumor cells, which were successfully sequenced only 67% of the time. Overall, NGS was able to provide clinically relevant information for 83% of DQ smears and for 90% of Pap smears tested. The data show a significantly higher likelihood of successful NGS with cytologic smears with more than 100 tumor cells. There was a trend for a higher NGS success rate with Pap smears versus DQ smears. Cancer Cytopathol 2017;125:398-406. © 2017 American Cancer Society. © 2017 American Cancer Society.

EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

PubMed Central

Yeoh, Sharon; Jackson, George

2017-01-01

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome. PMID:28872581

EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients.

PubMed

Sabir, Sarah R; Yeoh, Sharon; Jackson, George; Bayliss, Richard

2017-09-05

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.

Large-scale identification and characterization of alternative splicing variants of human gene transcripts using 56 419 completely sequenced and manually annotated full-length cDNAs

PubMed Central

Takeda, Jun-ichi; Suzuki, Yutaka; Nakao, Mitsuteru; Barrero, Roberto A.; Koyanagi, Kanako O.; Jin, Lihua; Motono, Chie; Hata, Hiroko; Isogai, Takao; Nagai, Keiichi; Otsuki, Tetsuji; Kuryshev, Vladimir; Shionyu, Masafumi; Yura, Kei; Go, Mitiko; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Wiemann, Stefan; Nomura, Nobuo; Sugano, Sumio; Gojobori, Takashi; Imanishi, Tadashi

2006-01-01

We report the first genome-wide identification and characterization of alternative splicing in human gene transcripts based on analysis of the full-length cDNAs. Applying both manual and computational analyses for 56 419 completely sequenced and precisely annotated full-length cDNAs selected for the H-Invitational human transcriptome annotation meetings, we identified 6877 alternative splicing genes with 18 297 different alternative splicing variants. A total of 37 670 exons were involved in these alternative splicing events. The encoded protein sequences were affected in 6005 of the 6877 genes. Notably, alternative splicing affected protein motifs in 3015 genes, subcellular localizations in 2982 genes and transmembrane domains in 1348 genes. We also identified interesting patterns of alternative splicing, in which two distinct genes seemed to be bridged, nested or having overlapping protein coding sequences (CDSs) of different reading frames (multiple CDS). In these cases, completely unrelated proteins are encoded by a single locus. Genome-wide annotations of alternative splicing, relying on full-length cDNAs, should lay firm groundwork for exploring in detail the diversification of protein function, which is mediated by the fast expanding universe of alternative splicing variants. PMID:16914452

Identification of copy number variants in horses.

PubMed

Doan, Ryan; Cohen, Noah; Harrington, Jessica; Veazey, Kylee; Veazy, Kylee; Juras, Rytis; Cothran, Gus; McCue, Molly E; Skow, Loren; Dindot, Scott V

2012-05-01

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.

Identification of common variants associated with human hippocampal and intracranial volumes

PubMed Central

Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias; Hibar, Derrek P; Senstad, Rudy E; Winkler, Anderson M; Toro, Roberto; Appel, Katja; Bartecek, Richard; Bergmann, Ørjan; Bernard, Manon; Brown, Andrew A; Cannon, Dara M; Chakravarty, M Mallar; Christoforou, Andrea; Domin, Martin; Grimm, Oliver; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hottenga, Jouke-Jan; Langan, Camilla; Lopez, Lorna M; Hansell, Narelle K; Hwang, Kristy S; Kim, Sungeun; Laje, Gonzalo; Lee, Phil H; Liu, Xinmin; Loth, Eva; Lourdusamy, Anbarasu; Mattingsdal, Morten; Mohnke, Sebastian; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; O’Brien, Carol; Papmeyer, Martina; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rijpkema, Mark; Risacher, Shannon L; Roddey, J Cooper; Rose, Emma J; Ryten, Mina; Shen, Li; Sprooten, Emma; Strengman, Eric; Teumer, Alexander; Trabzuni, Daniah; Turner, Jessica; van Eijk, Kristel; van Erp, Theo G M; van Tol, Marie-Jose; Wittfeld, Katharina; Wolf, Christiane; Woudstra, Saskia; Aleman, Andre; Alhusaini, Saud; Almasy, Laura; Binder, Elisabeth B; Brohawn, David G; Cantor, Rita M; Carless, Melanie A; Corvin, Aiden; Czisch, Michael; Curran, Joanne E; Davies, Gail; de Almeida, Marcio A A; Delanty, Norman; Depondt, Chantal; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fagerness, Jesen; Fox, Peter T; Freimer, Nelson B; Gill, Michael; Göring, Harald H H; Hagler, Donald J; Hoehn, David; Holsboer, Florian; Hoogman, Martine; Hosten, Norbert; Jahanshad, Neda; Johnson, Matthew P; Kasperaviciute, Dalia; Kent, Jack W; Kochunov, Peter; Lancaster, Jack L; Lawrie, Stephen M; Liewald, David C; Mandl, René; Matarin, Mar; Mattheisen, Manuel; Meisenzahl, Eva; Melle, Ingrid; Moses, Eric K; Mühleisen, Thomas W; Nauck, Matthias; Nöthen, Markus M; Olvera, Rene L; Pandolfo, Massimo; Pike, G Bruce; Puls, Ralf; Reinvang, Ivar; Rentería, Miguel E; Rietschel, Marcella; Roffman, Joshua L; Royle, Natalie A; Rujescu, Dan; Savitz, Jonathan; Schnack, Hugo G; Schnell, Knut; Seiferth, Nina; Smith, Colin; Steen, Vidar M; Valdés Hernández, Maria C; Van den Heuvel, Martijn; van der Wee, Nic J; Van Haren, Neeltje E M; Veltman, Joris A; Völzke, Henry; Walker, Robert; Westlye, Lars T; Whelan, Christopher D; Agartz, Ingrid; Boomsma, Dorret I; Cavalleri, Gianpiero L; Dale, Anders M; Djurovic, Srdjan; Drevets, Wayne C; Hagoort, Peter; Hall, Jeremy; Heinz, Andreas; Jack, Clifford R; Foroud, Tatiana M; Le Hellard, Stephanie; Macciardi, Fabio; Montgomery, Grant W; Poline, Jean Baptiste; Porteous, David J; Sisodiya, Sanjay M; Starr, John M; Sussmann, Jessika; Toga, Arthur W; Veltman, Dick J; Walter, Henrik; Weiner, Michael W; Bis, Joshua C; Ikram, M Arfan; Smith, Albert V; Gudnason, Vilmundur; Tzourio, Christophe; Vernooij, Meike W; Launer, Lenore J; DeCarli, Charles; Seshadri, Sudha; Andreassen, Ole A; Apostolova, Liana G; Bastin, Mark E; Blangero, John; Brunner, Han G; Buckner, Randy L; Cichon, Sven; Coppola, Giovanni; de Zubicaray, Greig I; Deary, Ian J; Donohoe, Gary; de Geus, Eco J C; Espeseth, Thomas; Fernández, Guillén; Glahn, David C; Grabe, Hans J; Hardy, John; Hulshoff Pol, Hilleke E; Jenkinson, Mark; Kahn, René S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meyer-Lindenberg, Andreas; Morris, Derek W; Müller-Myhsok, Bertram; Nichols, Thomas E; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W; Potkin, Steven G; Sämann, Philipp G; Saykin, Andrew J; Schumann, Gunter; Smoller, Jordan W; Wardlaw, Joanna M; Weale, Michael E; Martin, Nicholas G; Franke, Barbara; Wright, Margaret J; Thompson, Paul M

2013-01-01

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer’s disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7). PMID:22504417

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

PubMed

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.

A knowledge-based, concept-oriented view generation system for clinical data.

PubMed

Zeng, Q; Cimino, J J

2001-04-01

Information overload is a well-known problem for clinicians who must review large amounts of data in patient records. Concept-oriented views, which organize patient data around clinical concepts such as diagnostic strategies and therapeutic goals, may offer a solution to the problem of information overload. However, although concept-oriented views are desirable, they are difficult to create and maintain. We have developed a general-purpose, knowledge-based approach to the generation of concept-oriented views and have developed a system to test our approach. The system creates concept-oriented views through automated identification of relevant patient data. The knowledge in the system is represented by both a semantic network and rules. The key relevant data identification function is accomplished by a rule-based traversal of the semantic network. This paper focuses on the design and implementation of the system; an evaluation of the system is reported separately.

Identification of a novel alternative splicing variant of hemocyanin from shrimp Litopenaeus vannamei.

PubMed

Zhao, Shan; Lu, Xin; Zhang, Yueling; Zhao, Xianliang; Zhong, Mingqi; Li, Shengkang; Lun, Jingsheng

2013-01-01

Recent evidences suggest that invertebrates express families of immune molecules with high levels of sequence diversity. Hemocyanin is an important non-specific immune molecule present in the hemolymph of both mollusks and arthropods. In the present study, we characterized a novel alternative splicing variant of hemocyanin (cHE1) from Litopenaeus vannamei that produced mRNA transcript of 2579 bp in length. The isoform contained two additional sequences of 296 and 267 bp in the 5'- and 3'-terminus respectively, in comparison to that of wild type hemocyanin (cHE). Sequence of cHE1 shows 100% identity to that of hemocyanin genomic DNA (HE, which does not form an open reading frame), suggesting that cHE1 might be an alternative splicing variant due to intron retention. Moreover, cHE1 could be detected by RT-PCR from five tissues (heart, gill, stomach, intestine and brain), and from shrimps at stages from nauplius to mysis larva. Further, cHE1 mRNA transcripts were significantly increased in hearts after 12h of infection with Vibrio parahemolyticus or poly I: C, while no significant difference in the transcript levels of hepatopancreas cHE was detected in the pathogen-treated shrimps during the period. In summary, these studies suggested a novel splicing variant of hemocyanin in shrimp, which might be involved in shrimp resistance to pathogenic infection. Copyright © 2013 Elsevier B.V. All rights reserved.

Embodied memory allows accurate and stable perception of hidden objects despite orientation change.

PubMed

Pan, Jing Samantha; Bingham, Ned; Bingham, Geoffrey P

2017-07-01

Rotating a scene in a frontoparallel plane (rolling) yields a change in orientation of constituent images. When using only information provided by static images to perceive a scene after orientation change, identification performance typically decreases (Rock & Heimer, 1957). However, rolling generates optic flow information that relates the discrete, static images (before and after the change) and forms an embodied memory that aids recognition. The embodied memory hypothesis predicts that upon detecting a continuous spatial transformation of image structure, or in other words, seeing the continuous rolling process and objects undergoing rolling observers should accurately perceive objects during and after motion. Thus, in this case, orientation change should not affect performance. We tested this hypothesis in three experiments and found that (a) using combined optic flow and image structure, participants identified locations of previously perceived but currently occluded targets with great accuracy and stability (Experiment 1); (b) using combined optic flow and image structure information, participants identified hidden targets equally well with or without 30° orientation changes (Experiment 2); and (c) when the rolling was unseen, identification of hidden targets after orientation change became worse (Experiment 3). Furthermore, when rolling was unseen, although target identification was better when participants were told about the orientation change than when they were not told, performance was still worse than when there was no orientation change. Therefore, combined optic flow and image structure information, not mere knowledge about the rolling, enables accurate and stable perception despite orientation change. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

DaMold: A data-mining platform for variant annotation and visualization in molecular diagnostics research.

PubMed

Pandey, Ram Vinay; Pabinger, Stephan; Kriegner, Albert; Weinhäusel, Andreas

2017-07-01

Next-generation sequencing (NGS) has become a powerful and efficient tool for routine mutation screening in clinical research. As each NGS test yields hundreds of variants, the current challenge is to meaningfully interpret the data and select potential candidates. Analyzing each variant while manually investigating several relevant databases to collect specific information is a cumbersome and time-consuming process, and it requires expertise and familiarity with these databases. Thus, a tool that can seamlessly annotate variants with clinically relevant databases under one common interface would be of great help for variant annotation, cross-referencing, and visualization. This tool would allow variants to be processed in an automated and high-throughput manner and facilitate the investigation of variants in several genome browsers. Several analysis tools are available for raw sequencing-read processing and variant identification, but an automated variant filtering, annotation, cross-referencing, and visualization tool is still lacking. To fulfill these requirements, we developed DaMold, a Web-based, user-friendly tool that can filter and annotate variants and can access and compile information from 37 resources. It is easy to use, provides flexible input options, and accepts variants from NGS and Sanger sequencing as well as hotspots in VCF and BED formats. DaMold is available as an online application at http://damold.platomics.com/index.html, and as a Docker container and virtual machine at https://sourceforge.net/projects/damold/. © 2017 Wiley Periodicals, Inc.

LitVar: a semantic search engine for linking genomic variant data in PubMed and PMC.

PubMed

Allot, Alexis; Peng, Yifan; Wei, Chih-Hsuan; Lee, Kyubum; Phan, Lon; Lu, Zhiyong

2018-05-14

The identification and interpretation of genomic variants play a key role in the diagnosis of genetic diseases and related research. These tasks increasingly rely on accessing relevant manually curated information from domain databases (e.g. SwissProt or ClinVar). However, due to the sheer volume of medical literature and high cost of expert curation, curated variant information in existing databases are often incomplete and out-of-date. In addition, the same genetic variant can be mentioned in publications with various names (e.g. 'A146T' versus 'c.436G>A' versus 'rs121913527'). A search in PubMed using only one name usually cannot retrieve all relevant articles for the variant of interest. Hence, to help scientists, healthcare professionals, and database curators find the most up-to-date published variant research, we have developed LitVar for the search and retrieval of standardized variant information. In addition, LitVar uses advanced text mining techniques to compute and extract relationships between variants and other associated entities such as diseases and chemicals/drugs. LitVar is publicly available at https://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/LitVar.

Blind restoration of retinal images degraded by space-variant blur with adaptive blur estimation

NASA Astrophysics Data System (ADS)

Marrugo, Andrés. G.; Millán, María. S.; Å orel, Michal; Å roubek, Filip

2013-11-01

Retinal images are often degraded with a blur that varies across the field view. Because traditional deblurring algorithms assume the blur to be space-invariant they typically fail in the presence of space-variant blur. In this work we consider the blur to be both unknown and space-variant. To carry out the restoration, we assume that in small regions the space-variant blur can be approximated by a space-invariant point-spread function (PSF). However, instead of deblurring the image on a per-patch basis, we extend individual PSFs by linear interpolation and perform a global restoration. Because the blind estimation of local PSFs may fail we propose a strategy for the identification of valid local PSFs and perform interpolation to obtain the space-variant PSF. The method was tested on artificial and real degraded retinal images. Results show significant improvement in the visibility of subtle details like small blood vessels.

Variant discovery in the sheep milk transcriptome using RNA sequencing.

PubMed

Suárez-Vega, Aroa; Gutiérrez-Gil, Beatriz; Klopp, Christophe; Tosser-Klopp, Gwenola; Arranz, Juan José

2017-02-15

The identification of genetic variation underlying desired phenotypes is one of the main challenges of current livestock genetic research. High-throughput transcriptome sequencing (RNA-Seq) offers new opportunities for the detection of transcriptome variants (SNPs and short indels) in different tissues and species. In this study, we used RNA-Seq on Milk Sheep Somatic Cells (MSCs) with the goal of characterizing the genetic variation within the coding regions of the milk transcriptome in Churra and Assaf sheep, two common dairy sheep breeds farmed in Spain. A total of 216,637 variants were detected in the MSCs transcriptome of the eight ewes analyzed. Among them, a total of 57,795 variants were detected in the regions harboring Quantitative Trait Loci (QTL) for milk yield, protein percentage and fat percentage, of which 21.44% were novel variants. Among the total variants detected, 561 (2.52%) and 1,649 (7.42%) were predicted to produce high or moderate impact changes in the corresponding transcriptional unit, respectively. In the functional enrichment analysis of the genes positioned within selected QTL regions harboring novel relevant functional variants (high and moderate impact), the KEGG pathway with the highest enrichment was "protein processing in endoplasmic reticulum". Additionally, a total of 504 and 1,063 variants were identified in the genes encoding principal milk proteins and molecules involved in the lipid metabolism, respectively. Of these variants, 20 mutations were found to have putative relevant effects on the encoded proteins. We present herein the first transcriptomic approach aimed at identifying genetic variants of the genes expressed in the lactating mammary gland of sheep. Through the transcriptome analysis of variability within regions harboring QTL for milk yield, protein percentage and fat percentage, we have found several pathways and genes that harbor mutations that could affect dairy production traits. Moreover, remarkable variants

Identification of a novel inherited ALK variant M1199L in the WNT type of medulloblastoma.

PubMed

Trubicka, J; Szperl, M; Grajkowska, W; Karkucińska-Więckowska, A; Tarasińska, M; Falana, K; Dembowska-Bagińska, B; Łastowska, M

2016-01-01

Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour - medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.

Identification, Characterisation and Clinical Development of the New Generation of Breast Cancer Susceptibility Alleles

DTIC Science & Technology

2010-03-01

amino acid substitution in this gene has been associated with uric acid nephrolithiasis (32). Recent GWAS have identified another variant within this...Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Am J Hum Genet 72

Cellulase variants

DOEpatents

Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

2015-07-14

This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

NaV channel variants in patients with painful and nonpainful peripheral neuropathy

PubMed Central

Wadhawan, Samir; Pant, Saumya; Golhar, Ryan; Kirov, Stefan; Thompson, John; Jacobsen, Leslie; Qureshi, Irfan; Ajroud-Driss, Senda; Freeman, Roy; Simpson, David M.; Smith, A. Gordon; Hoke, Ahmet

2017-01-01

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy. Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful). Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations. Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed. PMID:29264398

Sex, Sexual Orientation, and Identification of Positive and Negative Facial Affect

ERIC Educational Resources Information Center

Rahman, Qazi; Wilson, Glenn D.; Abrahams, Sharon

2004-01-01

Sex and sexual orientation related differences in processing of happy and sad facial emotions were examined using an experimental facial emotion recognition paradigm with a large sample (N=240). Analysis of covariance (controlling for age and IQ) revealed that women (irrespective of sexual orientation) had faster reaction times than men for…

Systematic Identification of Genes Required for Expression of Androgen Receptor Splice Variants

DTIC Science & Technology

2016-08-01

engineering tool has been developed from bacterial Clustered Regularly Interspaced Short Palindromic Repeats ( CRISPR )/ CRISPR ‐Associated System (Cas...regulation of AR splice variant through CRISPR /Cas screening system. 15. SUBJECT TERMS CRISPR /Cas, Androgen receptor, castration resistance, biomarker 16...control (non-targeting) gRNAs available from Addgene (http://www.addgene.org/ CRISPR /libraries/). Generation of AR3 reporter: We used molecular cloning

Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.

PubMed

Hitomi, Yuki; Tokunaga, Katsushi

2017-01-01

Human genome variation may cause differences in traits and disease risks. Disease-causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine.

Occurrence of Fuligo gyrosa Causing Slime Mold of Oriental Melon.

PubMed

Kim, Wan Gyu; Choi, Hyo Won; Hong, Sung Kee; Lee, Young Kee; Lee, Su Heon

2009-09-01

Recently, a severe slime mold infestation affected oriental melon plants in fields in Chilgok county, Gyeongbuk province, Korea. Specimens were collected from the fields and examined for identification. A species of Myxomycetes, Fuligo gyrosa, was identified based on its morphological characteristics. This is the first report that F. gyrosa causes slime mold of oriental melon.

Class and ideological orientations revisited: an exploration of class-based mechanisms.

PubMed

Bengtsson, Mattias; Berglund, Tomas; Oskarson, Maria

2013-12-01

Studies of the relationship between class position and political outlooks still only have a limited understanding of the class-related mechanisms that matter for ideological orientations. This article presents a comprehensive analysis of the mechanisms that link class position and left/right and authoritarian/libertarian orientations. Besides main factors such as income, career prospects, job security, education, class origin and class identification, the significance of work-related factors such as work autonomy, working in a team, a physically demanding job and a mentally demanding job is studied. The findings are based on a survey specifically designed for this purpose and collected in Sweden in 2008/2009. A great deal of the association between class position and left/right orientations is explained by socio-economic conditions; different classes sympathize with policies that will benefit them economically. Another important factor is class identification. Work-related factors also have relevance, but the effect of class position on left/right orientations works mainly through the remuneration system. Class position is also related to authoritarian/libertarian orientations. However, this relationship is less explained by socio-economic position per se, but is rather an effect of the educational system and its allocation of the workforce into different class positions. It also turns out that work-related factors do not explain the class effects; however, a physically demanding job shows a unique effect. Overall, our findings suggest that besides factors such as class position, income, education and class identification, we need to consider work-related aspects to derive a more complete understanding of the distribution of ideological orientations in Western societies. © London School of Economics and Political Science 2013.

Exploring the unknown: assumptions about allelic architecture and strategies for susceptibility variant discovery.

PubMed

McCarthy, Mark I

2009-07-03

Identification of common-variant associations for many common disorders has been highly effective, but the loci detected so far typically explain only a small proportion of the genetic predisposition to disease. Extending explained genetic variance is one of the major near-term goals of human genetic research. Next-generation sequencing technologies offer great promise, but optimal strategies for their deployment remain uncertain, not least because we lack a clear view of the characteristics of the variants being sought. Here, I discuss what can and cannot be inferred about complex trait disease architecture from the information currently available and review the implications for future research strategies.

Epigenome-wide inheritance of cytosine methylation variants in a recombinant inbred population

PubMed Central

Schmitz, Robert J.; He, Yupeng; Valdés-López, Oswaldo; Khan, Saad M.; Joshi, Trupti; Urich, Mark A.; Nery, Joseph R.; Diers, Brian; Xu, Dong; Stacey, Gary; Ecker, Joseph R.

2013-01-01

Cytosine DNA methylation is one avenue for passing information through cell divisions. Here, we present epigenomic analyses of soybean recombinant inbred lines (RILs) and their parents. Identification of differentially methylated regions (DMRs) revealed that DMRs mostly cosegregated with the genotype from which they were derived, but examples of the uncoupling of genotype and epigenotype were identified. Linkage mapping of methylation states assessed from whole-genome bisulfite sequencing of 83 RILs uncovered widespread evidence for local methylQTL. This epigenomics approach provides a comprehensive study of the patterns and heritability of methylation variants in a complex genetic population over multiple generations, paving the way for understanding how methylation variants contribute to phenotypic variation. PMID:23739894

Epigenome-wide inheritance of cytosine methylation variants in a recombinant inbred population.

PubMed

Schmitz, Robert J; He, Yupeng; Valdés-López, Oswaldo; Khan, Saad M; Joshi, Trupti; Urich, Mark A; Nery, Joseph R; Diers, Brian; Xu, Dong; Stacey, Gary; Ecker, Joseph R

2013-10-01

Cytosine DNA methylation is one avenue for passing information through cell divisions. Here, we present epigenomic analyses of soybean recombinant inbred lines (RILs) and their parents. Identification of differentially methylated regions (DMRs) revealed that DMRs mostly cosegregated with the genotype from which they were derived, but examples of the uncoupling of genotype and epigenotype were identified. Linkage mapping of methylation states assessed from whole-genome bisulfite sequencing of 83 RILs uncovered widespread evidence for local methylQTL. This epigenomics approach provides a comprehensive study of the patterns and heritability of methylation variants in a complex genetic population over multiple generations, paving the way for understanding how methylation variants contribute to phenotypic variation.

Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene

PubMed Central

Vodo, Dan; Sarig, Ofer; Ben-Asher, Edna; Olender, Tsviya; Bochner, Ron; Goldberg, Ilan; Nosgorodsky, Judith; Alkelai, Anna; Tatarskyy, Pavel; Peled, Alon; Baum, Sharon; Barzilai, Aviv; Ibrahim, Saleh M.; Zillikens, Detlef; Lancet, Doron; Sprecher, Eli

2016-01-01

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease. PMID:27148741

Occurrence of Fuligo gyrosa Causing Slime Mold of Oriental Melon

PubMed Central

Choi, Hyo Won; Hong, Sung Kee; Lee, Young Kee; Lee, Su Heon

2009-01-01

Recently, a severe slime mold infestation affected oriental melon plants in fields in Chilgok county, Gyeongbuk province, Korea. Specimens were collected from the fields and examined for identification. A species of Myxomycetes, Fuligo gyrosa, was identified based on its morphological characteristics. This is the first report that F. gyrosa causes slime mold of oriental melon. PMID:23983540

Genome-Independent Identification of RNA Editing by Mutual Information (GIREMI) | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

Identification of single-nucleotide variants in RNA-seq data. Current version focuses on detection of RNA editing sites without requiring genome sequence data. New version is under development to separately identify RNA editing sites and genetic variants using RNA-seq data alone.

Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants*

PubMed Central

G. Lavoie, Elise; Dranoff, Jonathan A.

2017-01-01

Liver myofibroblasts are specialized effector cells that drive hepatic fibrosis, a hallmark process of chronic liver diseases, leading to progressive scar formation and organ failure. Liver myofibroblasts are increasingly recognized as heterogeneous with regards to their origin, phenotype, and functions. For instance, liver myofibroblasts express cell markers that are universally represented such as, ItgαV and Pdgfrβ, or restricted to a given subpopulation such as, Lrat exclusively expressed in hepatic stellate cells, and Gpm6a in mesothelial cells. To study liver myofibroblasts in vitro, we have previously generated and characterized a SV40-immortalized polyclonal rat activated portal fibroblast cell line called RGF-N2 expressing multiple mesothelin mRNA transcripts. Mesothelin, a cell-surface molecule expressed in normal mesothelial cells and overexpressed in several cancers such as, mesothelioma and cholangiocarcinoma, was recently identified as a key regulator of portal myofibroblast proliferation, and fibrosis progression in the setting of chronic cholestatic liver disease. Here, we identify novel mesothelin splice variants expressed in rat activated portal fibroblasts. RGF-N2 portal fibroblast cDNA was used as template for insertion of hemagglutinin tag consensus sequence into the complete open reading frame of rat mesothelin variant coding sequences by extension PCR. Purified amplicons were subsequently cloned into an expression vector for in vitro translation and transfection in monkey COS7 fibroblasts, before characterization of fusion proteins by immunoblot and immunofluorescence. We show that rat activated portal fibroblasts, hepatic stellate cells, and cholangiocarcinoma cells express wild-type mesothelin and additional splice variants, while mouse activated hepatic stellate cells appear to only express wild-type mesothelin. Notably, rat mesothelin splice variants differ from the wild-type isoform by their protein properties and cellular distribution

Introduction to Deep Sequencing and Its Application to Drug Addiction Research with a Focus on Rare Variants

PubMed Central

Wang, Shaolin; Yang, Zhongli; Ma, Jennie Z.; Payne, Thomas J.; Li, Ming D

2013-01-01

Through linkage analysis, candidate gene approach, and genome-wide association studies (GWAS), many genetic susceptibility factors for substance dependence have been discovered, such as the alcohol dehydrogenase gene (ALDH2) for alcohol dependence (AD) and nicotinic acetylcholine receptor (nAChR) subunit variants on chromosomes 8 and 15 for nicotine dependence (ND). However, these confirmed genetic factors contribute only a small portion of the heritability responsible for each addiction. Among many potential factors, rare variants in those identified and unidentified susceptibility genes are supposed to contribute greatly to the missing heritability. Several studies focusing on rare variants have been conducted by taking advantage of next-generation sequencing technologies, which revealed that some rare variants of nAChR subunits are associated with ND in both genetic and functional studies. However, these studies investigated variants for only a small number of genes and need to be expanded to broad regions/genes in a larger population. This review presents an update on recently developed methods for rare-variant identification and association analysis and on studies focused on rare-variant discovery and function related to addictions. PMID:23990377

Apolipoprotein ɛ4 breaks the association between declarative long-term memory and memory-based orienting of spatial attention in middle-aged individuals.

PubMed

Salvato, Gerardo; Patai, Eva Z; McCloud, Tayla; Nobre, Anna C

2016-09-01

Apolipoprotein (APOE) ɛ4 genotype has been identified as a risk factor for late-onset Alzheimer disease (AD). The memory system is mostly involved in AD, and memory deficits represent its key feature. A growing body of studies has focused on the earlier identification of cognitive dysfunctions in younger and older APOE ɛ4 carriers, but investigation on middle-aged individuals remains rare. Here we sought to investigate if the APOE ɛ4 genotype modulates declarative memory and its influences on perception in the middle of the life span. We tested 60 middle-aged individuals recruited according to their APOE allele variants (ɛ3/ɛ3, ɛ3/ɛ4, ɛ4/ɛ4) on a long-term memory-based orienting of attention task. Results showed that the APOE ɛ4 genotype impaired neither explicit memory nor memory-based orienting of spatial attention. Interestingly, however, we found that the possession of the ɛ4 allele broke the relationship between declarative long-term memory and memory-guided orienting of visuo-spatial attention, suggesting an earlier modulation exerted by pure genetic characteristics on cognition. These findings are discussed in light of possible accelerated brain ageing in middle-aged ɛ4-carriers, and earlier structural changes in the brain occurring at this stage of the lifespan. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates

PubMed Central

Tachmazidou, Ioanna; Dedoussis, George; Southam, Lorraine; Farmaki, Aliki-Eleni; Ritchie, Graham R. S.; Xifara, Dionysia K.; Matchan, Angela; Hatzikotoulas, Konstantinos; Rayner, Nigel W.; Chen, Yuan; Pollin, Toni I.; O’Connell, Jeffrey R.; Yerges-Armstrong, Laura M.; Kiagiadaki, Chrysoula; Panoutsopoulou, Kalliope; Schwartzentruber, Jeremy; Moutsianas, Loukas; Tsafantakis, Emmanouil; Tyler-Smith, Chris; McVean, Gil; Xue, Yali; Zeggini, Eleftheria

2013-01-01

Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance. PMID:24343240

A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates.

PubMed

Tachmazidou, Ioanna; Dedoussis, George; Southam, Lorraine; Farmaki, Aliki-Eleni; Ritchie, Graham R S; Xifara, Dionysia K; Matchan, Angela; Hatzikotoulas, Konstantinos; Rayner, Nigel W; Chen, Yuan; Pollin, Toni I; O'Connell, Jeffrey R; Yerges-Armstrong, Laura M; Kiagiadaki, Chrysoula; Panoutsopoulou, Kalliope; Schwartzentruber, Jeremy; Moutsianas, Loukas; Tsafantakis, Emmanouil; Tyler-Smith, Chris; McVean, Gil; Xue, Yali; Zeggini, Eleftheria

2013-01-01

Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance.

Measuring Filament Orientation: A New Quantitative, Local Approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Green, C.-E.; Cunningham, M. R.; Jones, P. A.

The relative orientation between filamentary structures in molecular clouds and the ambient magnetic field provides insight into filament formation and stability. To calculate the relative orientation, a measurement of filament orientation is first required. We propose a new method to calculate the orientation of the one-pixel-wide filament skeleton that is output by filament identification algorithms such as filfinder. We derive the local filament orientation from the direction of the intensity gradient in the skeleton image using the Sobel filter and a few simple post-processing steps. We call this the “Sobel-gradient method.” The resulting filament orientation map can be compared quantitativelymore » on a local scale with the magnetic field orientation map to then find the relative orientation of the filament with respect to the magnetic field at each point along the filament. It can also be used for constructing radial profiles for filament width fitting. The proposed method facilitates automation in analyses of filament skeletons, which is imperative in this era of “big data.”.« less

Measuring Filament Orientation: A New Quantitative, Local Approach

NASA Astrophysics Data System (ADS)

Green, C.-E.; Dawson, J. R.; Cunningham, M. R.; Jones, P. A.; Novak, G.; Fissel, L. M.

2017-09-01

The relative orientation between filamentary structures in molecular clouds and the ambient magnetic field provides insight into filament formation and stability. To calculate the relative orientation, a measurement of filament orientation is first required. We propose a new method to calculate the orientation of the one-pixel-wide filament skeleton that is output by filament identification algorithms such as filfinder. We derive the local filament orientation from the direction of the intensity gradient in the skeleton image using the Sobel filter and a few simple post-processing steps. We call this the “Sobel-gradient method.” The resulting filament orientation map can be compared quantitatively on a local scale with the magnetic field orientation map to then find the relative orientation of the filament with respect to the magnetic field at each point along the filament. It can also be used for constructing radial profiles for filament width fitting. The proposed method facilitates automation in analyses of filament skeletons, which is imperative in this era of “big data.”

Controlling Protein Surface Orientation by Strategic Placement of Oligo-Histidine Tags

PubMed Central

2017-01-01

We report oriented immobilization of proteins using the standard hexahistidine (His6)-Ni2+:NTA (nitrilotriacetic acid) methodology, which we systematically tuned to give control of surface coverage. Fluorescence microscopy and surface plasmon resonance measurements of self-assembled monolayers (SAMs) of red fluorescent proteins (TagRFP) showed that binding strength increased by 1 order of magnitude for each additional His6-tag on the TagRFP proteins. All TagRFP variants with His6-tags located on only one side of the barrel-shaped protein yielded a 1.5 times higher surface coverage compared to variants with His6-tags on opposite sides of the so-called β-barrel. Time-resolved fluorescence anisotropy measurements supported by polarized infrared spectroscopy verified that the orientation (and thus coverage and functionality) of proteins on surfaces can be controlled by strategic placement of a His6-tag on the protein. Molecular dynamics simulations show how the differently tagged proteins reside at the surface in “end-on” and “side-on” orientations with each His6-tag contributing to binding. Also, not every dihistidine subunit in a given His6-tag forms a full coordination bond with the Ni2+:NTA SAMs, which varied with the position of the His6-tag on the protein. At equal valency but different tag positions on the protein, differences in binding were caused by probing for Ni2+:NTA moieties and by additional electrostatic interactions between different fractions of the β-barrel structure and charged NTA moieties. Potential of mean force calculations indicate there is no specific single-protein interaction mode that provides a clear preferential surface orientation, suggesting that the experimentally measured preference for the end-on orientation is a supra-protein, not a single-protein, effect. PMID:28850777

CDKL5 variants

PubMed Central

Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

2017-01-01

Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

GWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits.

PubMed

Huang, Dandan; Yi, Xianfu; Zhang, Shijie; Zheng, Zhanye; Wang, Panwen; Xuan, Chenghao; Sham, Pak Chung; Wang, Junwen; Li, Mulin Jun

2018-05-16

Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.

Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina.

PubMed

Bañares, Virginia G; Corral, Pablo; Medeiros, Ana Margarida; Araujo, María Beatriz; Lozada, Alfredo; Bustamante, Juan; Cerretini, Roxana; López, Graciela; Bourbon, Mafalda; Schreier, Laura E

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy

PubMed Central

Blesneac, Iulia; Themistocleous, Andreas C.; Fratter, Carl; Conrad, Linus J.; Ramirez, Juan D.; Cox, James J.; Tesfaye, Solomon; Shillo, Pallai R.; Rice, Andrew S.C.; Tucker, Stephen J.

2018-01-01

Abstract Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively. PMID:29176367

Olfactory Performance Is Predicted by Individual Sex-Atypicality, but Not Sexual Orientation

PubMed Central

Nováková, Lenka; Varella Valentová, Jaroslava; Havlíček, Jan

2013-01-01

Many previous studies have reported robust sex differences in olfactory perception. However, both men and women can be expected to vary in the degree to which they exhibit olfactory performance considered typical of their own or the opposite sex. Sex-atypicality is often described in terms of childhood gender nonconformity, which, however, is not a perfect correlate of non-heterosexual orientation. Here we explored intrasexual variability in psychophysical olfactory performance in a sample of 156 individuals (83 non-heterosexual) and found the lowest odor identification scores in heterosexual men. However, when childhood gender nonconformity was entered in the model along with sexual orientation, better odor identification scores were exhibited by gender-nonconforming men, and greater olfactory sensitivity by gender-conforming women, irrespective of their sexual orientation. Thus, sex-atypicality, but not sexual orientation predicts olfactory performance, and we propose that this might not be limited to olfaction, but represent a more general phenomenon. PMID:24244657

Olfactory performance is predicted by individual sex-atypicality, but not sexual orientation.

PubMed

Nováková, Lenka; Varella Valentová, Jaroslava; Havlíček, Jan

2013-01-01

Many previous studies have reported robust sex differences in olfactory perception. However, both men and women can be expected to vary in the degree to which they exhibit olfactory performance considered typical of their own or the opposite sex. Sex-atypicality is often described in terms of childhood gender nonconformity, which, however, is not a perfect correlate of non-heterosexual orientation. Here we explored intrasexual variability in psychophysical olfactory performance in a sample of 156 individuals (83 non-heterosexual) and found the lowest odor identification scores in heterosexual men. However, when childhood gender nonconformity was entered in the model along with sexual orientation, better odor identification scores were exhibited by gender-nonconforming men, and greater olfactory sensitivity by gender-conforming women, irrespective of their sexual orientation. Thus, sex-atypicality, but not sexual orientation predicts olfactory performance, and we propose that this might not be limited to olfaction, but represent a more general phenomenon.

Novel de novo AVPR2 Variant in a Patient with Congenital Nephrogenic Diabetes Insipidus

PubMed Central

Joshi, Shivani; Brandstrom, Per; Gregersen, Niels; Rittig, Søren; Christensen, Jane Hvarregaard

2017-01-01

Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant. PMID:29177155

Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error.

PubMed

Kim, Wonkuk; Londono, Douglas; Zhou, Lisheng; Xing, Jinchuan; Nato, Alejandro Q; Musolf, Anthony; Matise, Tara C; Finch, Stephen J; Gordon, Derek

2012-01-01

As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to those data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have

Single variant and multi-variant trend tests for genetic association with next generation sequencing that are robust to sequencing error

PubMed Central

Kim, Wonkuk; Londono, Douglas; Zhou, Lisheng; Xing, Jinchuan; Nato, Andrew; Musolf, Anthony; Matise, Tara C.; Finch, Stephen J.; Gordon, Derek

2013-01-01

As with any new technology, next generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model, based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to that data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have

[Improvement of laboratory diagnostics of cholera due to genetically altered (hybrid) variants of cholera Vibrio biovar El Tor].

PubMed

Savel'eva, I V; Khatsukov, K X; Savel'eva, E I; Moskvitina, S I; Kovalev, D A; Savel'ev, V N; Kulichenko, A N; Antonenko, A D; Babenyshev, B V

2015-01-01

Improvement of laboratory diagnostics of cholera taking into the account appearance of hybrid variants of cholera vibrio El Tor biovar in the 1990s. Phenotypic and molecular-genetic properties of typical toxigenic (151 strains) and hybrid (102 strains) variants of El Tor biovar cholera vibrios, isolated in the Caucuses in 1970-1990 and 1993-1998, respectively, were studied. Toxigenicity gene DNA fragments, inherent to El Tor biovars or classic, were detected by using a reagent kit "Genes of Vibrio cholerae variant ctxB-rstR-rstC, REF" developed by us. Reagent kit "Genes of V. cholerae variant ctxB-rstR-rstC, REF" is proposed to be used for laboratory diagnostics of cholera during study of material from humans or environmental objects and for identification of V. cholerae 01 on genome level in PCR-analysis as a necessary addition to the classic scheme of bacteriological analysis. Laboratory diagnostics of cholera due to genetically altered (hybrid) variants of cholera vibrio El Tor biovar is based on a complex study of material from humans and environmental objects by routine bacteriologic and PCR-analysis methods with the aim of detection of gene DNA fragments in the studied material, that determine biovar (classic or El Tor), identification of V. cholerae O1 strains with differentiation of El Tor vibrios into typical and altered, as well as determination of enterotoxin, produced by the specific cholera vibrio strain (by the presence ctxB(El) or ctxB(Cl) gene DNA fragment, coding biosynthesis of CT-2 or CT-1, respectively).

Identification of rare paired box 3 variant in strabismus by whole exome sequencing.

PubMed

Gong, Hui-Min; Wang, Jing; Xu, Jing; Zhou, Zhan-Yu; Li, Jing-Wen; Chen, Shu-Fang

2017-01-01

To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.

Identification of a missense variant in LNPEP that confers psoriasis risk.

PubMed

Cheng, Hui; Li, Yang; Zuo, Xian-Bo; Tang, Hua-Yang; Tang, Xian-Fa; Gao, Jin-Ping; Sheng, Yu-Jun; Yin, Xian-Yong; Zhou, Fu-Sheng; Zhang, Chi; Chen, Gang; Zhu, Jun; Pan, Qian; Liang, Bo; Zheng, Xiao-Dong; Li, Pan; Ding, Yan-Tao; Cheng, Fang; Luo, Jing; Chang, Rui-Xue; Pan, Gong-Bu; Fan, Xing; Wang, Zai-Xing; Zhang, An-Ping; Liu, Jian-Jun; Yang, Sen; Sun, Liang-Dan; Zhang, Xue-Jun

2014-02-01

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To further advance gene discovery, we extended our genome-wide association study data set of 1,139 cases and 2,234 controls and replicated two independent cohorts of 7,200 cases and 10,491 controls. We identified the missense variant rs2303138 (p.Ala763Thr) within the LNPEP gene associated with psoriasis (Pcombined=1.83 × 10(-13), odds ratio=1.16) and validated four previously reported genes: IL28RA, NFKBIA, TRAF3IP2, and CARD14 (9.74 × 10(-11)P9.37 × 10(-5)), which confirmed the involvement of the nuclear factor-κB signaling pathway in psoriasis pathogenesis. LNPEP, also named insulin-responsive aminopeptidase, was identified as an angiotensin IV receptor. Protein function prediction suggested that this missense variant of LNPEP was most likely deleterious. Expression analysis showed that LNPEP was significantly downregulated in psoriatic lesions compared with the control skin (P=1.44 × 10(-6)) and uninvolved patient skin (P=2.95 × 10(-4)). Pathway analysis indicated that LNPEP was involved in the renin-angiotensin system, which also has a key role in cardiovascular disease and diabetes. These results provided genetic evidence that psoriasis might share common mechanisms with hypertension and diabetes, which was consistent with clinical observations. Our study identified a genetic susceptibility factor and provided genetic evidence of insight into psoriasis pathogenesis with the involvement of the renin-angiotensin system pathway.

Polymorphism at donkey β-lactoglobulin II locus: identification and characterization of a new genetic variant with a very low expression.

PubMed

Criscione, Andrea; Cunsolo, Vincenzo; Tumino, Serena; Di Francesco, Antonella; Bordonaro, Salvatore; Muccilli, Vera; Saletti, Rosaria; Marletta, Donata

2018-06-01

In the last years, donkey milk had evidenced a renewed interest as a potential functional food and a breast milk substitute. In this light, the study of the protein composition assumes an important role. In particular, β-lactoglobulin (β-LG), which is considered as one of the main allergenic milk protein, in donkey species consists of two molecular forms, namely β-LG I and β-LG II. In the present research, a genetic analysis coupled with a proteomic approach showed the presence of a new allele, here named F, which is apparently associated with a null or a severely reduced expression of β-LG II protein. The new β-LG II F genetic variant shows a theoretical average mass (M av ) of 18,310.64 Da, a value practically corresponding with that of the variant D (∆ mass  < 0.07 Da), but differs from β-LG II D for two amino acid substitutions: Thr 100 (variant F) → Ala 100 (variant D) and Thr 118 (variant F) → Met 118 (variant D). Proteomic investigation of the whey protein fraction of an individual milk sample, homozygous FF at β-LG II locus, allowed to identify, as very minor component, the new β-LG II F genetic variant. By MS/MS analysis of enzymatic digests, the sequence of the β-LG II F was characterized, and the predicted genomic data confirmed.

Identification and functional characterization of three novel human melanocortin-4 receptor gene variants in an obese Chinese population.

PubMed

Rong, Rong; Tao, Ya-Xiong; Cheung, Bernard M Y; Xu, Aimin; Cheung, Grace C N; Lam, Karen S L

2006-08-01

Mutations in the melanocortin-4 receptor gene (MC4R) are the most common monogenic form of human obesity. However, the contribution of MC4R mutations to obesity in Chinese has not been investigated. We studied the frequency of MC4R mutations in an obese southern Chinese population and the functional consequences of the novel variants identified. We screened for MC4R mutations in 227 obese [body mass index (BMI) 35.29 +/- 5.75 kg/m2] and 100 lean (BMI 21.57 +/- 0.29 kg/m2) southern Chinese subjects using PCR-direct sequencing. In vitro functional studies, including cell surface expression, ligand binding, and cyclic adenosine monophosphate (cAMP) accumulation, were performed to examine the functional properties of three novel missense mutations. Apart from two previously reported polymorphisms, V103I and -176 A > C, three novel missense heterozygous variants (Y35C, C40R and M218T) were identified. The polymorphisms -176 A > C and Y35C were detected in both obese and normal subjects with similar frequency. C40R was identified only in an obese subject. Pedigree analysis revealed M218T carriers in both lean and obese subjects. The prevalence of V103I carriers in normal-weight controls was significantly higher than that in obese subjects (5.3%vs. 1.3%, P < 0.05). In vitro functional studies showed that all three novel missense variants have normal functions. Two known polymorphisms and three novel variants of the MC4R were identified. No overt functional defects were observed for the three novel MC4R variants, suggesting that they might not be the cause of obesity in variant carriers.

Identification of a rare variant haemoglobin (Hb Sinai-Baltimore) causing spuriously low haemoglobin A(1c) values on ion exchange chromatography.

PubMed

Smith, Geoff; Murray, Heather; Brennan, Stephen O

2013-01-01

Commonly used methods for assay of haemoglobin A(1c) (HbA(1c)) are susceptible to interference from the presence of haemoglobin variants. In many systems, the common variants can be identified but scientists and pathologists must remain vigilant for more subtle variants that may result in spuriously high or low HbA(1c) values. It is clearly important to recognize these events whether HbA(1c) is being used as a monitoring tool or, as is increasingly the case, for diagnostic purposes. We report a patient with a rare haemoglobin variant (Hb Sinai-Baltimore) that resulted in spuriously low values of HbA(1c) when assayed using ion exchange chromatography, and the steps taken to elucidate the nature of the variant.

Experimental evidence of stress-field-induced selection of variants in Ni-Mn-Ga ferromagnetic shape-memory alloys

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Y. D.; Key Laboratory for Anisotropy and Texture of Materials; Brown, D. W.

2007-05-01

The in situ time-of-flight neutron-diffraction measurements captured well the martensitic transformation behavior of the Ni-Mn-Ga ferromagnetic shape-memory alloys under uniaxial stress fields. We found that a small uniaxial stress applied during phase transformation dramatically disturbed the distribution of variants in the product phase. The observed changes in the distributions of variants may be explained by considering the role of the minimum distortion energy of the Bain transformation in the effective partition among the variants belonging to the same orientation of parent phase. It was also found that transformation kinetics under various stress fields follows the scale law. The present investigationsmore » provide the fundamental approach for scaling the evolution of microstructures in martensitic transitions, which is of general interest to the condensed matter community.« less

Family studies to find rare high risk variants in migraine.

PubMed

Hansen, Rikke Dyhr; Christensen, Anne Francke; Olesen, Jes

2017-12-01

Migraine has long been known as a common complex disease caused by genetic and environmental factors. The pathophysiology and the specific genetic susceptibility are poorly understood. Common variants only explain a small part of the heritability of migraine. It is thought that rare genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families. A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising application of a family approach to migraine. PubMed was searched to find studies that looked for rare genetic variants in common complex diseases through a family-based design using NGS, excluding studies looking for de-novo mutations, or using a candidate-gene approach and studies on cancer. All issues from Nature Genetics and PLOS genetics 2014, 2015 and 2016 (UTAI June) were screened for relevant papers. Reference lists from included and other relevant papers were also searched. For the description of the family-based study design using NGS an in-house protocol was used. Thirty-two successful studies, which covered 16 different common complex diseases, were included in this paper. We also found a single migraine study. Twenty-three studies found one or a few family specific

Effects of social identity salience on motivational orientation and conflict strategies in intergenerational conflict.

PubMed

Ho, Henry C Y; Yeung, Dannii Y

2017-06-01

With the upsurge of older adults still working, the labour force is becoming increasingly diverse in age. Age diversity in an organisation can increase the likelihood of intergenerational conflict. The present study aims to integrate the dual concern model and social identity theory to explain the underlying mechanisms of intergenerational conflict by examining the effects of social identity salience on motivational orientation and conflict strategies. A 2 (subgroup identity salience: low vs. high younger/older group membership) × 2 (superordinate identity salience: low vs. high organisational group membership) factorial design with a structured questionnaire on motivational orientation and conflict strategies in relation to a hypothetical work conflict scenario was implemented among 220 postgraduate university students in Hong Kong. Results revealed that subgroup and superordinate identities had a combined influence on conflict strategies but not in motivational orientation. Subgroup and superordinate identification promoted integrating and compromising strategies, superordinate identification promoted obliging strategy, subgroup identification promoted dominating strategy and no identification promoted avoiding strategy. Age did not moderate these relationships. This study contributes to the development of the integrated model of conflict. © 2017 International Union of Psychological Science.

Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development

PubMed Central

Tannour-Louet, Mounia; Han, Shuo; Corbett, Sean T.; Louet, Jean-Francois; Yatsenko, Svetlana; Meyers, Lindsay; Shaw, Chad A.; Kang, Sung-Hae L.; Cheung, Sau Wai; Lamb, Dolores J.

2010-01-01

Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10−12). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development. PMID:21048976

Analysis of the Association between Catechol-O-Methyltransferase Val158Met and Male Sexual Orientation.

PubMed

Yu, Wei; Tu, Dan; Hong, Fuchang; Wang, Jing; Liu, Xiaoli; Cai, Yumao; Xu, Ruiwei; Zhao, Guanglu; Wang, Feng; Pan, Hong; Wu, Shinan; Feng, Tiejian; Wang, Binbin

2015-09-01

Male sexual orientation is thought to have a genetic component. However, previous studies have failed to generate positive results from among candidate genes. Catechol-O-methyltransferase (COMT), located on chromosome 22, has six exons, spans 27 kb, and encodes a protein of 271 amino acids. COMT has an important role in regulating the embryonic levels of catecholamine neurotransmitters (such as dopamine, norepinephrine, and epinephrine) and estrogens. COMT is also thought to be related to sexual orientation. This study aimed to investigate the relationship between the COMT Val158Met variant and male sexual orientation. We performed association analysis of the COMT gene single nucleotide polymorphism, Val158Met, in 409 homosexual cases and 387 heterosexual control Chinese men. COMT polymorphism status was determined using a polymerase chain reaction-based assay. Polymerase chain reaction was performed to genotype the COMT Val158Met polymorphism. The frequency differences of the genotype and alleles distribution between the male homosexual and control groups. Significant differences, both in genotype and alleles, between male homosexual individuals and controls indicated a genetic component related to male homosexuality. The Val allele recessive model could be an interrelated genetic model of the cause of male homosexuality. The COMT Val158Met variant might be associated with male sexual orientation and a recessive model was suggested. © 2015 International Society for Sexual Medicine.

Friendships Moderate an Association Between a Dopamine Gene Variant and Political Ideology.

PubMed

Settle, Jaime E; Dawes, Christopher T; Christakis, Nicholas A; Fowler, James H

2010-01-01

Scholars in many fields have long noted the importance of social context in the development of political ideology. Recent work suggests that political ideology also has a heritable component, but no specific gene variant or combination of variants associated with political ideology have so far been identified. Here, we hypothesize that individuals with a genetic predisposition toward seeking out new experiences will tend to be more liberal, but only if they are embedded in a social context that provides them with multiple points of view. Using data from the National Longitudinal Study of Adolescent Health, we test this hypothesis by investigating an association between self-reported political ideology and the 7R variant of the dopamine receptor D4 gene (DRD4), which has previously been associated with novelty seeking. Among those with DRD4-7R, we find that the number of friendships a person has in adolescence is significantly associated with liberal political ideology. Among those without the gene variant, there is no association. This is the first study to elaborate a specific gene-environment interaction that contributes to ideological self-identification, and it highlights the importance of incorporating both nature and nurture into the study of political preferences.

Friendships Moderate an Association Between a Dopamine Gene Variant and Political Ideology

PubMed Central

Settle, Jaime E.; Dawes, Christopher T.; Christakis, Nicholas A.; Fowler, James H.

2012-01-01

Scholars in many fields have long noted the importance of social context in the development of political ideology. Recent work suggests that political ideology also has a heritable component, but no specific gene variant or combination of variants associated with political ideology have so far been identified. Here, we hypothesize that individuals with a genetic predisposition toward seeking out new experiences will tend to be more liberal, but only if they are embedded in a social context that provides them with multiple points of view. Using data from the National Longitudinal Study of Adolescent Health, we test this hypothesis by investigating an association between self-reported political ideology and the 7R variant of the dopamine receptor D4 gene (DRD4), which has previously been associated with novelty seeking. Among those with DRD4-7R, we find that the number of friendships a person has in adolescence is significantly associated with liberal political ideology. Among those without the gene variant, there is no association. This is the first study to elaborate a specific gene-environment interaction that contributes to ideological self-identification, and it highlights the importance of incorporating both nature and nurture into the study of political preferences. PMID:22282583

A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data.

PubMed

Stark, Zornitza; Dashnow, Harriet; Lunke, Sebastian; Tan, Tiong Y; Yeung, Alison; Sadedin, Simon; Thorne, Natalie; Macciocca, Ivan; Gaff, Clara; Oshlack, Alicia; White, Susan M; James, Paul A

2017-11-01

Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services.

Proteomic characterization of histone variants in the mouse testis by mass spectrometry-based top-down analysis.

PubMed

Kwak, Ho-Geun; Dohmae, Naoshi

2016-11-15

Various histones, including testis-specific histones, exist during spermatogenesis and some of them have been reported to play a key role in chromatin remodeling. Mass spectrometry (MS)-based characterization has become the important step to understand histone structures. Although individual histones or partial histone variant groups have been characterized, the comprehensive analysis of histone variants has not yet been conducted in the mouse testis. Here, we present the comprehensive separation and characterization of histone variants from mouse testes by a top-down approach using MS. Histone variants were successfully separated on a reversed phase column using high performance liquid chromatography (HPLC) with an ion-pairing reagent. Increasing concentrations of testis-specific histones were observed in the mouse testis and some somatic histones increased in the epididymis. Specifically, the increase of mass abundance in H3.2 in the epididymis was inversely proportional to the decrease in H3t in the testis, which was approximately 80%. The top-down characterization of intact histone variants in the mouse testis was performed using LC-MS/MS. The masses of separated histone variants and their expected post-translation modifications were calculated by performing deconvolution with information taken from the database. TH2A, TH2B and H3t were characterized by MS/MS fragmentation. Our approach provides comprehensive knowledge for identification of histone variants in the mouse testis that will contribute to the structural and functional research of histone variants during spermatogenesis.

Common Variants in the MKL1 Gene Confer Risk of Schizophrenia

PubMed Central

Luo, Xiong-jian; Huang, Liang; van den Oord, Edwin J.; Aberg, Karolina A.; Gan, Lin; Zhao, Zhongming; Yao, Yong-Gang

2015-01-01

Genome-wide association studies (GWAS) of schizophrenia have identified multiple risk variants with robust association signals for schizophrenia. However, these variants could explain only a small proportion of schizophrenia heritability. Furthermore, the effect size of these risk variants is relatively small (eg, most of them had an OR less than 1.2), suggesting that additional risk variants may be detected when increasing sample size in analysis. Here, we report the identification of a genome-wide significant schizophrenia risk locus at 22q13.1 by combining 2 large-scale schizophrenia cohort studies. Our meta-analysis revealed that 7 single nucleotide polymorphism (SNPs) on chromosome 22q13.1 reached the genome-wide significance level (P < 5.0×10–8) in the combined samples (a total of 38441 individuals). Among them, SNP rs6001946 had the most significant association with schizophrenia (P = 2.04×10–8). Interestingly, all 7 SNPs are in high linkage disequilibrium and located in the MKL1 gene. Expression analysis showed that MKL1 is highly expressed in human and mouse brains. We further investigated functional links between MKL1 and proteins encoded by other schizophrenia susceptibility genes in the whole human protein interaction network. We found that MKL1 physically interacts with GSK3B, a protein encoded by a well-characterized schizophrenia susceptibility gene. Collectively, our results revealed that genetic variants in MKL1 might confer risk to schizophrenia. Further investigation of the roles of MKL1 in the pathogenesis of schizophrenia is warranted. PMID:25380769

Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones.

PubMed

van Zwieten, Rob; Veldthuis, Martijn; Delzenne, Barend; Berghuis, Jeffrey; Groen, Joke; Ait Ichou, Fatima; Clifford, Els; Harteveld, Cornelis L; Stroobants, An K

2014-01-01

More than 20,000 blood samples of individuals living in The Netherlands and suspected of hemolytic anemia or diabetes were analyzed by high resolution cation exchange high performance liquid chromatography (HPLC). Besides common disease-related hemoglobins (Hbs), rare variants were also detected. The variant Hbs were retrospectively analyzed by capillary zone electrophoresis (CZE) and by isoelectric focusing (IEF). For unambiguous identification, the globin genes were sequenced. Most of the 80 Hb variants detected by initial screening on HPLC were also separated by capillary electrophoresis (CE), but a few variants were only detectable with one of these methods. Some variants were unstable, had thalassemic properties or increased oxygen affinity, and some interfered with Hb A2 measurement, detection of sickle cell Hb or Hb A1c quantification. Two of the six novel variants, Hb Enschede (HBA2: c.308G  > A, p.Ser103Asn) and Hb Weesp (HBA1: c.301C > T, p.Leu101Phe), had no clinical consequences. In contrast, two others appeared clinically significant: Hb Ede (HBB: c.53A > T, p.Lys18Met) caused thalassemia and Hb Waterland (HBB: c.428C > T, pAla143Val) was related to mild polycytemia. Hb A2-Venlo (HBD: c.193G > A, p.Gly65Ser) and Hb A2-Rotterdam (HBD: c.38A > C, p.Asn13Thr) interfered with Hb A2 quantification. This survey shows that HPLC analysis followed by globin gene sequencing of rare variants is an effective method to reveal Hb variants.

Implication of common and disease specific variants in CLU, CR1, and PICALM.

PubMed

Ferrari, Raffaele; Moreno, Jorge H; Minhajuddin, Abu T; O'Bryant, Sid E; Reisch, Joan S; Barber, Robert C; Momeni, Parastoo

2012-08-01

Two recent genome-wide association studies (GWAS) for late onset Alzheimer's disease (LOAD) revealed 3 new genes: clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and complement receptor 1 (CR1). In order to evaluate association with these genome-wide association study-identified genes and to isolate the variants contributing to the pathogenesis of LOAD, we genotyped the top single nucleotide polymorphisms (SNPs), rs11136000 (CLU), rs3818361 (CR1), and rs3851179 (PICALM), and sequenced the entire coding regions of these genes in our cohort of 342 LOAD patients and 277 control subjects. We confirmed the association of rs3851179 (PICALM) (p = 7.4 × 10(-3)) with the disease status. Through sequencing we identified 18 variants in CLU, 3 of which were found exclusively in patients; 8 variants (out of 65) in CR1 gene were only found in patients and the 16 variants identified in PICALM gene were present in both patients and controls. In silico analysis of the variants in PICALM did not predict any damaging effect on the protein. The haplotype analysis of the variants in each gene predicted a common haplotype when the 3 single nucleotide polymorphisms rs11136000 (CLU), rs3818361 (CR1), and rs3851179 (PICALM), respectively, were included. For each gene the haplotype structure and size differed between patients and controls. In conclusion, we confirmed association of CLU, CR1, and PICALM genes with the disease status in our cohort through identification of a number of disease-specific variants among patients through the sequencing of the coding region of these genes. Published by Elsevier Inc.

Identification of causal genes for complex traits.

PubMed

Hormozdiari, Farhad; Kichaev, Gleb; Yang, Wen-Yun; Pasaniuc, Bogdan; Eskin, Eleazar

2015-06-15

Although genome-wide association studies (GWAS) have identified thousands of variants associated with common diseases and complex traits, only a handful of these variants are validated to be causal. We consider 'causal variants' as variants which are responsible for the association signal at a locus. As opposed to association studies that benefit from linkage disequilibrium (LD), the main challenge in identifying causal variants at associated loci lies in distinguishing among the many closely correlated variants due to LD. This is particularly important for model organisms such as inbred mice, where LD extends much further than in human populations, resulting in large stretches of the genome with significantly associated variants. Furthermore, these model organisms are highly structured and require correction for population structure to remove potential spurious associations. In this work, we propose CAVIAR-Gene (CAusal Variants Identification in Associated Regions), a novel method that is able to operate across large LD regions of the genome while also correcting for population structure. A key feature of our approach is that it provides as output a minimally sized set of genes that captures the genes which harbor causal variants with probability ρ. Through extensive simulations, we demonstrate that our method not only speeds up computation, but also have an average of 10% higher recall rate compared with the existing approaches. We validate our method using a real mouse high-density lipoprotein data (HDL) and show that CAVIAR-Gene is able to identify Apoa2 (a gene known to harbor causal variants for HDL), while reducing the number of genes that need to be tested for functionality by a factor of 2. Software is freely available for download at genetics.cs.ucla.edu/caviar. © The Author 2015. Published by Oxford University Press.

Gender Variance and Sexual Orientation Among Male Spirit Mediums in Myanmar.

PubMed

Coleman, Eli; Allen, Mariette Pathy; Ford, Jessie V

2018-05-01

This article describes the gender identity, gender expression, and sexual orientation of male spirit mediums in Myanmar. Our analysis is based on ethnographic work, field observation, and 10 semi-structured interviews. These observations were conducted from 2010 to 2015, mostly in Mandalay, with some fieldwork in Yangon and Bagan. The focus of this investigation was specifically on achout (gender variant individuals) who were spirit mediums (nat kadaw). Semi-structured interviews explored the ways that participants understood their gender identity, gender expression, and sexuality in relation to their work as spirit mediums and broader social life. Myanmar remains quite a homophobic and transphobic culture but is undergoing rapid economic and social change. Therefore, it provides an interesting context to study how safe spaces are produced for sexual/gender minorities amidst broader social change. We find that, through the animistic belief structure, there is a growing space for gender nonconforming people, gender variant, and same-sex-oriented individuals (achout) to neutralize their stigmatized status and attain a level of respect and economic advantage. Their ability to become nat kadaw (mediums of spirits) mitigates or trumps their stigmatized status.

Identification of rare paired box 3 variant in strabismus by whole exome sequencing

PubMed Central

Gong, Hui-Min; Wang, Jing; Xu, Jing; Zhou, Zhan-Yu; Li, Jing-Wen; Chen, Shu-Fang

2017-01-01

AIM To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder. PMID:28861346

An automatic and efficient pipeline for disease gene identification through utilizing family-based sequencing data.

PubMed

Song, Dandan; Li, Ning; Liao, Lejian

2015-01-01

Due to the generation of enormous amounts of data at both lower costs as well as in shorter times, whole-exome sequencing technologies provide dramatic opportunities for identifying disease genes implicated in Mendelian disorders. Since upwards of thousands genomic variants can be sequenced in each exome, it is challenging to filter pathogenic variants in protein coding regions and reduce the number of missing true variants. Therefore, an automatic and efficient pipeline for finding disease variants in Mendelian disorders is designed by exploiting a combination of variants filtering steps to analyze the family-based exome sequencing approach. Recent studies on the Freeman-Sheldon disease are revisited and show that the proposed method outperforms other existing candidate gene identification methods.

Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants

PubMed Central

Paumard-Hernández, Beatriz; Berges-Soria, Julia; Barroso, Eva; Rivera-Pedroza, Carlos I; Pérez-Carrizosa, Virginia; Benito-Sanz, Sara; López-Messa, Eva; Santos, Fernando; García-Recuero, Ignacio I; Romance, Ana; Ballesta-Martínez, Juliana María; López-González, Vanesa; Campos-Barros, Ángel; Cruz, Jaime; Guillén-Navarro, Encarna; Sánchez del Pozo, Jaime; Lapunzina, Pablo; García-Miñaur, Sixto; Heath, Karen E

2015-01-01

Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected. Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. During routine diagnostics, we screened 182 Spanish craniosynostosis probands, implementing a four-tiered cascade screening of FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1. A total of 43 variants, eight novel, were identified in 113 (62%) patients: 104 (92%) detected in level 1; eight (7%) in level 2 and one (1%) in level 3. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants, four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. In the 19 Saethre–Chotzen syndrome (SCS) individuals in whom a variant was detected, 15 (79%) carried a TWIST1 variant, whereas four (21%) had a TCF12 variant. Thus, we propose that TCF12 screening should be included for TWIST1 negative SCS patients and in patients where the coronal suture is affected. In summary, a molecular diagnosis was obtained in a total of 119/182 patients (65%), allowing the correct craniosynostosis syndrome classification, aiding genetic counselling and in some cases provided a better planning on how and when surgical intervention should take place and, subsequently the appropriate clinical follow up. PMID:25271085

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene.

PubMed

Thonberg, Håkan; Chiang, Huei-Hsin; Lilius, Lena; Forsell, Charlotte; Lindström, Anna-Karin; Johansson, Charlotte; Björkström, Jenny; Thordardottir, Steinunn; Sleegers, Kristel; Van Broeckhoven, Christine; Rönnbäck, Annica; Graff, Caroline

2017-06-09

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them.

Identification of the chemical constituents of Chinese medicine Yi-Xin-Shu capsule by molecular feature orientated precursor ion selection and tandem mass spectrometry structure elucidation.

PubMed

Wang, Hong-ping; Chen, Chang; Liu, Yan; Yang, Hong-Jun; Wu, Hong-Wei; Xiao, Hong-Bin

2015-11-01

The incomplete identification of the chemical components of traditional Chinese medicinal formula has been one of the bottlenecks in the modernization of traditional Chinese medicine. Tandem mass spectrometry has been widely used for the identification of chemical substances. Current automatic tandem mass spectrometry acquisition, where precursor ions were selected according to their signal intensity, encounters a drawback in chemical substances identification when samples contain many overlapping signals. Compounds in minor or trace amounts could not be identified because most tandem mass spectrometry information was lost. Herein, a molecular feature orientated precursor ion selection and tandem mass spectrometry structure elucidation method for complex Chinese medicine chemical constituent analysis was developed. The precursor ions were selected according to their two-dimensional characteristics of retention times and mass-to-charge ratio ranges from herbal compounds, so that all precursor ions from herbal compounds were included and more minor chemical constituents in Chinese medicine were identified. Compared to the conventional automatic tandem mass spectrometry setups, the approach is novel and can overcome the drawback for chemical substances identification. As an example, 276 compounds from the Chinese Medicine of Yi-Xin-Shu capsule were identified. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

VAS: A Vision Advisor System combining agents and object-oriented databases

NASA Technical Reports Server (NTRS)

Eilbert, James L.; Lim, William; Mendelsohn, Jay; Braun, Ron; Yearwood, Michael

1994-01-01

A model-based approach to identifying and finding the orientation of non-overlapping parts on a tray has been developed. The part models contain both exact and fuzzy descriptions of part features, and are stored in an object-oriented database. Full identification of the parts involves several interacting tasks each of which is handled by a distinct agent. Using fuzzy information stored in the model allowed part features that were essentially at the noise level to be extracted and used for identification. This was done by focusing attention on the portion of the part where the feature must be found if the current hypothesis of the part ID is correct. In going from one set of parts to another the only thing that needs to be changed is the database of part models. This work is part of an effort in developing a Vision Advisor System (VAS) that combines agents and objected-oriented databases.

Mortar and artillery variants classification by exploiting characteristics of the acoustic signature

NASA Astrophysics Data System (ADS)

Hohil, Myron E.; Grasing, David; Desai, Sachi; Morcos, Amir

2007-10-01

Feature extraction methods based on the discrete wavelet transform and multiresolution analysis facilitate the development of a robust classification algorithm that reliably discriminates mortar and artillery variants via acoustic signals produced during the launch/impact events. Utilizing acoustic sensors to exploit the sound waveform generated from the blast for the identification of mortar and artillery variants. Distinct characteristics arise within the different mortar variants because varying HE mortar payloads and related charges emphasize concussive and shrapnel effects upon impact employing varying magnitude explosions. The different mortar variants are characterized by variations in the resulting waveform of the event. The waveform holds various harmonic properties distinct to a given mortar/artillery variant that through advanced signal processing techniques can employed to classify a given set. The DWT and other readily available signal processing techniques will be used to extract the predominant components of these characteristics from the acoustic signatures at ranges exceeding 2km. Exploiting these techniques will help develop a feature set highly independent of range, providing discrimination based on acoustic elements of the blast wave. Highly reliable discrimination will be achieved with a feed-forward neural network classifier trained on a feature space derived from the distribution of wavelet coefficients, frequency spectrum, and higher frequency details found within different levels of the multiresolution decomposition. The process that will be described herein extends current technologies, which emphasis multi modal sensor fusion suites to provide such situational awareness. A two fold problem of energy consumption and line of sight arise with the multi modal sensor suites. The process described within will exploit the acoustic properties of the event to provide variant classification as added situational awareness to the solider.

Rare variant association analysis in case-parents studies by allowing for missing parental genotypes.

PubMed

Li, Yumei; Xiang, Yang; Xu, Chao; Shen, Hui; Deng, Hongwen

2018-01-15

The development of next-generation sequencing technologies has facilitated the identification of rare variants. Family-based design is commonly used to effectively control for population admixture and substructure, which is more prominent for rare variants. Case-parents studies, as typical strategies in family-based design, are widely used in rare variant-disease association analysis. Current methods in case-parents studies are based on complete case-parents data; however, parental genotypes may be missing in case-parents trios, and removing these data may lead to a loss in statistical power. The present study focuses on testing for rare variant-disease association in case-parents study by allowing for missing parental genotypes. In this report, we extended the collapsing method for rare variant association analysis in case-parents studies to allow for missing parental genotypes, and investigated the performance of two methods by using the difference of genotypes between affected offspring and their corresponding "complements" in case-parent trios and TDT framework. Using simulations, we showed that, compared with the methods just only using complete case-parents data, the proposed strategy allowing for missing parental genotypes, or even adding unrelated affected individuals, can greatly improve the statistical power and meanwhile is not affected by population stratification. We conclude that adding case-parents data with missing parental genotypes to complete case-parents data set can greatly improve the power of our strategy for rare variant-disease association.

Group-based variant calling leveraging next-generation supercomputing for large-scale whole-genome sequencing studies.

PubMed

Standish, Kristopher A; Carland, Tristan M; Lockwood, Glenn K; Pfeiffer, Wayne; Tatineni, Mahidhar; Huang, C Chris; Lamberth, Sarah; Cherkas, Yauheniya; Brodmerkel, Carrie; Jaeger, Ed; Smith, Lance; Rajagopal, Gunaretnam; Curran, Mark E; Schork, Nicholas J

2015-09-22

Next-generation sequencing (NGS) technologies have become much more efficient, allowing whole human genomes to be sequenced faster and cheaper than ever before. However, processing the raw sequence reads associated with NGS technologies requires care and sophistication in order to draw compelling inferences about phenotypic consequences of variation in human genomes. It has been shown that different approaches to variant calling from NGS data can lead to different conclusions. Ensuring appropriate accuracy and quality in variant calling can come at a computational cost. We describe our experience implementing and evaluating a group-based approach to calling variants on large numbers of whole human genomes. We explore the influence of many factors that may impact the accuracy and efficiency of group-based variant calling, including group size, the biogeographical backgrounds of the individuals who have been sequenced, and the computing environment used. We make efficient use of the Gordon supercomputer cluster at the San Diego Supercomputer Center by incorporating job-packing and parallelization considerations into our workflow while calling variants on 437 whole human genomes generated as part of large association study. We ultimately find that our workflow resulted in high-quality variant calls in a computationally efficient manner. We argue that studies like ours should motivate further investigations combining hardware-oriented advances in computing systems with algorithmic developments to tackle emerging 'big data' problems in biomedical research brought on by the expansion of NGS technologies.

De novo assembly and next-generation sequencing to analyse full-length gene variants from codon-barcoded libraries.

PubMed

Cho, Namjin; Hwang, Byungjin; Yoon, Jung-ki; Park, Sangun; Lee, Joongoo; Seo, Han Na; Lee, Jeewon; Huh, Sunghoon; Chung, Jinsoo; Bang, Duhee

2015-09-21

Interpreting epistatic interactions is crucial for understanding evolutionary dynamics of complex genetic systems and unveiling structure and function of genetic pathways. Although high resolution mapping of en masse variant libraries renders molecular biologists to address genotype-phenotype relationships, long-read sequencing technology remains indispensable to assess functional relationship between mutations that lie far apart. Here, we introduce JigsawSeq for multiplexed sequence identification of pooled gene variant libraries by combining a codon-based molecular barcoding strategy and de novo assembly of short-read data. We first validate JigsawSeq on small sub-pools and observed high precision and recall at various experimental settings. With extensive simulations, we then apply JigsawSeq to large-scale gene variant libraries to show that our method can be reliably scaled using next-generation sequencing. JigsawSeq may serve as a rapid screening tool for functional genomics and offer the opportunity to explore evolutionary trajectories of protein variants.

Palm-Vein Classification Based on Principal Orientation Features

PubMed Central

Zhou, Yujia; Liu, Yaqin; Feng, Qianjin; Yang, Feng; Huang, Jing; Nie, Yixiao

2014-01-01

Personal recognition using palm–vein patterns has emerged as a promising alternative for human recognition because of its uniqueness, stability, live body identification, flexibility, and difficulty to cheat. With the expanding application of palm–vein pattern recognition, the corresponding growth of the database has resulted in a long response time. To shorten the response time of identification, this paper proposes a simple and useful classification for palm–vein identification based on principal direction features. In the registration process, the Gaussian-Radon transform is adopted to extract the orientation matrix and then compute the principal direction of a palm–vein image based on the orientation matrix. The database can be classified into six bins based on the value of the principal direction. In the identification process, the principal direction of the test sample is first extracted to ascertain the corresponding bin. One-by-one matching with the training samples is then performed in the bin. To improve recognition efficiency while maintaining better recognition accuracy, two neighborhood bins of the corresponding bin are continuously searched to identify the input palm–vein image. Evaluation experiments are conducted on three different databases, namely, PolyU, CASIA, and the database of this study. Experimental results show that the searching range of one test sample in PolyU, CASIA and our database by the proposed method for palm–vein identification can be reduced to 14.29%, 14.50%, and 14.28%, with retrieval accuracy of 96.67%, 96.00%, and 97.71%, respectively. With 10,000 training samples in the database, the execution time of the identification process by the traditional method is 18.56 s, while that by the proposed approach is 3.16 s. The experimental results confirm that the proposed approach is more efficient than the traditional method, especially for a large database. PMID:25383715

Functional Assessment of Disease-Associated Regulatory Variants In Vivo Using a Versatile Dual Colour Transgenesis Strategy in Zebrafish

PubMed Central

Bhatia, Shipra; Gordon, Christopher T.; Foster, Robert G.; Melin, Lucie; Abadie, Véronique; Baujat, Geneviève; Vazquez, Marie-Paule; Amiel, Jeanne; Lyonnet, Stanislas; van Heyningen, Veronica; Kleinjan, Dirk A.

2015-01-01

Disruption of gene regulation by sequence variation in non-coding regions of the genome is now recognised as a significant cause of human disease and disease susceptibility. Sequence variants in cis-regulatory elements (CREs), the primary determinants of spatio-temporal gene regulation, can alter transcription factor binding sites. While technological advances have led to easy identification of disease-associated CRE variants, robust methods for discerning functional CRE variants from background variation are lacking. Here we describe an efficient dual-colour reporter transgenesis approach in zebrafish, simultaneously allowing detailed in vivo comparison of spatio-temporal differences in regulatory activity between putative CRE variants and assessment of altered transcription factor binding potential of the variant. We validate the method on known disease-associated elements regulating SHH, PAX6 and IRF6 and subsequently characterise novel, ultra-long-range SOX9 enhancers implicated in the craniofacial abnormality Pierre Robin Sequence. The method provides a highly cost-effective, fast and robust approach for simultaneously unravelling in a single assay whether, where and when in embryonic development a disease-associated CRE-variant is affecting its regulatory function. PMID:26030420

Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression

PubMed Central

Yanek, Lisa R.; Yang, Xiao Ping; Mathias, Rasika; Herrera-Galeano, J. Enrique; Suktitipat, Bhoom; Qayyum, Rehan; Johnson, Andrew D.; Chen, Ming-Huei; Tofler, Geoffrey H.; Ruczinski, Ingo; Friedman, Alan D.; Gylfason, Arnaldur; Thorsteinsdottir, Unnur; Bray, Paul F.; O'Donnell, Christopher J.; Becker, Diane M.; Becker, Lewis C.

2011-01-01

Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for ≤ 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 × 10−8) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 × 10−27) and in an independent sample of 2755 persons of European descent (P = 1.64 × 10−5). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 × 10−6) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype. PMID:21791418

Gene profiling-based phenotyping for identification of cellular parameters that contribute to fitness, stress-tolerance and virulence of Listeria monocytogenes variants.

PubMed

Koomen, Jeroen; den Besten, Heidy M W; Metselaar, Karin I; Tempelaars, Marcel H; Wijnands, Lucas M; Zwietering, Marcel H; Abee, Tjakko

2018-06-07

Microbial population heterogeneity allows for a differential microbial response to environmental stresses and can lead to the selection of stress resistant variants. In this study, we have used two different stress resistant variants of Listeria monocytogenes LO28 with mutations in the rpsU gene encoding ribosomal protein S21, to elucidate features that can contribute to fitness, stress-tolerance and host interaction using a comparative gene profiling and phenotyping approach. Transcriptome analysis showed that 116 genes were upregulated and 114 genes were downregulated in both rpsU variants. Upregulated genes included a major contribution of SigB-controlled genes such as intracellular acid resistance-associated glutamate decarboxylase (GAD) (gad3), genes involved in compatible solute uptake (opuC), glycerol metabolism (glpF, glpK, glpD), and virulence (inlA, inlB). Downregulated genes in the two variants involved mainly genes involved in flagella synthesis and motility. Phenotyping results of the two rpsU variants matched the gene profiling data including enhanced freezing resistance conceivably linked to compatible solute accumulation, higher glycerol utilisation rates, and better adhesion to Caco 2 cells presumably linked to higher expression of internalins. Also, bright field and electron microscopy analysis confirmed reduced flagellation of the variants. The activation of SigB-mediated stress defence offers an explanation for the multiple-stress resistant phenotype in rpsU variants. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome-like phenotype and hypogammaglobulinemia.

PubMed

Khandelwal, Kriti D; Ockeloen, Charlotte W; Venselaar, Hanka; Boulanger, Cécile; Brichard, Bénédicte; Sokal, Etienne; Pfundt, Rolph; Rinne, Tuula; van Beusekom, Ellen; Bloemen, Marjon; Vriend, Gerrit; Revencu, Nicole; Carels, Carine E L; van Bokhoven, Hans; Zhou, Huiqing

2017-05-17

The cardinal features of Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC), and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndromes are ectodermal dysplasia (ED), orofacial clefting, and limb anomalies. EEC and AEC are caused by heterozygous mutations in the transcription factor p63 encoded by TP63. Here, we report a patient with an EEC/AEC syndrome-like phenotype, including ankyloblepharon, ED, cleft palate, ectrodactyly, syndactyly, additional hypogammaglobulinemia, and growth delay. Neither pathogenic mutations in TP63 nor CNVs at the TP63 locus were identified. Exome sequencing revealed de novo heterozygous variants in CHUK (conserved helix-loop-helix ubiquitous kinase), PTGER4, and IFIT2. While the variant in PTGER4 might contribute to the immunodeficiency and growth delay, the variant in CHUK appeared to be most relevant for the EEC/AEC-like phenotype. CHUK is a direct target gene of p63 and encodes a component of the IKK complex that plays a key role in NF-κB pathway activation. The identified CHUK variant (g.101980394T>C; c.425A>G; p.His142Arg) is located in the kinase domain which is responsible for the phosphorylation activity of the protein. The variant may affect CHUK function and thus contribute to the disease phenotype in three ways: (1) the variant exhibits a dominant negative effect and results in an inactive IKK complex that affects the canonical NF-κB pathway; (2) it affects the feedback loop of the canonical and non-canonical NF-κB pathways that are CHUK kinase activity-dependent; and (3) it disrupts NF-κB independent epidermal development that is often p63-dependent. Therefore, we propose that the heterozygous CHUK variant is highly likely to be causative to the EEC/AEC-like and additional hypogammaglobulinemia phenotypes in the patient presented here. © 2017 Wiley Periodicals, Inc.

Biometrics, identification and surveillance.

PubMed

Lyon, David

2008-11-01

Governing by identity describes the emerging regime of a globalizing, mobile world. Governance depends on identification but identification increasingly depends on biometrics. This 'solution' to difficulties of verification is described and some technical weaknesses are discussed. The role of biometrics in classification systems is also considered and is shown to contain possible prejudice in relation to racialized criteria of identity. Lastly, the culture of biometric identification is shown to be limited to abstract data, artificially separated from the lived experience of the body including the orientation to others. It is proposed that creators of national ID systems in particular address these crucial deficiencies in their attempt to provide new modes of verification.

Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease.

PubMed

Nho, Kwangsik; Horgusluoglu, Emrin; Kim, Sungeun; Risacher, Shannon L; Kim, Dokyoon; Foroud, Tatiana; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2016-08-12

. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ε4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.

Identification of causal genes for complex traits

PubMed Central

Hormozdiari, Farhad; Kichaev, Gleb; Yang, Wen-Yun; Pasaniuc, Bogdan; Eskin, Eleazar

2015-01-01

Motivation: Although genome-wide association studies (GWAS) have identified thousands of variants associated with common diseases and complex traits, only a handful of these variants are validated to be causal. We consider ‘causal variants’ as variants which are responsible for the association signal at a locus. As opposed to association studies that benefit from linkage disequilibrium (LD), the main challenge in identifying causal variants at associated loci lies in distinguishing among the many closely correlated variants due to LD. This is particularly important for model organisms such as inbred mice, where LD extends much further than in human populations, resulting in large stretches of the genome with significantly associated variants. Furthermore, these model organisms are highly structured and require correction for population structure to remove potential spurious associations. Results: In this work, we propose CAVIAR-Gene (CAusal Variants Identification in Associated Regions), a novel method that is able to operate across large LD regions of the genome while also correcting for population structure. A key feature of our approach is that it provides as output a minimally sized set of genes that captures the genes which harbor causal variants with probability ρ. Through extensive simulations, we demonstrate that our method not only speeds up computation, but also have an average of 10% higher recall rate compared with the existing approaches. We validate our method using a real mouse high-density lipoprotein data (HDL) and show that CAVIAR-Gene is able to identify Apoa2 (a gene known to harbor causal variants for HDL), while reducing the number of genes that need to be tested for functionality by a factor of 2. Availability and implementation: Software is freely available for download at genetics.cs.ucla.edu/caviar. Contact: eeskin@cs.ucla.edu PMID:26072484

Generalizations Related to Concepts Important for Youth Orientation to the World of Work.

ERIC Educational Resources Information Center

Warren, Mary A.; And Others

A basic first step in building a curriculum contributing to the orientation of youth to world of work is identification of concepts important to that orientation. In this study, the generalizations within the concept framework were identified through a developmental process of analysis and synthesis, including a review of current literature, a…

Sexual orientation and gender identity after prenatal exposure to the Dutch famine.

PubMed

de Rooij, Susanne R; Painter, Rebecca C; Swaab, Dick F; Roseboom, Tessa J

2009-06-01

Sexual differentiation of the human brain has been suggested to take place through exposure to sex steroids during intrauterine development. Animal experiments have shown that interference in this process by underfeeding of the mother can result in feminization of the male offspring. We explored the possible effects of prenatal exposure to famine on sexual orientation and gender identity in humans. We used the Klein Sexual Orientation Grid to assess sexual orientation and also assessed gender identity in a group of 380 men and 472 women who were born as term singletons around the time of the 1944-1945 Dutch famine. Prenatal exposure to famine did not affect sexual orientation in men or in women. Three people indicated having some gender identity problems: one woman born before the famine and one man and woman exposed to famine in late gestation. In men, a later birth order was associated with a non-exclusively heterosexual identification. In conclusion, we found no evidence for a significant association between exposure to famine in utero and altered sexual orientation and gender identity. The small sample size of participants with non-exclusively heterosexual identification (possibly due to underreporting of homosexuality) may have reduced our power to detect any differences.

An Object-Oriented Collection of Minimum Degree Algorithms: Design, Implementation, and Experiences

NASA Technical Reports Server (NTRS)

Kumfert, Gary; Pothen, Alex

1999-01-01

The multiple minimum degree (MMD) algorithm and its variants have enjoyed 20+ years of research and progress in generating fill-reducing orderings for sparse, symmetric positive definite matrices. Although conceptually simple, efficient implementations of these algorithms are deceptively complex and highly specialized. In this case study, we present an object-oriented library that implements several recent minimum degree-like algorithms. We discuss how object-oriented design forces us to decompose these algorithms in a different manner than earlier codes and demonstrate how this impacts the flexibility and efficiency of our C++ implementation. We compare the performance of our code against other implementations in C or Fortran.

Three-dimensional shape perception from chromatic orientation flows

PubMed Central

Zaidi, Qasim; Li, Andrea

2010-01-01

The role of chromatic information in 3-D shape perception is controversial. We resolve this controversy by showing that chromatic orientation flows are sufficient for accurate perception of 3-D shape. Chromatic flows required less cone contrast to convey shape than did achromatic flows, thus ruling out luminance artifacts as a problem. Luminance artifacts were also ruled out by a protanope’s inability to see 3-D shape from chromatic flows. Since chromatic orientation flows can only be extracted from retinal images by neurons that are responsive to color modulations and selective for orientation, the psychophysical results also resolve the controversy over the existence of such neurons. In addition, we show that identification of 3-D shapes from chromatic flows can be masked by luminance modulations, indicating that it is subserved by orientation-tuned neurons sensitive to both chromatic and luminance modulations. PMID:16961963

Whole Exome Sequencing Identifies Rare Protein-Coding Variants in Behçet's Disease.

PubMed

Ognenovski, Mikhail; Renauer, Paul; Gensterblum, Elizabeth; Kötter, Ina; Xenitidis, Theodoros; Henes, Jörg C; Casali, Bruno; Salvarani, Carlo; Direskeneli, Haner; Kaufman, Kenneth M; Sawalha, Amr H

2016-05-01

Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We undertook this study to investigate the role of rare variants in BD by performing whole exome sequencing in BD patients of European descent. Whole exome sequencing was performed in a discovery set comprising 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in 2 additional independent sets of 49 German BD patients and 129 Italian BD patients of European descent. Genetic association analysis was then performed in BD patients and 503 controls of European descent. Functional effects of associated genetic variants were assessed using bioinformatic approaches. Using whole exome sequencing, we identified 77 rare variants (in 74 genes) with predicted protein-damaging effects in BD. These variants were genotyped in 2 additional patient sets and then analyzed to reveal significant associations with BD at 2 genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and between BD and NEIL1 (rs5745908), involved in base excision DNA repair (P = 3.22 × 10(-4) and P = 5.16 × 10(-4) , respectively). The LIMK2 association is a missense variant with predicted protein damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni-corrected P = 5.63 × 10(-14) , P = 7.29 × 10(-6) , P = 1.15 × 10(-5) , and P = 6.40 × 10(-3) , respectively). The genetic association in NEIL1 is a predicted splice

Identification and location tasks rely on different mental processes: a diffusion model account of validity effects in spatial cueing paradigms with emotional stimuli.

PubMed

Imhoff, Roland; Lange, Jens; Germar, Markus

2018-02-22

Spatial cueing paradigms are popular tools to assess human attention to emotional stimuli, but different variants of these paradigms differ in what participants' primary task is. In one variant, participants indicate the location of the target (location task), whereas in the other they indicate the shape of the target (identification task). In the present paper we test the idea that although these two variants produce seemingly comparable cue validity effects on response times, they rest on different underlying processes. Across four studies (total N = 397; two in the supplement) using both variants and manipulating the motivational relevance of cue content, diffusion model analyses revealed that cue validity effects in location tasks are primarily driven by response biases, whereas the same effect rests on delay due to attention to the cue in identification tasks. Based on this, we predict and empirically support that a symmetrical distribution of valid and invalid cues would reduce cue validity effects in location tasks to a greater extent than in identification tasks. Across all variants of the task, we fail to replicate the effect of greater cue validity effects for arousing (vs. neutral) stimuli. We discuss the implications of these findings for best practice in spatial cueing research.

Designing an orientation program for new faculty.

PubMed

Holyfield, Lavern J; Berry, Charles W

2008-12-01

The Faculty Development Committee (FDC) at Baylor College of Dentistry (BCD) is charged with providing programs and activities that facilitate the success of existing faculty in the constantly changing environment of academia. In response to concerns regarding the challenges wrought by current and projected shortages of dental faculty across the nation, the FDC was prompted to assess development opportunities available to BCD faculty. A professional development resource that we found deficient was a formal, comprehensive orientation program for newly hired faculty. To guide the efforts of the committee in developing this program, a survey was designed and administered during an annual faculty retreat. Respondents were new and junior faculty, senior faculty, and some administrators. The results of the survey to determine requirements for new faculty orientation became the basis for formalizing BCD's new faculty orientation program. This article provides an overview of the new faculty orientation process from design to program implementation and describes the development and use of a faculty survey to determine the fundamental elements of a faculty development program, identification of essential individuals for designing/implementing the program, and implementation of a new faculty orientation program at BCD.

Identification of five novel STAR variants in ten Chinese patients with congenital lipoid adrenal hyperplasia.

PubMed

Huang, Zhuo; Ye, Jun; Han, Lianshu; Qiu, Wenjuan; Zhang, Huiwen; Yu, Yongguo; Liang, Lili; Gong, Zhuwen; Gu, Xuefan

2016-04-01

Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder caused by defective synthesis of all steroids. This disorder is characterized by 46,XY sex reversal, skin hyperpigmentation, early-onset adrenal crisis and enlarged adrenal with fatty accumulation. CLAH is caused by mutations in the STAR gene. The clinical features and STAR gene mutation spectrum of a large cohort of Chinese patients with CLAH were not reported previously. We performed clinical retrospective review and genetic analysis of the STAR gene in ten unrelated Chinese phenotypic female patients who were clinically diagnosed with CLAH and followed up in our hospital from 2006 to 2015. All ten patients, including two 46,XY females and eight 46,XX females, presented skin hyperpigmentation and early salt-wasting episode, and showed normal growth and development after steroid replacement treatment. Totally 20 mutant alleles containing 11 different STAR gene mutations were identified in these ten patients, including five novel variants (two missense and three null variants), all predicted to be pathogenic in bioinformatics analysis, and six mutations described in previous literature. Among these 11 mutations, a reported mutation c.772C>T and a novel variant c.707_708delinsCTT were most frequent, accounting for 35% and 15% of the total mutant alleles, respectively. This is the first report of a large Chinese cohort with CLAH, presenting the mutation spectrum of the STAR gene and two possible founder mutations in the Chinese population, which may contribute to better genetic counseling and prenatal diagnosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants contributing to lipid levels and coronary artery disease

PubMed Central

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J.; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N.; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H.-H.; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B.; Adair, Linda S.; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; da Chen, Yii-Der I; Shu, XiaoOu; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K.; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars; Nielsen, Jonas Bille; Tse, Hung-fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y. Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Consortium, GLGC; Kathiresan, Sekar; Mohlke, Karen L.; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-01-01

Most genome-wide association studies have been conducted in European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we examined protein-coding genetic variants in 47,532 East Asian individuals using an exome array. We identified 255 variants at 41 loci reaching chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After meta-analysis with > 300,000 European samples, we identified an additional 9 novel loci. The same 16 genes were identified by the protein-altering variants in both East Asians and Europeans, likely pointing to the functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population-specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci. PMID:29083407

Identification and functional characterization of four TRPA1 variants in Apolygus lucorum (Meyer-Dür)

USDA-ARS?s Scientific Manuscript database

As signal integrators that respond to various physical and chemical stimuli, transient receptor potential (TRP) channels fulfil critical functional roles in the sensory systems of both vertebrate and invertebrate organisms. Here, four variants of TRP ankyrin 1 (TRPA1) were identified and cloned from...

Variant pathogenicity evaluation in the community-driven Inherited Neuropathy Variant Browser.

PubMed

Saghira, Cima; Bis, Dana M; Stanek, David; Strickland, Alleene; Herrmann, David N; Reilly, Mary M; Scherer, Steven S; Shy, Michael E; Züchner, Stephan

2018-05-01

Charcot-Marie-Tooth disease (CMT) is an umbrella term for inherited neuropathies affecting an estimated one in 2,500 people. Over 120 CMT and related genes have been identified and clinical gene panels often contain more than 100 genes. Such a large genomic space will invariantly yield variants of uncertain clinical significance (VUS) in nearly any person tested. This rise in number of VUS creates major challenges for genetic counseling. Additionally, fewer individual variants in known genes are being published as the academic merit is decreasing, and most testing now happens in clinical laboratories, which typically do not correlate their variants with clinical phenotypes. For CMT, we aim to encourage and facilitate the global capture of variant data to gain a large collection of alleles in CMT genes, ideally in conjunction with phenotypic information. The Inherited Neuropathy Variant Browser provides user-friendly open access to currently reported variation in CMT genes. Geneticists, physicians, and genetic counselors can enter variants detected by clinical tests or in research studies in addition to genetic variation gathered from published literature, which are then submitted to ClinVar biannually. Active participation of the broader CMT community will provide an advance over existing resources for interpretation of CMT genetic variation. © 2018 Wiley Periodicals, Inc.

Venomics of the Australian eastern brown snake (Pseudonaja textilis): Detection of new venom proteins and splicing variants.

PubMed

Viala, Vincent Louis; Hildebrand, Diana; Trusch, Maria; Fucase, Tamara Mieco; Sciani, Juliana Mozer; Pimenta, Daniel Carvalho; Arni, Raghuvir K; Schlüter, Hartmut; Betzel, Christian; Mirtschin, Peter; Dunstan, Nathan; Spencer, Patrick Jack

2015-12-01

The eastern brown snake is the predominant cause of snakebites in mainland Australia. Its venom induces defibrination coagulopathy, renal failure and microangiopathic hemolytic anemia. Cardiovascular collapse has been described as an early cause of death in patients, but, so far, the mechanisms involved have not been fully identified. In the present work, we analysed the venome of Pseudonaja textilis by combining high throughput proteomics and transcriptomics, aiming to further characterize the components of this venom. The combination of these techniques in the analysis and identification of toxins, venom proteins and putative toxins allowed the sequence description and the identification of the following: prothrombinase coagulation factors, neurotoxic textilotoxin phospholipase A2 (PLA2) subunits and "acidic PLA2", three-finger toxins (3FTx) and the Kunitz-type protease inhibitor textilinin, venom metalloproteinase, C-type lectins, cysteine rich secretory proteins, calreticulin, dipeptidase 2, as well as evidences of Heloderma lizard peptides. Deep data-mining analysis revealed the secretion of a new transcript variant of venom coagulation factor 5a and the existence of a splicing variant of PLA2 modifying the UTR and signal peptide from a same mature protein. The transcriptome revealed the diversity of transcripts and mutations, and also indicates that splicing variants can be an important source of toxin variation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Public variant databases: liability?

PubMed

Thorogood, Adrian; Cook-Deegan, Robert; Knoppers, Bartha Maria

2017-07-01

Public variant databases support the curation, clinical interpretation, and sharing of genomic data, thus reducing harmful errors or delays in diagnosis. As variant databases are increasingly relied on in the clinical context, there is concern that negligent variant interpretation will harm patients and attract liability. This article explores the evolving legal duties of laboratories, public variant databases, and physicians in clinical genomics and recommends a governance framework for databases to promote responsible data sharing.Genet Med advance online publication 15 December 2016.

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

PubMed Central

Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

2017-01-01

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6) and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing.

PubMed

Chang, Lun-Ching; Das, Biswajit; Lih, Chih-Jian; Si, Han; Camalier, Corinne E; McGregor, Paul M; Polley, Eric

2016-01-01

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly (r = 0.96-0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

Benchmarking distributed data warehouse solutions for storing genomic variant information

PubMed Central

Wiewiórka, Marek S.; Wysakowicz, Dawid P.; Okoniewski, Michał J.

2017-01-01

Abstract Genomic-based personalized medicine encompasses storing, analysing and interpreting genomic variants as its central issues. At a time when thousands of patientss sequenced exomes and genomes are becoming available, there is a growing need for efficient database storage and querying. The answer could be the application of modern distributed storage systems and query engines. However, the application of large genomic variant databases to this problem has not been sufficiently far explored so far in the literature. To investigate the effectiveness of modern columnar storage [column-oriented Database Management System (DBMS)] and query engines, we have developed a prototypic genomic variant data warehouse, populated with large generated content of genomic variants and phenotypic data. Next, we have benchmarked performance of a number of combinations of distributed storages and query engines on a set of SQL queries that address biological questions essential for both research and medical applications. In addition, a non-distributed, analytical database (MonetDB) has been used as a baseline. Comparison of query execution times confirms that distributed data warehousing solutions outperform classic relational DBMSs. Moreover, pre-aggregation and further denormalization of data, which reduce the number of distributed join operations, significantly improve query performance by several orders of magnitude. Most of distributed back-ends offer a good performance for complex analytical queries, while the Optimized Row Columnar (ORC) format paired with Presto and Parquet with Spark 2 query engines provide, on average, the lowest execution times. Apache Kudu on the other hand, is the only solution that guarantees a sub-second performance for simple genome range queries returning a small subset of data, where low-latency response is expected, while still offering decent performance for running analytical queries. In summary, research and clinical applications that require

Public variant databases: liability?

PubMed Central

Thorogood, Adrian; Cook-Deegan, Robert; Knoppers, Bartha Maria

2017-01-01

Public variant databases support the curation, clinical interpretation, and sharing of genomic data, thus reducing harmful errors or delays in diagnosis. As variant databases are increasingly relied on in the clinical context, there is concern that negligent variant interpretation will harm patients and attract liability. This article explores the evolving legal duties of laboratories, public variant databases, and physicians in clinical genomics and recommends a governance framework for databases to promote responsible data sharing. Genet Med advance online publication 15 December 2016 PMID:27977006

Dealing with the incidental finding of secondary variants by the example of SRNS patients undergoing targeted next-generation sequencing.

PubMed

Weber, Stefanie; Büscher, Anja K; Hagmann, Henning; Liebau, Max C; Heberle, Christian; Ludwig, Michael; Rath, Sabine; Alberer, Martin; Beissert, Antje; Zenker, Martin; Hoyer, Peter F; Konrad, Martin; Klein, Hanns-Georg; Hoefele, Julia

2016-01-01

Steroid-resistant nephrotic syndrome (SRNS) is a severe cause of progressive renal disease. Genetic forms of SRNS can present with autosomal recessive or autosomal dominant inheritance. Recent studies have identified mutations in multiple podocyte genes responsible for SRNS. Improved sequencing methods (next-generation sequencing, NGS) now promise rapid mutational testing of SRNS genes. In the present study, a simultaneous screening of ten SRNS genes in 37 SRNS patients was performed by NGS. In 38 % of the patients, causative mutations in one SRNS gene were found. In 22 % of the patients, in addition to these mutations, a secondary variant in a different gene was identified. This high incidence of accumulating sequence variants was unexpected but, although they might have modifier effects, the pathogenic potential of these additional sequence variants seems unclear so far. The example of molecular diagnostics by NGS in SRNS patients shows that these new sequencing technologies might provide further insight into molecular pathogenicity in genetic disorders but will also generate results, which will be difficult to interpret and complicate genetic counseling. Although NGS promises more frequent identification of disease-causing mutations, the identification of causative mutations, the interpretation of incidental findings and possible pitfalls might pose problems, which hopefully will decrease by further experience and elucidation of molecular interactions.

Penicillinase Studies on L-Phase Variants, G-Phase Variants, and Reverted Strains of Staphylococcus aureus

PubMed Central

Simon, Harold J.; Yin, Elaine Jong

1970-01-01

L-phase variants and small colony (G-phase) variants derived from penicillinase-producing Staphylococcus aureus strains were tested for penicillinase (beta lactamase) production. A refined variation of the modified Gots test for penicillinase was used to demonstrate penicillinase synthesis. Penicillinase synthesis was reduced in L-phase variants and G-phase variants when compared to parental strains. After reversion of variants to vegetative stages had been induced, revertants were tested for production of penicillinase, coagulase, and alpha hemolysin, mannitol fermentation, and pigment production, and comparisons were made between parent and reverted vegetative forms. All revertants of G-phase variants retained penicillinase activity. Most revertants of L-phase variants showed reduction or loss of penicillinase activity. Retention of coagulase activity, alpha hemolysin production, mannitol fermentation, pigmentation, and phage type varied among revertants. Images PMID:16557890

A novel succinate dehydrogenase subunit B germline variant associated with head and neck paraganglioma in a Dutch kindred: A family-based study.

PubMed

de Vos, B; Rijken, J A; Adank, M A; Hoksbergen, A W J; Bayley, J P; Leemans, C R; Hensen, E F

2018-06-01

In the Netherlands, the majority of hereditary head and neck paragangliomas (HNPGL) are caused by germline variants in the succinate dehydrogenase genes (SDHD, SDHB, SDHAF2). Here, we evaluate a four-generation family linked to a novel SDHB gene variant with the manifestation of a HNPGL. A family-based study. The VU University Medical Center (VUmc) Amsterdam, a tertiary clinic for Otolaryngology and Head and Neck Surgery. The index patients presented with an embryonic rhabdomyosarcoma and a non-Hodgkin lymphoma. Array-based comparative genomic hybridisation (aCGH) analysis and multiplex ligation-dependent probe amplification (MLPA) revealed a novel deletion of exon 1-3 in the SDHB gene, suspected to predispose to paraganglioma (PGL)/pheochromocytoma (PHEO) syndrome type 4. Subsequently, genetic counselling and DNA testing were offered to all family members at risk. Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO. The DNA of 18 family members was tested, resulting in the identification of 10 carriers of the exon 1-3 deletion in the SDHB gene. One carrier was diagnosed with a carotid body PGL and serum catecholamine excess, which was surgically excised. Negative SDHB immunostaining of the carotid body tumour confirmed that it was caused by the SDHB variant. The remaining 9 carriers showed no evidence of PGL/PHEO. Deletion of exon 1-3 in the SDHB gene is a novel germline variant associated with the formation of hereditary HNPGL. © 2018 The Authors. Clinical Otolaryngology Published by John Wiley & Sons Ltd.

Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study.

PubMed

Lai, Kah Nyin; Ho, Weang Kee; Kang, In Nee; Kang, Peter Choon Eng; Phuah, Sze Yee; Mariapun, Shivaani; Yip, Cheng-Har; Mohd Taib, Nur Aishah; Teo, Soo-Hwang

2017-02-22

Genetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach. The MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history. Our study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9-62.3; p = 0.06). Our study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.

Effect of attention on the detection and identification of masked spatial patterns.

PubMed

Põder, Endel

2005-01-01

The effect of attention on the detection and identification of vertically and horizontally oriented Gabor patterns in the condition of simultaneous masking with obliquely oriented Gabors was studied. Attention was manipulated by varying the set size in a visual-search experiment. In the first experiment, small target Gabors were presented on the background of larger masking Gabors. In the detection task, the effect of set size was as predicted by unlimited-capacity signal detection theory. In the orientation identification task, increasing the set size from 1 to 8 resulted in a much larger decline in performance. The results of the additional experiments suggest that attention can reduce the crowding effect of maskers.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.

PubMed

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-Man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H-H; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B; Adair, Linda S; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; Chen, Yii-Der Ida; Shu, Xiao-Ou; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars G; Nielsen, Jonas Bille; Tse, Hung-Fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Kathiresan, Sekar; Mohlke, Karen L; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-12-01

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

Genetic variants of human serum cholinesterase influence metabolism of the muscle relaxant succinylcholine.

PubMed

Lockridge, O

1990-01-01

People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

New genetic variants of LATS1 detected in urinary bladder and colon cancer.

PubMed

Saadeldin, Mona K; Shawer, Heba; Mostafa, Ahmed; Kassem, Neemat M; Amleh, Asma; Siam, Rania

2014-01-01

LATS1, the large tumor suppressor 1 gene, encodes for a serine/threonine kinase protein and is implicated in cell cycle progression. LATS1 is down-regulated in various human cancers, such as breast cancer, and astrocytoma. Point mutations in LATS1 were reported in human sarcomas. Additionally, loss of heterozygosity of LATS1 chromosomal region predisposes to breast, ovarian, and cervical tumors. In the current study, we investigated LATS1 genetic variations including single nucleotide polymorphisms (SNPs), in 28 Egyptian patients with either urinary bladder or colon cancers. The LATS1 gene was amplified and sequenced and the expression of LATS1 at the RNA level was assessed in 12 urinary bladder cancer samples. We report, the identification of a total of 29 variants including previously identified SNPs within LATS1 coding and non-coding sequences. A total of 18 variants were novel. Majority of the novel variants, 13, were mapped to intronic sequences and un-translated regions of the gene. Four of the five novel variants located in the coding region of the gene, represented missense mutations within the serine/threonine kinase catalytic domain. Interestingly, LATS1 RNA steady state levels was lost in urinary bladder cancerous tissue harboring four specific SNPs (16045 + 41736 + 34614 + 56177) positioned in the 5'UTR, intron 6, and two silent mutations within exon 4 and exon 8, respectively. This study identifies novel single-base-sequence alterations in the LATS1 gene. These newly identified variants could potentially be used as novel diagnostic or prognostic tools in cancer.

Study on the crystallographic orientation relationship and formation mechanism of reversed austenite in economical Cr12 super martensitic stainless steel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, Dong; Li, Shaohong; Li, Jun

Effect of carbides and crystallographic orientation relationship on the formation mechanism of reversed austenite of economical Cr12 super martensitic stainless steel (SMSS) has been investigated mainly by transmission electron microscopy (TEM) and electron backscatter diffraction (EBSD). The results indicate that the M{sub 23}C{sub 6} precipitation and the formation of the reversed austenite have the interaction effect during tempering process in SMSS. The reversed austenite forms intensively at the sub-block boundary and the lath boundary within a misorientation range of 0–60°. M{sub 23}C{sub 6} has the same crystallographic orientation relationship with reversed austenite. There are two different kinds of formation modesmore » for reversed austenite. One is a nondiffusional shear reversion; the other is a diffusion transformation. Both are strictly limited by crystallographic orientation relationship. The austenite variants are limited to two kinds within one packet and five kinds within one prior austenite grain. - Highlights: • Reversed austenite forms at martensite boundaries with misorientation of 0–60° • M{sub 23}C{sub 6} precipitation and reversed austenite formation have the interaction effect. • Two austenite variants with different orientations can be formed inside a packet. • Two reversed austenite formation modes: shear reversion; diffusion transformation.« less

A Nonsense Variant in the ACADVL Gene in German Hunting Terriers with Exercise Induced Metabolic Myopathy.

PubMed

Lepori, Vincent; Mühlhause, Franziska; Sewell, Adrian C; Jagannathan, Vidhya; Janzen, Nils; Rosati, Marco; Alves de Sousa, Filipe Miguel Maximiano; Tschopp, Aurélie; Schüpbach, Gertraud; Matiasek, Kaspar; Tipold, Andrea; Leeb, Tosso; Kornberg, Marion

2018-05-04

Several enzymes are involved in fatty acid oxidation, which is a key process in mitochondrial energy production. Inherited defects affecting any step of fatty acid oxidation can result in clinical disease. We present here an extended family of German Hunting Terriers with 10 dogs affected by clinical signs of exercise induced weakness, muscle pain, and suspected rhabdomyolysis. The combination of clinical signs, muscle histopathology and acylcarnitine analysis with an elevated tetradecenoylcarnitine (C14:1) peak suggested a possible diagnosis of acyl-CoA dehydrogenase very long chain deficiency (ACADVLD). Whole genome sequence analysis of one affected dog and 191 controls revealed a nonsense variant in the ACADVL gene encoding acyl-CoA dehydrogenase very long chain, c.1728C>A or p.(Tyr576*). The variant showed perfect association with the phenotype in the 10 affected and more than 500 control dogs of various breeds. Pathogenic variants in the ACADVL gene have been reported in humans with similar myopathic phenotypes. We therefore considered the detected variant to be the most likely candidate causative variant for the observed exercise induced myopathy. To our knowledge, this is the first description of this disease in dogs, which we propose to name exercise induced metabolic myopathy (EIMM), and the identification of the first canine pathogenic ACADVL variant. Our findings provide a large animal model for a known human disease and will enable genetic testing to avoid the unintentional breeding of affected offspring. Copyright © 2018 Lepori et al.

Lost and forgotten? Orientation versus memory in Alzheimer's disease and frontotemporal dementia.

PubMed

Yew, Belinda; Alladi, Suvarna; Shailaja, Mekala; Hodges, John R; Hornberger, Michael

2013-01-01

Recent studies suggest that significant memory problems are not specific to Alzheimer's disease (AD) but can be also observed in other neurodegenerative conditions, such as behavioral variant frontotemporal dementia (bvFTD). We investigated whether orientation (spatial & temporal) information is a better diagnostic marker for AD compared to memory and whether their atrophy correlates of orientation and memory differ. A large sample (n = 190) of AD patients (n = 73), bvFTD patients (n = 54), and healthy controls (n = 63) underwent testing. A subset of the patients (n = 72) underwent structural imaging using voxel-based morphometry analysis of magnetic resonance brain imaging. Orientation and memory scores from the Addenbrooke's Cognitive Examination showed that AD patients had impaired orientation and memory, while bvFTD patients performing at control level for orientation but had impaired memory. A logistic regression showed that 78% of patients could be classified on the basis of orientation and memory scores alone at clinic presentation. Voxel-based morphometry analysis was conducted using orientation and memory scores as covariates, which showed that the neural correlates for orientation and memory also dissociated with posterior hippocampus cortex being related to orientation in AD, while the anterior hippocampus was associated with memory performance in the AD and bvFTD patients. Orientation and memory measures discriminate AD and bvFTD to a high degree and tap into different hippocampal regions. Disorientation and posterior hippocampus appears therefore specific to AD and will allow clinicians to discriminate AD patients from other neurodegenerative conditions with similar memory deficits at clinic presentation.

Three New Alpha1-Antitrypsin Deficiency Variants Help to Define a C-Terminal Region Regulating Conformational Change and Polymerization

PubMed Central

Fra, Anna M.; Gooptu, Bibek; Ferrarotti, Ilaria; Miranda, Elena; Scabini, Roberta; Ronzoni, Riccardo; Benini, Federica; Corda, Luciano; Medicina, Daniela; Luisetti, Maurizio; Schiaffonati, Luisa

2012-01-01

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state. PMID:22723858

Decoding the Effect of Isobaric Substitutions on Identifying Missing Proteins and Variant Peptides in Human Proteome.

PubMed

Choong, Wai-Kok; Lih, Tung-Shing Mamie; Chen, Yu-Ju; Sung, Ting-Yi

2017-12-01

To confirm the existence of missing proteins, we need to identify at least two unique peptides with length of 9-40 amino acids of a missing protein in bottom-up mass-spectrometry-based proteomic experiments. However, an identified unique peptide of the missing protein, even identified with high level of confidence, could possibly coincide with a peptide of a commonly observed protein due to isobaric substitutions, mass modifications, alternative splice isoforms, or single amino acid variants (SAAVs). Besides unique peptides of missing proteins, identified variant peptides (SAAV-containing peptides) could also alternatively map to peptides of other proteins due to the aforementioned issues. Therefore, we conducted a thorough comparative analysis on data sets in PeptideAtlas Tiered Human Integrated Search Proteome (THISP, 2017-03 release), including neXtProt (2017-01 release), to systematically investigate the possibility of unique peptides in missing proteins (PE2-4), unique peptides in dubious proteins, and variant peptides affected by isobaric substitutions, causing doubtful identification results. In this study, we considered 11 isobaric substitutions. From our analysis, we found <5% of the unique peptides of missing proteins and >6% of variant peptides became shared with peptides of PE1 proteins after isobaric substitutions.

Understanding the molecular aspects of oriental obesity pattern differentiation using DNA microarray.

PubMed

Hong, Sun Woo; Yoo, Jae-Wook; Bose, Shambhunath; Park, Jung-Hyun; Han, Kyungsun; Kim, Soyoun; Lim, Chi-Yeon; Kim, Hojun; Lee, Dong-Ki

2015-10-19

Human constitution, the fundamental basis of oriental medicine, is categorized into different patterns for a particular disease according to the physical, physiological, and clinical characteristics of the individuals. Obesity, a condition of metabolic disorder, is classified according to six patterns in oriental medicine, as follows: spleen deficiency syndrome, phlegm fluid syndrome, yang deficiency syndrome (YDS), food accumulation syndrome (FAS), liver depression syndrome (LDS), and blood stasis syndrome. In oriental medicine, identification of the disease pattern for individual obese patients is performed on the basis of differentiation in obesity syndrome index and, accordingly, personalized treatment is provided to the patients. The aim of the current study was to understand the obesity patterns in oriental medicine from the genomic point of view via determining the gene expression signature of obese patients using peripheral blood mononuclear cells as the samples. The study was conducted in 23 South Korean obese subjects (19 female and four male) with BMI ≥25 kg/m(2). Identification of oriental obesity pattern was based on the software-guided evaluation of the responses of the subjects to a questionnaire developed by the Korean Institute of Oriental Medicine. The expression profiles of genes were determined using DNA microarray and the level of transcription of genes of interest was further evaluated using quantitative real-time PCR (qRT-PCR). Gene clustering analysis of the microarray data from the FAS, LDS, and YDS subjects exhibited disease pattern-specific upregulation of expression of several genes in a particular cluster. Further analysis of transcription of selected genes using qRT-PCR led to identification of specific genes, including prostaglandin endoperoxide synthase 2, G0/G1 switch 2, carcinoembryonic antigen-related cell adhesion molecule 3, cystein-serine-rich nuclear protein 1, and interleukin 8 receptor, alpha which were highly expressed in

Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes

PubMed Central

Lam, Tze Hau; Tay, Matthew Zirui; Wang, Bei; Xiao, Ziwei; Ren, Ee Chee

2015-01-01

Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases. PMID:26593880

Identification of specific angiotensin-converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy.

PubMed

Ezzidi, Intissar; Mtiraoui, Nabil; Kacem, Maha; Chaieb, Molka; Mahjoub, Touhami; Almawi, Wassim Y

2009-11-01

Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups. We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based). Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates. Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus.

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women.

PubMed

Novak, David J; Chen, Long Qi; Ghadirian, Parviz; Hamel, Nancy; Zhang, Phil; Rossiny, Vanessa; Cardinal, Guy; Robidoux, André; Tonin, Patricia N; Rousseau, Francois; Narod, Steven A; Foulkes, William D

2008-08-15

BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population. The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques. Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73). The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women

PubMed Central

Novak, David J; Chen, Long Qi; Ghadirian, Parviz; Hamel, Nancy; Zhang, Phil; Rossiny, Vanessa; Cardinal, Guy; Robidoux, André; Tonin, Patricia N; Rousseau, Francois; Narod, Steven A; Foulkes, William D

2008-01-01

Background BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population. Methods The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques. Results Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73). Conclusion The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women. PMID:18706089

Molecular diagnosis of populational variants of Anthonomus grandis (Coleoptera: Curculionidae) in North America.

PubMed

Barr, Norman; Ruiz-Arce, Raul; Obregón, Oscar; De Leon, Rosita; Foster, Nelson; Reuter, Chris; Boratynski, Theodore; Vacek, Don

2013-02-01

The utility of the cytochrome oxidase I (COI) DNA sequence used for DNA barcoding and a Sequence Characterized Amplified Region for diagnosing boll weevil, Anthonomus grandis Boheman, variants was evaluated. Maximum likelihood analysis of COI DNA sequences from 154 weevils collected from the United States and Mexico supports previous evidence for limited gene flow between weevil populations on wild cotton and commercial cotton in northern Mexico and southern United States. The wild cotton populations represent a variant of the species called the thurberia weevil, which is not regarded as a significant pest. The 31 boll weevil COI haplotypes observed in the study form two distinct haplogroups (A and B) that are supported by five fixed nucleotide differences and a phylogenetic analysis. Although wild and commercial cotton populations are closely associated with specific haplogroups, there is not a fixed difference between the thurberia weevil variant and other populations. The Sequence Characterized Amplified Region marker generated a larger number of inconclusive results than the COI gene but also supported evidence of shared genotypes between wild and commercial cotton weevil populations. These methods provide additional markers that can assist in the identification of pest weevil populations but not definitively diagnose samples.

Identification of Differentially Expressed K-Ras Transcript Variants in Patients With Leiomyoma.

PubMed

Zolfaghari, Nooshin; Shahbazi, Shirin; Torfeh, Mahnaz; Khorasani, Maryam; Hashemi, Mehrdad; Mahdian, Reza

2017-10-01

Molecular studies have demonstrated a wide range of gene expression variations in uterine leiomyoma. The rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (RAS/RAF/MAPK) is the crucial cellular pathway in transmitting external signals into nucleus. Deregulation of this pathway contributes to excessive cell proliferation and tumorigenesis. The present study aims to investigate the expression profile of the K-Ras transcripts in tissue samples from patients with leiomyoma. The patients were leiomyoma cases who had no mutation in mediator complex subunit 12 ( MED12) gene. A quantitative approach has been applied to determine the difference in the expression of the 2 main K-Ras messenger RNA (mRNA) variants. The comparison between gene expression levels in leiomyoma and normal myometrium group was performed using relative expression software tool. The expression of K-Ras4B gene was upregulated in leiomyoma group ( P = .016), suggesting the involvement of K-Ras4B in the disease pathogenesis. Pairwise comparison of the K-Ras4B expression between each leiomyoma tissue and its matched adjacent normal myometrium revealed gene upregulation in 68% of the cases. The expression of K-Ras4A mRNA was relatively upregulated in leiomyoma group ( P = .030). In addition, the mean expression of K-Ras4A gene in leiomyoma tissues relative to normal samples was 4.475 (95% confidence interval: 0.10-20.42; standard error: 0.53-12.67). In total, 58% of the cases showed more than 2-fold increase in K-Ras4A gene expression. Our results demonstrated increased expression of both K-Ras mRNA splicing variants in leiomyoma tissue. However, the ultimate result of KRAS expression on leiomyoma development depends on the overall KRAS isoform balance and, consequently, on activated signaling pathways.

OPTICAL correlation identification technology applied in underwater laser imaging target identification

NASA Astrophysics Data System (ADS)

Yao, Guang-tao; Zhang, Xiao-hui; Ge, Wei-long

2012-01-01

the speed and orientation efficiency of target identification effectively, and validate the feasibility of this method primarily.

Screening of whole genome sequences identified high-impact variants for stallion fertility.

PubMed

Schrimpf, Rahel; Gottschalk, Maren; Metzger, Julia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

2016-04-14

Stallion fertility is an economically important trait due to the increase of artificial insemination in horses. The availability of whole genome sequence data facilitates identification of rare high-impact variants contributing to stallion fertility. The aim of our study was to genotype rare high-impact variants retrieved from next-generation sequencing (NGS)-data of 11 horses in order to unravel harmful genetic variants in large samples of stallions. Gene ontology (GO) terms and search results from public databases were used to obtain a comprehensive list of human und mice genes predicted to participate in the regulation of male reproduction. The corresponding equine orthologous genes were searched in whole genome sequence data of seven stallions and four mares and filtered for high-impact genetic variants using SnpEFF, SIFT and Polyphen 2 software. All genetic variants with the missing homozygous mutant genotype were genotyped on 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. Mixed linear model analysis was employed for an association analysis with de-regressed estimated breeding values of the paternal component of the pregnancy rate per estrus (EBV-PAT). We screened next generation sequenced data of whole genomes from 11 horses for equine genetic variants in 1194 human and mice genes involved in male fertility and linked through common gene ontology (GO) with male reproductive processes. Variants were filtered for high-impact on protein structure and validated through SIFT and Polyphen 2. Only those genetic variants were followed up when the homozygote mutant genotype was missing in the detection sample comprising 11 horses. After this filtering process, 17 single nucleotide polymorphism (SNPs) were left. These SNPs were genotyped in 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. An association analysis in 216 Hanoverian stallions revealed a significant association of the splice-site disruption variant

Enterovirus meningitis in Tunisia (Monastir, Mahdia, 2011-2013): identification of virus variants cocirculating in France.

PubMed

Othman, Ines; Volle, Romain; Elargoubi, Aida; Guediche, Mohamed Neji; Chakroun, Mohamed; Sfar, Mohamed Tahar; Pereira, Bruno; Peigue-Lafeuille, Hélène; Aouni, Mahjoub; Archimbaud, Christine; Bailly, Jean-Luc

2016-02-01

Acute enterovirus (EV) meningitis is a frequent cause of hospitalisation, and over 100 EV serotypes may be involved. A total of 215 patients of all ages with meningitis signs were investigated in 2 Tunisian hospitals. Their cerebrospinal fluid (CSF) was analysed retrospectively for EVs with a TaqMan real-time RT-qPCR. The virus strains were typed, and their evolutionary relationships were determined by Bayesian phylogenetic methods. An EV genome was detected in 21/215 patients (9.8%). The CSF viral loads ranged from 3.27 to 5.63 log10 genome copies/mL. The strains were identified in 13/21 patients and assigned to EV-B types. Viruses identified in Tunisian patients were genetically related to variants detected in France. The viral loads were similar in Tunisian and French patients for most EV types. The phylogenetic data and viral loads determined in Tunisian and French patients suggest that close EV variants were involved in aseptic meningitis in the 2 countries over a same period. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties

DOE PAGES

Ye, Changhuai; Wang, Chao; Wang, Jing; ...

2017-08-17

Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (V ZA) of this gradient significantly impacts the extent of crystal orientation. Here in this work, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of V ZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi-crystalline polymer. These RZA results aremore » confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. Lastly, RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics.« less

Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, Changhuai; Wang, Chao; Wang, Jing

Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (V ZA) of this gradient significantly impacts the extent of crystal orientation. Here in this work, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of V ZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi-crystalline polymer. These RZA results aremore » confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. Lastly, RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics.« less

A near full-length open reading frame next generation sequencing assay for genotyping and identification of resistance-associated variants in hepatitis C virus.

PubMed

Pedersen, M S; Fahnøe, U; Hansen, T A; Pedersen, A G; Jenssen, H; Bukh, J; Schønning, K

2018-06-01

The current treatment options for hepatitis C virus (HCV), based on direct acting antivirals (DAA), are dependent on virus genotype and previous treatment experience. Treatment failures have been associated with detection of resistance-associated substitutions (RASs) in the DAA targets of HCV, the NS3, NS5A and NS5 B proteins. To develop a next generation sequencing based method that provides genotype and detection of HCV NS3, NS5A, and NS5 B RASs without prior knowledge of sample genotype. In total, 101 residual plasma samples from patients with HCV covering 10 different viral subtypes across 4 genotypes with viral loads of 3.84-7.61 Log IU/mL were included. All samples were de-identified and consequently prior treatment status for patients was unknown. Almost full open reading frame amplicons (∼ 9 kb) were generated using RT-PCR with a single primer set. The resulting amplicons were sequenced with high throughput sequencing and analysed using an in-house developed script for detecting RASs. The method successfully amplified and sequenced 94% (95/101) of samples with an average coverage of 14,035; four of six failed samples were genotype 4a. Samples analysed twice yielded reproducible nucleotide frequencies across all sites. RASs were detected in 21/95 (22%) samples at a 15% threshold. The method identified one patient infected with two genotype 2b variants, and the presence of subgenomic deletion variants in 8 (8.4%) of 95 successfully sequenced samples. The presented method may provide identification of HCV genotype, RASs detection, and detect multiple HCV infection without prior knowledge of sample genotype. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessing Politicized Sexual Orientation Identity: Validating the Queer Consciousness Scale.

PubMed

Duncan, Lauren E; Mincer, Elizabeth; Dunn, Sarah R

2017-01-01

Building on psychological theories of motivation for collective action, we introduce a new individual difference measure of queer consciousness, defined as a politicized collective identity around sexual orientation. The Queer Consciousness Scale (QCS) consists of 12 items measuring five aspects of a politicized queer identity: sense of common fate, power discontent, system blame, collective orientation, and cognitive centrality. In four samples of adult women and men of varied sexual orientations, the QCS showed good test-retest and Cronbach's reliability and excellent known-groups and predictive validity. Specifically, the QCS was positively correlated with identification as a member of the LGBTQ community, political liberalism, personal political salience, and LGBTQ activism and negatively correlated with right-wing authoritarianism and social dominance orientation. QCS mediated relationships between several individual difference variables and gay rights activism and can be used with both LGBTQ people and allies.

Auditory orienting of attention: Effects of cues and verbal workload with children and adults.

PubMed

Phélip, Marion; Donnot, Julien; Vauclair, Jacques

2016-01-01

The use of tone cues has an improving effect on the auditory orienting of attention for children as for adults. Verbal cues, on the contrary, do not seem to orient attention as efficiently before the age of 9 years. However, several studies have reported inconsistent effects of orienting attention on ear asymmetries. Multiple factors are questioned, such as the role of verbal workload. Indeed, the semantic nature of the dichotic pairs and their load of processing may explain orienting of attention performance. Thus, by controlling for the role of verbal workload, the present experiment aimed to evaluate the development of capacities for the auditory orienting of attention. Right-handed, 6- to 12-year-olds and adults were recruited to complete either a tone cue or a verbal cue dichotic listening task in the identification of familiar words or nonsense words. A factorial design analysis of variance showed a significant right-ear advantage for all the participants and for all the types of stimuli. A major developmental effect was observed in which verbal cues played an important role: they allowed the 6- to 8-year-olds to improve their performance of identification in the left ear. These effects were taken as evidence of the implication of top-down processes in cognitive flexibility across development.

Beyond Same-Sex Attraction: Gender-Variant-Based Victimization Is Associated with Suicidal Behavior and Substance Use for Other-Sex Attracted Adolescents

PubMed Central

Chen, Peter Y.; Cigularov, Konstantin P.; Tomazic, Rocco G.

2015-01-01

Gender-variant-based victimization is victimization based on the way others perceive an individual to convey masculine, feminine, and androgynous characteristics through their appearance, mannerisms, and behaviors. Previous work identifies gender-variant-based victimization as a risk factor for health-risking outcomes among same-sex attracted youths. The current study seeks to examine this relationship among other-sex attracted youths and same-sex attracted youth, and determine if gender-variant-based victimization is similarly or differentially associated with poor outcomes between these two groups. Anonymous data from a school-based survey of 2,438 racially diverse middle and high school students in the Eastern U.S. was examined. For other-sex attracted adolescents, gender-variant-based victimization was associated with a higher odds of suicidal thoughts and behaviors, regular use of cigarettes, and drug use. When compared to same-sex attracted adolescents, the harmful relationship between gender-variant-based victimization and each of these outcomes was similar in nature. These findings suggest that gender-variant-based victimization has potentially serious implications for the psychological wellbeing and substance use of other-sex attracted adolescents, not just same-sex attracted adolescents, supporting the need to address gender expression as a basis for victimization separate from sexuality- or gender-minority status. The impact that gender-variant-based victimization has on all adolescents should not be overlooked in research and interventions aimed at addressing sexual orientation-based and gender-variant-based victimization, substance use, and suicide prevention. PMID:26068796

Novel genetic risk variants for pediatric celiac disease.

PubMed

Balasopoulou, Angeliki; Stanković, Biljana; Panagiotara, Angeliki; Nikčevic, Gordana; Peters, Brock A; John, Anne; Mendrinou, Effrosyni; Stratopoulos, Apostolos; Legaki, Aigli Ioanna; Stathakopoulou, Vasiliki; Tsolia, Aristoniki; Govaris, Nikolaos; Govari, Sofia; Zagoriti, Zoi; Poulas, Konstantinos; Kanariou, Maria; Constantinidou, Nikki; Krini, Maro; Spanou, Kleopatra; Radlovic, Nedeljko; Ali, Bassam R; Borg, Joseph; Drmanac, Radoje; Chrousos, George; Pavlovic, Sonja; Roma, Eleftheria; Zukic, Branka; Patrinos, George P; Katsila, Theodora

2016-10-24

Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing.

PubMed

Schrijver, Iris; Pique, Lynn; Graham, Steve; Pearl, Michelle; Cherry, Athena; Kharrazi, Martin

2016-01-01

Despite the implementation of cystic fibrosis (CF) newborn screening programs across the United States, the identification of CFTR gene variants in nonwhite populations compared with whites remains suboptimal. Our objective was to establish the spectrum of CFTR variants and their frequencies in CF patients in the United States with African, Native American, Asian, East Indian, or Middle Eastern backgrounds. By using direct DNA sequencing, we identified two CFTR variants in 89 of 140 affected nonwhite individuals with uncharacterized genotypes. Seven variants were novel. Multiplex ligation-dependent probe amplification detected 14 rearrangements in the remaining 51 patients, 6 of which were novel. Deletions and duplications accounted for 17% of unidentified alleles. A cross-sectional analysis of genotyping data from the CF Foundation Patient Registry was performed, comparing 3496 nonwhite patients with 22,206 white CF patients. Patients of Hispanic, black, or Asian ancestry were less likely to have two identified CFTR variants (P < 0.0001 for Hispanics and blacks, P = 0.003 for Asians), and more likely to carry no mutations on the commonly used 23 mutation carrier screening panel (P < 0.0001). We analyzed the mutations recorded for each ancestry and summarized the most frequent ones. This research could facilitate equity in mutation detection between white and nonwhite or mixed-ethnicity CF patients, enabling an earlier diagnosis improving their quality of life. Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

A Novel β-Globin Chain Hemoglobin Variant, Hb Allentown [β137(H15)Val→Trp (GTG>TGG) HBB: c.412_413delinsTG, p.Val138Trp], Associated with Low Oxygen Saturation, Intermittent Aplastic Crises and Splenomegaly.

PubMed

Collier, Anderson B; Coon, Lea M; Monteleone, Philip; Umaru, Samuel; Swanson, Kenneth C; Hoyer, James D; Oliveira, Jennifer L

2016-01-01

Hemoglobin (Hb) variants may be associated with low oxygen saturation and exacerbated episodes of anemia from common stressors such as viral infections. These attributes frequently cause increased clinical concern and unnecessary and expensive testing if not considered early in the evaluation of the patient. Some clinically significant Hb variants result in a normal Hb electrophoresis result, which can be method-dependent. Herein we describe a patient with low oxygen saturation and a history of hemolytic anemia who was subsequently found to carry a novel, unstable β-globin variant that we have named Hb Allentown [β137(H15)Val→Trp (GTG>TGG) HBB: c.412_413delinsTG, p.Val138Trp] for the place of identification of the variant. Hb Allentown is formed by a rare double nucleotide substitution within the same codon. Additionally, positive identification of rare Hb variants characterized by a single method is discouraged, as the Hb variant was misclassified as Hb S-South End or β6(A3)Glu→Val;β132(H10)Lys→Asn (HBB: c.[20A > T;399A > C]) by the initial laboratory.

In-situ neutron diffraction study of martensitic variant redistribution in polycrystalline Ni-Mn-Ga alloy under cyclic thermo-mechanical treatment

NASA Astrophysics Data System (ADS)

Li, Zongbin; Zhang, Yudong; Esling, Claude; Gan, Weimin; Zou, Naifu; Zhao, Xiang; Zuo, Liang

2014-07-01

The influences of uniaxial compressive stress on martensitic transformation were studied on a polycrystalline Ni-Mn-Ga bulk alloy prepared by directional solidification. Based upon the integrated in-situ neutron diffraction measurements, direct experimental evidence was obtained on the variant redistribution of seven-layered modulated (7M) martensite, triggered by external uniaxial compression during martensitic transformation. Large anisotropic lattice strain, induced by the cyclic thermo-mechanical treatment, has led to the microstructure modification by forming martensitic variants with a strong ⟨0 1 0⟩7M preferential orientation along the loading axis. As a result, the saturation of magnetization became easier to be reached.

In-situ neutron diffraction study of martensitic variant redistribution in polycrystalline Ni-Mn-Ga alloy under cyclic thermo-mechanical treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Zongbin; Zou, Naifu; Zhao, Xiang

2014-07-14

The influences of uniaxial compressive stress on martensitic transformation were studied on a polycrystalline Ni-Mn-Ga bulk alloy prepared by directional solidification. Based upon the integrated in-situ neutron diffraction measurements, direct experimental evidence was obtained on the variant redistribution of seven-layered modulated (7M) martensite, triggered by external uniaxial compression during martensitic transformation. Large anisotropic lattice strain, induced by the cyclic thermo-mechanical treatment, has led to the microstructure modification by forming martensitic variants with a strong 〈0 1 0〉{sub 7M} preferential orientation along the loading axis. As a result, the saturation of magnetization became easier to be reached.

Common breast cancer risk variants in the post-COGS era: a comprehensive review.

PubMed

Maxwell, Kara N; Nathanson, Katherine L

2013-12-20

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene-environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of

Common breast cancer risk variants in the post-COGS era: a comprehensive review

PubMed Central

2013-01-01

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene–environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of

Identification of Nitrogen Consumption Genetic Variants in Yeast Through QTL Mapping and Bulk Segregant RNA-Seq Analyses.

PubMed

Cubillos, Francisco A; Brice, Claire; Molinet, Jennifer; Tisné, Sebastién; Abarca, Valentina; Tapia, Sebastián M; Oporto, Christian; García, Verónica; Liti, Gianni; Martínez, Claudio

2017-06-07

Saccharomyces cerevisiae is responsible for wine must fermentation. In this process, nitrogen represents a limiting nutrient and its scarcity results in important economic losses for the wine industry. Yeast isolates use different strategies to grow in poor nitrogen environments and their genomic plasticity enables adaptation to multiple habitats through improvements in nitrogen consumption. Here, we used a highly recombinant S. cerevisiae multi-parent population (SGRP-4X) derived from the intercross of four parental strains of different origins to identify new genetic variants responsible for nitrogen consumption differences during wine fermentation. Analysis of 165 fully sequenced F12 segregants allowed us to map 26 QTL in narrow intervals for 14 amino acid sources and ammonium, the majority of which represent genomic regions previously unmapped for these traits. To complement this strategy, we performed Bulk segregant RNA-seq (BSR-seq) analysis in segregants exhibiting extremely high and low ammonium consumption levels. This identified several QTL overlapping differentially expressed genes and refined the gene candidate search. Based on these approaches, we were able to validate ARO1 , PDC1 , CPS1 , ASI2 , LYP1 , and ALP1 allelic variants underlying nitrogen consumption differences between strains, providing evidence of many genes with small phenotypic effects. Altogether, these variants significantly shape yeast nitrogen consumption with important implications for evolution, ecological, and quantitative genomics. Copyright © 2017 Cubillos et al.

Identification of Nitrogen Consumption Genetic Variants in Yeast Through QTL Mapping and Bulk Segregant RNA-Seq Analyses

PubMed Central

Cubillos, Francisco A.; Brice, Claire; Molinet, Jennifer; Tisné, Sebastién; Abarca, Valentina; Tapia, Sebastián M.; Oporto, Christian; García, Verónica; Liti, Gianni; Martínez, Claudio

2017-01-01

Saccharomyces cerevisiae is responsible for wine must fermentation. In this process, nitrogen represents a limiting nutrient and its scarcity results in important economic losses for the wine industry. Yeast isolates use different strategies to grow in poor nitrogen environments and their genomic plasticity enables adaptation to multiple habitats through improvements in nitrogen consumption. Here, we used a highly recombinant S. cerevisiae multi-parent population (SGRP-4X) derived from the intercross of four parental strains of different origins to identify new genetic variants responsible for nitrogen consumption differences during wine fermentation. Analysis of 165 fully sequenced F12 segregants allowed us to map 26 QTL in narrow intervals for 14 amino acid sources and ammonium, the majority of which represent genomic regions previously unmapped for these traits. To complement this strategy, we performed Bulk segregant RNA-seq (BSR-seq) analysis in segregants exhibiting extremely high and low ammonium consumption levels. This identified several QTL overlapping differentially expressed genes and refined the gene candidate search. Based on these approaches, we were able to validate ARO1, PDC1, CPS1, ASI2, LYP1, and ALP1 allelic variants underlying nitrogen consumption differences between strains, providing evidence of many genes with small phenotypic effects. Altogether, these variants significantly shape yeast nitrogen consumption with important implications for evolution, ecological, and quantitative genomics. PMID:28592651

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

PubMed

Emdin, Connor A; Khera, Amit V; Chaffin, Mark; Klarin, Derek; Natarajan, Pradeep; Aragam, Krishna; Haas, Mary; Bick, Alexander; Zekavat, Seyedeh M; Nomura, Akihiro; Ardissino, Diego; Wilson, James G; Schunkert, Heribert; McPherson, Ruth; Watkins, Hugh; Elosua, Roberto; Bown, Matthew J; Samani, Nilesh J; Baber, Usman; Erdmann, Jeanette; Gupta, Namrata; Danesh, John; Chasman, Daniel; Ridker, Paul; Denny, Joshua; Bastarache, Lisa; Lichtman, Judith H; D'Onofrio, Gail; Mattera, Jennifer; Spertus, John A; Sheu, Wayne H-H; Taylor, Kent D; Psaty, Bruce M; Rich, Stephen S; Post, Wendy; Rotter, Jerome I; Chen, Yii-Der Ida; Krumholz, Harlan; Saleheen, Danish; Gabriel, Stacey; Kathiresan, Sekar

2018-04-24

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

A new genus and three new species of tribe Oxycerini (Diptera: Stratiomyidae) from Oriental region.

PubMed

Yang, Zai-Hua; Rozkošný, Rudolf; Yang, Mao-Fa

2015-12-09

Oxyceroides gen. nov., including three new species, O. gracilis sp. nov., O. sinica sp. nov. and O. tangi sp. nov. from South China in the Oriental region are described and illustrated. Related genera from other biogeographical realms are briefly discussed. Identification keys to the known Oriental Oxycerini and to the three new species of Oxyceroides are given.

Pharmacogenetics and target identification in diabetes.

PubMed

Pearson, Ewan R

2018-02-24

In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Lepton identification at particle flow oriented detector for the future e+e- Higgs factories

NASA Astrophysics Data System (ADS)

Yu, Dan; Ruan, Manqi; Boudry, Vincent; Videau, Henri

2017-09-01

The lepton identification is essential for the physics programs at high-energy frontier, especially for the precise measurement of the Higgs boson. For this purpose, a toolkit for multivariate data analysis (TMVA) based lepton identification (LICH) has been developed for detectors using high granularity calorimeters. Using the conceptual detector geometry for the Circular Electron-Positron Collider (CEPC) and single charged particle samples with energy larger than 2 GeV, LICH identifies electrons/muons with efficiencies higher than 99.5% and controls the mis-identification rate of hadron to muons/electrons to better than 1/0.5%. Reducing the calorimeter granularity by 1-2 orders of magnitude, the lepton identification performance is stable for particles with E > 2 GeV. Applied to fully simulated eeH/μ μ H events, the lepton identification performance is consistent with the single particle case: the efficiency of identifying all the high energy leptons in an event, is 95.5-98.5%.

Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases

PubMed Central

2014-01-01

phagocytosis. Additionally, this study provides a new example of the identification of rare variants in common-allele-associated loci, which, because of their extremely low frequencies, are not statistically associated. However, the demonstration of their functional effects adds support to their contribution to disease risk, and questions the current notion of dismissing the contribution of very rare variants on purely statistical analyses. PMID:24886912

A statistical method for the detection of variants from next-generation resequencing of DNA pools.

PubMed

Bansal, Vikas

2010-06-15

Next-generation sequencing technologies have enabled the sequencing of several human genomes in their entirety. However, the routine resequencing of complete genomes remains infeasible. The massive capacity of next-generation sequencers can be harnessed for sequencing specific genomic regions in hundreds to thousands of individuals. Sequencing-based association studies are currently limited by the low level of multiplexing offered by sequencing platforms. Pooled sequencing represents a cost-effective approach for studying rare variants in large populations. To utilize the power of DNA pooling, it is important to accurately identify sequence variants from pooled sequencing data. Detection of rare variants from pooled sequencing represents a different challenge than detection of variants from individual sequencing. We describe a novel statistical approach, CRISP [Comprehensive Read analysis for Identification of Single Nucleotide Polymorphisms (SNPs) from Pooled sequencing] that is able to identify both rare and common variants by using two approaches: (i) comparing the distribution of allele counts across multiple pools using contingency tables and (ii) evaluating the probability of observing multiple non-reference base calls due to sequencing errors alone. Information about the distribution of reads between the forward and reverse strands and the size of the pools is also incorporated within this framework to filter out false variants. Validation of CRISP on two separate pooled sequencing datasets generated using the Illumina Genome Analyzer demonstrates that it can detect 80-85% of SNPs identified using individual sequencing while achieving a low false discovery rate (3-5%). Comparison with previous methods for pooled SNP detection demonstrates the significantly lower false positive and false negative rates for CRISP. Implementation of this method is available at http://polymorphism.scripps.edu/~vbansal/software/CRISP/.

Identification and characterization of a human smad3 splicing variant lacking part of the linker region.

PubMed

Kjellman, Christian; Honeth, Gabriella; Järnum, Sofia; Lindvall, Magnus; Darabi, Anna; Nilsson, Ingar; Edvardsen, Klaus; Salford, Leif G; Widegren, Bengt

2004-03-03

Smad3 is one of the signal transducers that are activated in response to transforming growth factor-beta (TGF-beta). We have identified and characterized a splicing variant of smad3. The splicing variant (smad3-Delta3) lacks exon 3 resulting in a truncated linker region. We could detect mRNA expression of smad3-Delta3 in all investigated human tissues. Real-time PCR analyses demonstrated that the fraction of smad3-Delta3 mRNA compared to normal smad3 varies between tissues. The amount of spliced mRNA was estimated to represent 0.5-5% of the normal smad3 mRNA. When smad3-Delta3 is overexpressed in a fibrosarcoma cell line, the Smad3-Delta3 is translocated to the nucleus upon TGF-beta stimulation and binds the Smad responsive element. Using a CAGA luciferase reporter system, we demonstrate that Smad3-Delta3 has transcriptional activity and we conclude that Smad3-Delta3 possesses functional transactivating properties.

Meta-analysis of gene-level associations for rare variants based on single-variant statistics.

PubMed

Hu, Yi-Juan; Berndt, Sonja I; Gustafsson, Stefan; Ganna, Andrea; Hirschhorn, Joel; North, Kari E; Ingelsson, Erik; Lin, Dan-Yu

2013-08-08

Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Connecting Self-Esteem and Achievement: Diversity in Academic Identification and Dis-Identification Patterns among Black College Students

ERIC Educational Resources Information Center

Hope, Elan C.; Chavous, Tabbye M.; Jagers, Robert J.; Sellers, Robert M.

2013-01-01

Using a person-oriented approach, we explored patterns of self-esteem and achievement among 324 Black college students across the freshman college year and identified four academic identification profiles. Multivariate analyses revealed profile differences in academic and psychological outcomes at beginning and end of freshman year (academic…

Identification and functional activity of a staphylocoagulase type XI variant originating from staphylococcal food poisoning isolates.

PubMed

Suzuki, Y; Matsushita, S; Kubota, H; Kobayashi, M; Murauchi, K; Higuchi, Y; Kato, R; Hirai, A; Sadamasu, K

2016-09-01

Staphylocoagulase, an extracellular protein secreted by Staphylococcus aureus, has been used as an epidemiological marker. At least 12 serotypes and 24 genotypes subdivided on the basis of nucleotide sequence have been reported to date. In this study, we identified a novel staphylocoagulase nucleotide sequence, coa310, from staphylococcal food poisoning isolates that had the ability to coagulate plasma, but could not be typed using the conventional method. The protein encoded by coa310 contained the six fundamental conserved domains of staphylocoagulase. The full-length nucleotide sequence of coa310 shared the highest similarity (77·5%) with that of staphylocoagulase-type (SCT) XIa. The sequence of the D1 region, which would be responsible for the determination of SCT, shared the highest similarity (91·8%) with that of SCT XIa. These results suggest that coa310 is a novel variant of SCT XI. Moreover, we demonstrated that coa310 encodes a functioning coagulase, by confirming the coagulating activity of the recombinant protein expressed from coa310. This is the first study to directly demonstrate that Coa310, a putative SCT XI, has coagulating activity. These findings may be useful for the improvement of the staphylocoagulase-typing method, including serotyping and genotyping. This is the first study to identify a novel variant of staphylocoagulase type XI based on its nucleotide sequence and to demonstrate coagulating activity in the variant using a recombinant protein. Elucidation of the variety of staphylocoagulases will provide suggestions for further improvement of the staphylocoagulase-typing method and contribute to our understanding of the epidemiologic characterization of Staphylococcus aureus. © 2016 The Society for Applied Microbiology.

Beta-glucosidase I variants with improved properties

DOEpatents

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.

Shock Condition Forensics and Cryptic Phase Transformations from Crystallographic Orientation Relationships in Zircon

NASA Astrophysics Data System (ADS)

Timms, N. E.; Erickson, T. M.; Cavosie, A. J.; Pearce, M. A.; Reddy, S. M.; Zanetti, M.; Tohver, E.; Schmieder, M.; Nemchin, A. A.; Wittmann, A.

2016-08-01

We present an approach to constrain pressure and temperature conditions during impact events involving identification of cryptic histories of phase transformations from orientation relationships in shocked zircon, linked to new P-T phase diagrams.

FOXG1 Is Responsible for the Congenital Variant of Rett Syndrome

PubMed Central

Ariani, Francesca; Hayek, Giuseppe; Rondinella, Dalila; Artuso, Rosangela; Mencarelli, Maria Antonietta; Spanhol-Rosseto, Ariele; Pollazzon, Marzia; Buoni, Sabrina; Spiga, Ottavia; Ricciardi, Sara; Meloni, Ilaria; Longo, Ilaria; Mari, Francesca; Broccoli, Vania; Zappella, Michele; Renieri, Alessandra

2008-01-01

Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization. PMID:18571142

A Novel, In-solution Separation of Endogenous Cardiac Sarcomeric Proteins and Identification of Distinct Charged Variants of Regulatory Light Chain*

PubMed Central

Scruggs, Sarah B.; Reisdorph, Rick; Armstrong, Mike L.; Warren, Chad M.; Reisdorph, Nichole; Solaro, R. John; Buttrick, Peter M.

2010-01-01

The molecular conformation of the cardiac myosin motor is modulated by intermolecular interactions among the heavy chain, the light chains, myosin binding protein-C, and titin and is governed by post-translational modifications (PTMs). In-gel digestion followed by LC/MS/MS has classically been applied to identify cardiac sarcomeric PTMs; however, this approach is limited by protein size, pI, and difficulties in peptide extraction. We report a solution-based work flow for global separation of endogenous cardiac sarcomeric proteins with a focus on the regulatory light chain (RLC) in which specific sites of phosphorylation have been unclear. Subcellular fractionation followed by OFFGEL electrophoresis resulted in isolation of endogenous charge variants of sarcomeric proteins, including regulatory and essential light chains, myosin heavy chain, and myosin-binding protein-C of the thick filament. Further purification of RLC using reverse-phase HPLC separation and UV detection enriched for RLC PTMs at the intact protein level and provided a stoichiometric and quantitative assessment of endogenous RLC charge variants. Digestion and subsequent LC/MS/MS unequivocally identified that the endogenous charge variants of cardiac RLC focused in unique OFFGEL electrophoresis fractions were unphosphorylated (78.8%), singly phosphorylated (18.1%), and doubly phosphorylated (3.1%) RLC. The novel aspects of this study are that 1) milligram amounts of endogenous cardiac sarcomeric subproteome were focused with resolution comparable with two-dimensional electrophoresis, 2) separation and quantification of post-translationally modified variants were achieved at the intact protein level, 3) separation of intact high molecular weight thick filament proteins was achieved in solution, and 4) endogenous charge variants of RLC were separated; a novel doubly phosphorylated form was identified in mouse, and singly phosphorylated, singly deamidated, and deamidated/phosphorylated forms were

Identification of OCTN2 variants and their association with phenotypes of Crohn’s disease in a Korean population

PubMed Central

Park, Hyo Jin; Jung, Eun Suk; Kong, Kyoung Ae; Park, Eun-Mi; Cheon, Jae Hee; Choi, Ji Ha

2016-01-01

Crohn’s disease (CD) is a chronic inflammatory bowel disease and a genetic variant in the OCTN2, g.-207G > C is significantly associated with CD susceptibility. This study was aimed to identify novel OCTN2 functional promoter variants and their roles in transcriptional regulation using various in vitro assays. In addition, we investigated the association between OCTN2 genotypes and CD through genetic analysis using DNA samples from 193 patients with CD and 281 healthy controls. Among the three major promoter haplotypes of OCTN2 identified, one haplotype, H3, showed a significant decrease in promoter activity: two polymorphisms in H3 were associated with a significant reduction in promoter activity. In particular, we found that the reduced transcriptional activity of those two polymorphisms results from a reduction in the binding affinity of the activators, NF-E2 and YY1, to the OCTN2 promoter. The functional haplotype of the OCTN2 promoter was associated with clinical course of CD such as the disease behavior and need for surgery. However, genetic variants or haplotypes of OCTN2 did not affect the susceptibility to CD. Our results suggest that a common promoter haplotype of OCTN2 regulates the transcriptional rate of OCTN2 and influences the clinical course of CD. PMID:26965072

Combined non-parametric and parametric approach for identification of time-variant systems

NASA Astrophysics Data System (ADS)

Dziedziech, Kajetan; Czop, Piotr; Staszewski, Wieslaw J.; Uhl, Tadeusz

2018-03-01

Identification of systems, structures and machines with variable physical parameters is a challenging task especially when time-varying vibration modes are involved. The paper proposes a new combined, two-step - i.e. non-parametric and parametric - modelling approach in order to determine time-varying vibration modes based on input-output measurements. Single-degree-of-freedom (SDOF) vibration modes from multi-degree-of-freedom (MDOF) non-parametric system representation are extracted in the first step with the use of time-frequency wavelet-based filters. The second step involves time-varying parametric representation of extracted modes with the use of recursive linear autoregressive-moving-average with exogenous inputs (ARMAX) models. The combined approach is demonstrated using system identification analysis based on the experimental mass-varying MDOF frame-like structure subjected to random excitation. The results show that the proposed combined method correctly captures the dynamics of the analysed structure, using minimum a priori information on the model.

Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

PubMed

Bustamante, M Leonor; Herrera, Luisa; Gaspar, Pablo A; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

2017-10-01

Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. © 2017 Wiley Periodicals, Inc.

Variants of cellobiohydrolases

DOEpatents

Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

2018-04-10

Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome.

PubMed

Yamamoto, Guilherme Lopes; Aguena, Meire; Gos, Monika; Hung, Christina; Pilch, Jacek; Fahiminiya, Somayyeh; Abramowicz, Anna; Cristian, Ingrid; Buscarilli, Michelle; Naslavsky, Michel Satya; Malaquias, Alexsandra C; Zatz, Mayana; Bodamer, Olaf; Majewski, Jacek; Jorge, Alexander A L; Pereira, Alexandre C; Kim, Chong Ae; Passos-Bueno, Maria Rita; Bertola, Débora Romeo

2015-06-01

Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases. A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently. We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations. We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Ureter smooth muscle cell orientation in rat is predominantly longitudinal.

PubMed

Spronck, Bart; Merken, Jort J; Reesink, Koen D; Kroon, Wilco; Delhaas, Tammo

2014-01-01

In ureter peristalsis, the orientation of the contracting smooth muscle cells is essential, yet current descriptions of orientation and composition of the smooth muscle layer in human as well as in rat ureter are inconsistent. The present study aims to improve quantification of smooth muscle orientation in rat ureters as a basis for mechanistic understanding of peristalsis. A crucial step in our approach is to use two-photon laser scanning microscopy and image analysis providing objective, quantitative data on smooth muscle cell orientation in intact ureters, avoiding the usual sectioning artifacts. In 36 rat ureter segments, originating from a proximal, middle or distal site and from a left or right ureter, we found close to the adventitia a well-defined longitudinal smooth muscle orientation. Towards the lamina propria, the orientation gradually became slightly more disperse, yet the main orientation remained longitudinal. We conclude that smooth muscle cell orientation in rat ureter is predominantly longitudinal, though the orientation gradually becomes more disperse towards the proprial side. These findings do not support identification of separate layers. The observed longitudinal orientation suggests that smooth muscle contraction would rather cause local shortening of the ureter, than cause luminal constriction. However, the net-like connective tissue of the ureter wall may translate local longitudinal shortening into co-local luminal constriction, facilitating peristalsis. Our quantitative, minimally invasive approach is a crucial step towards more mechanistic insight into ureter peristalsis, and may also be used to study smooth muscle cell orientation in other tube-like structures like gut and blood vessels.

Comparability of Essay Question Variants

ERIC Educational Resources Information Center

Bridgeman, Brent; Trapani, Catherine; Bivens-Tatum, Jennifer

2011-01-01

Writing task variants can increase test security in high-stakes essay assessments by substantially increasing the pool of available writing stimuli and by making the specific writing task less predictable. A given prompt (parent) may be used as the basis for one or more different variants. Six variant types based on argument essay prompts from a…

A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.

PubMed

Schoch, Kelly; Meng, Linyan; Szelinger, Szabolcs; Bearden, David R; Stray-Pedersen, Asbjorg; Busk, Oyvind L; Stong, Nicholas; Liston, Eriskay; Cohn, Ronald D; Scaglia, Fernando; Rosenfeld, Jill A; Tarpinian, Jennifer; Skraban, Cara M; Deardorff, Matthew A; Friedman, Jeremy N; Akdemir, Zeynep Coban; Walley, Nicole; Mikati, Mohamad A; Kranz, Peter G; Jasien, Joan; McConkie-Rosell, Allyn; McDonald, Marie; Wechsler, Stephanie Burns; Freemark, Michael; Kansagra, Sujay; Freedman, Sharon; Bali, Deeksha; Millan, Francisca; Bale, Sherri; Nelson, Stanley F; Lee, Hane; Dorrani, Naghmeh; Goldstein, David B; Xiao, Rui; Yang, Yaping; Posey, Jennifer E; Martinez-Agosto, Julian A; Lupski, James R; Wangler, Michael F; Shashi, Vandana

2017-02-02

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10 -14 ). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1. Copyright © 2017 American Society of Human Genetics. All rights reserved.

Variants of beta-glucosidase

DOEpatents

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.

Variants of beta-glucosidases

DOEpatents

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.

Variants of beta-glucosidase

DOEpatents

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.

Pooled-DNA Sequencing for Elucidating New Genomic Risk Factors, Rare Variants Underlying Alzheimer's Disease.

PubMed

Jin, Sheng Chih; Benitez, Bruno A; Deming, Yuetiva; Cruchaga, Carlos

2016-01-01

20:1711, 2010), for accurate identification of rare variants in large DNA pools. Given an average sequencing coverage of 30× per haploid genome, SPLINTER can detect rare variants and short indels up to 4 base pairs (bp) with high sensitivity and specificity (up to 1 haploid allele in a pool as large as 500 individuals). Step-by-step instructions on how to conduct pooled-DNA sequencing experiments and data analyses are described in this chapter.

Identification and characterization of yak (Bos grunniens) b-Boule gene and its alternative splice variants.

PubMed

Li, Bojiang; Ngo, Sherry; Wu, Wangjun; Xu, Hongtao; Xie, Zhuang; Li, Qifa; Pan, Zengxiang

2014-10-25

Boule is responsible for meiotic arrest of sperms and male sterility during mammalian spermatogenesis. In the present study, we first identified yak b-Boule gene and its two alternative splice variants. The full length coding region of yak b-Boule is 888bp and encodes a 295-amino acid protein with a typical RNA-recognition motif (RRM) and a Deleted in Azoospermia (DAZ) repetitive sequence motif. Two alternative splice variants of yak b-Boule were generated following the consensus "GT-AG" rule and named b-Boule1 (36bp deletion in exon 3) and b-Boule2 (deletion of integral exon 7), respectively. In male yak, b-Boule, b-Boule1 and b-Boule2 were found to be exclusively expressed in the testes at a ratio of 81:0.1:1. Intriguingly, the mRNA expression levels of b-Boule and b-Boule1 in yak testis were significantly higher than those in cattle-yak, although no significant difference was observed for b-Boule2 expression between the yak and cattle-yak. These results suggest that b-Boule gene, which is partially regulated by alternative splicing, may be involved in the process of yak spermatogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India.

PubMed

Mohan, Viswanathan; Radha, Venkatesan; Nguyen, Thong T; Stawiski, Eric W; Pahuja, Kanika Bajaj; Goldstein, Leonard D; Tom, Jennifer; Anjana, Ranjit Mohan; Kong-Beltran, Monica; Bhangale, Tushar; Jahnavi, Suresh; Chandni, Radhakrishnan; Gayathri, Vijay; George, Paul; Zhang, Na; Murugan, Sakthivel; Phalke, Sameer; Chaudhuri, Subhra; Gupta, Ravi; Zhang, Jingli; Santhosh, Sam; Stinson, Jeremy; Modrusan, Zora; Ramprasad, V L; Seshagiri, Somasekar; Peterson, Andrew S

2018-02-13

Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed. We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6-1 that may contribute to development of MODY. Functional assessment of the NKX6-1 variants showed that they are functionally impaired. Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6-1, and these require further validation.

Heritability estimates of the Big Five personality traits based on common genetic variants.

PubMed

Power, R A; Pluess, M

2015-07-14

According to twin studies, the Big Five personality traits have substantial heritable components explaining 40-60% of the variance, but identification of associated genetic variants has remained elusive. Consequently, knowledge regarding the molecular genetic architecture of personality and to what extent it is shared across the different personality traits is limited. Using genomic-relatedness-matrix residual maximum likelihood analysis (GREML), we here estimated the heritability of the Big Five personality factors (extraversion, agreeableness, conscientiousness, neuroticism and openness for experience) in a sample of 5011 European adults from 527,469 single-nucleotide polymorphisms across the genome. We tested for the heritability of each personality trait, as well as for the genetic overlap between the personality factors. We found significant and substantial heritability estimates for neuroticism (15%, s.e. = 0.08, P = 0.04) and openness (21%, s.e. = 0.08, P < 0.01), but not for extraversion, agreeableness and conscientiousness. The bivariate analyses showed that the variance explained by common variants entirely overlapped between neuroticism and openness (rG = 1.00, P < 0.001), despite low phenotypic correlation (r = - 0.09, P < 0.001), suggesting that the remaining unique heritability may be determined by rare or structural variants. As far as we are aware of, this is the first study estimating the shared and unique heritability of all Big Five personality traits using the GREML approach. Findings should be considered exploratory and suggest that detectable heritability estimates based on common variants is shared between neuroticism and openness to experiences.

Characterization of the two intra-individual sequence variants in the 18S rRNA gene in the plant parasitic nematode, Rotylenchulus reniformis.

PubMed

Nyaku, Seloame T; Sripathi, Venkateswara R; Kantety, Ramesh V; Gu, Yong Q; Lawrence, Kathy; Sharma, Govind C

2013-01-01

The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene.

Characterization of the Two Intra-Individual Sequence Variants in the 18S rRNA Gene in the Plant Parasitic Nematode, Rotylenchulus reniformis

PubMed Central

Nyaku, Seloame T.; Sripathi, Venkateswara R.; Kantety, Ramesh V.; Gu, Yong Q.; Lawrence, Kathy; Sharma, Govind C.

2013-01-01

The 18S rRNA gene is fundamental to cellular and organismal protein synthesis and because of its stable persistence through generations it is also used in phylogenetic analysis among taxa. Sequence variation in this gene within a single species is rare, but it has been observed in few metazoan organisms. More frequently it has mostly been reported in the non-transcribed spacer region. Here, we have identified two sequence variants within the near full coding region of 18S rRNA gene from a single reniform nematode (RN) Rotylenchulus reniformis labeled as reniform nematode variant 1 (RN_VAR1) and variant 2 (RN_VAR2). All sequences from three of the four isolates had both RN variants in their sequences; however, isolate 13B had only RN variant 2 sequence. Specific variable base sites (96 or 5.5%) were found within the 18S rRNA gene that can clearly distinguish the two 18S rDNA variants of RN, in 11 (25.0%) and 33 (75.0%) of the 44 RN clones, for RN_VAR1 and RN_VAR2, respectively. Neighbor-joining trees show that the RN_VAR1 is very similar to the previously existing R. reniformis sequence in GenBank, while the RN_VAR2 sequence is more divergent. This is the first report of the identification of two major variants of the 18S rRNA gene in the same single RN, and documents the specific base variation between the two variants, and hypothesizes on simultaneous co-existence of these two variants for this gene. PMID:23593343

Risk-Based Object Oriented Testing

NASA Technical Reports Server (NTRS)

Rosenberg, Linda H.; Stapko, Ruth; Gallo, Albert

2000-01-01

Software testing is a well-defined phase of the software development life cycle. Functional ("black box") testing and structural ("white box") testing are two methods of test case design commonly used by software developers. A lesser known testing method is risk-based testing, which takes into account the probability of failure of a portion of code as determined by its complexity. For object oriented programs, a methodology is proposed for identification of risk-prone classes. Risk-based testing is a highly effective testing technique that can be used to find and fix the most important problems as quickly as possible.

Cellobiohydrolase variants and polynucleotides encoding same

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wogulis, Mark

The present invention relates to variants of a parent cellobiohydrolase II. 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.

Characterization of form variants of Xenorhabdus luminescens.

PubMed Central

Gerritsen, L J; de Raay, G; Smits, P H

1992-01-01

From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed. Images PMID:1622273

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia.

PubMed

Torrell, Helena; Salas, Antonio; Abasolo, Nerea; Morén, Constanza; Garrabou, Glòria; Valero, Joaquín; Alonso, Yolanda; Vilella, Elisabet; Costas, Javier; Martorell, Lourdes

2014-10-01

It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia. © 2014 Wiley Periodicals, Inc.

Low-Pass Genome-Wide Sequencing and Variant Inference Using Identity-by-Descent in an Isolated Human Population

PubMed Central

Gusev, A.; Shah, M. J.; Kenny, E. E.; Ramachandran, A.; Lowe, J. K.; Salit, J.; Lee, C. C.; Levandowsky, E. C.; Weaver, T. N.; Doan, Q. C.; Peckham, H. E.; McLaughlin, S. F.; Lyons, M. R.; Sheth, V. N.; Stoffel, M.; De La Vega, F. M.; Friedman, J. M.; Breslow, J. L.

2012-01-01

Whole-genome sequencing in an isolated population with few founders directly ascertains variants from the population bottleneck that may be rare elsewhere. In such populations, shared haplotypes allow imputation of variants in unsequenced samples without resorting to complex statistical methods as in studies of outbred cohorts. We focus on an isolated population cohort from the Pacific Island of Kosrae, Micronesia, where we previously collected SNP array and rich phenotype data for the majority of the population. We report identification of long regions with haplotypes co-inherited between pairs of individuals and methodology to leverage such shared genetic content for imputation. Our estimates show that sequencing as few as 40 personal genomes allows for inference in up to 60% of the 3000-person cohort at the average locus. We ascertained a pilot data set of whole-genome sequences from seven Kosraean individuals, with average 5× coverage. This assay identified 5,735,306 unique sites of which 1,212,831 were previously unknown. Additionally, these variants are unusually enriched for alleles that are rare in other populations when compared to geographic neighbors (published Korean genome SJK). We used the presence of shared haplotypes between the seven Kosraen individuals to estimate expected imputation accuracy of known and novel homozygous variants at 99.6% and 97.3%, respectively. This study presents whole-genome analysis of a homogenous isolate population with emphasis on optimal rare variant inference. PMID:22135348

An iterated local search algorithm for the team orienteering problem with variable profits

NASA Astrophysics Data System (ADS)

Gunawan, Aldy; Ng, Kien Ming; Kendall, Graham; Lai, Junhan

2018-07-01

The orienteering problem (OP) is a routing problem that has numerous applications in various domains such as logistics and tourism. The objective is to determine a subset of vertices to visit for a vehicle so that the total collected score is maximized and a given time budget is not exceeded. The extensive application of the OP has led to many different variants, including the team orienteering problem (TOP) and the team orienteering problem with time windows. The TOP extends the OP by considering multiple vehicles. In this article, the team orienteering problem with variable profits (TOPVP) is studied. The main characteristic of the TOPVP is that the amount of score collected from a visited vertex depends on the duration of stay on that vertex. A mathematical programming model for the TOPVP is first presented and an algorithm based on iterated local search (ILS) that is able to solve modified benchmark instances is then proposed. It is concluded that ILS produces solutions which are comparable to those obtained by the commercial solver CPLEX for smaller instances. For the larger instances, ILS obtains good-quality solutions that have significantly better objective value than those found by CPLEX under reasonable computational times.

Requirements Modeling with the Aspect-oriented User Requirements Notation (AoURN): A Case Study

NASA Astrophysics Data System (ADS)

Mussbacher, Gunter; Amyot, Daniel; Araújo, João; Moreira, Ana

The User Requirements Notation (URN) is a recent ITU-T standard that supports requirements engineering activities. The Aspect-oriented URN (AoURN) adds aspect-oriented concepts to URN, creating a unified framework that allows for scenario-based, goal-oriented, and aspect-oriented modeling. AoURN is applied to the car crash crisis management system (CCCMS), modeling its functional and non-functional requirements (NFRs). AoURN generally models all use cases, NFRs, and stakeholders as individual concerns and provides general guidelines for concern identification. AoURN handles interactions between concerns, capturing their dependencies and conflicts as well as the resolutions. We present a qualitative comparison of aspect-oriented techniques for scenario-based and goal-oriented requirements engineering. An evaluation carried out based on the metrics adapted from literature and a task-based evaluation suggest that AoURN models are more scalable than URN models and exhibit better modularity, reusability, and maintainability.

Crystallographic features of the martensitic transformation and their impact on variant organization in the intermetallic compound Ni50Mn38Sb12 studied by SEM/EBSD.

PubMed

Zhang, Chunyang; Zhang, Yudong; Esling, Claude; Zhao, Xiang; Zuo, Liang

2017-09-01

The mechanical and magnetic properties of Ni-Mn-Sb intermetallic compounds are closely related to the martensitic transformation and martensite variant organization. However, studies of these issues are very limited. Thus, a thorough crystallographic investigation of the martensitic transformation orientation relationship (OR), the transformation deformation and their impact on the variant organization of an Ni 50 Mn 38 Sb 12 alloy using scanning electron microscopy/electron backscatter diffraction (SEM/EBSD) was conducted in this work. It is shown that the martensite variants are hierarchically organized into plates, each possessing four distinct twin-related variants, and the plates into plate colonies, each containing four distinct plates delimited by compatible and incompatible plate interfaces. Such a characteristic organization is produced by the martensitic transformation. It is revealed that the transformation obeys the Pitsch relation ({0[Formula: see text]} A // {2[Formula: see text]} M and 〈0[Formula: see text]1〉 A // 〈[Formula: see text]2〉 M ; the subscripts A and M refer to austenite and martensite, respectively). The type I twinning plane K 1 of the intra-plate variants and the compatible plate interface plane correspond to the respective orientation relationship planes {0[Formula: see text]} A and {0[Formula: see text]} A of austenite. The three {0[Formula: see text]} A planes possessed by each pair of compatible plates, one corresponding to the compatible plate interface and the other two to the variants in the two plates, are interrelated by 60° and belong to a single 〈11[Formula: see text]〉 A axis zone. The {0[Formula: see text]} A planes representing the two pairs of compatible plates in each plate colony belong to two 〈11[Formula: see text]〉 A axis zones having one {0[Formula: see text]} A plane in common. This common plane defines the compatible plate interfaces of the two pairs of plates. The transformation strains to form the

Revisions to the 1995 map of ecological subregions that affect users of the southern variant of the Forest Vegetation Simulator

Treesearch

W. Henry McNab; Chad E. Keyser

2011-01-01

The Southern Variant of the Forest Vegetation Simulator utilizes ecological units mapped in 1995 by the Forest Service, U.S. Department of Agriculture, to refine tree growth models for the Southern United States. The 2007 revision of the 1995 map resulted in changes of identification and boundary delineation for some ecoregion units. In this report, we summarize the...

The quest for rare variants: pooled multiplexed next generation sequencing in plants.

PubMed

Marroni, Fabio; Pinosio, Sara; Morgante, Michele

2012-01-01

Next generation sequencing (NGS) instruments produce an unprecedented amount of sequence data at contained costs. This gives researchers the possibility of designing studies with adequate power to identify rare variants at a fraction of the economic and labor resources required by individual Sanger sequencing. As of today, few research groups working in plant sciences have exploited this potentiality, showing that pooled NGS provides results in excellent agreement with those obtained by individual Sanger sequencing. The aim of this review is to convey to the reader the general ideas underlying the use of pooled NGS for the identification of rare variants. To facilitate a thorough understanding of the possibilities of the method, we will explain in detail the possible experimental and analytical approaches and discuss their advantages and disadvantages. We will show that information on allele frequency obtained by pooled NGS can be used to accurately compute basic population genetics indexes such as allele frequency, nucleotide diversity, and Tajima's D. Finally, we will discuss applications and future perspectives of the multiplexed NGS approach.

Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases

PubMed Central

Puffenberger, Erik G.; Jinks, Robert N.; Sougnez, Carrie; Cibulskis, Kristian; Willert, Rebecca A.; Achilly, Nathan P.; Cassidy, Ryan P.; Fiorentini, Christopher J.; Heiken, Kory F.; Lawrence, Johnny J.; Mahoney, Molly H.; Miller, Christopher J.; Nair, Devika T.; Politi, Kristin A.; Worcester, Kimberly N.; Setton, Roni A.; DiPiazza, Rosa; Sherman, Eric A.; Eastman, James T.; Francklyn, Christopher; Robey-Bond, Susan; Rider, Nicholas L.; Gabriel, Stacey; Morton, D. Holmes; Strauss, Kevin A.

2012-01-01

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data. PMID:22279524

Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus.

PubMed

Zhang, Xiao-Feng; Guo, Jiangbo; Zhang, Xiuchun; Meulia, Tea; Paul, Pierce; Madden, Laurence V; Li, Dawei; Qu, Feng

2015-10-20

Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants.

Identification of Disciplines and Fields. Edis Task I Report, Work Unit 1.4.

ERIC Educational Resources Information Center

Howard Research Co., Arlington, VA.

This report presents the identification and definitions of subject oriented engineering and scientific disciplines and fields which are included in the EDIS Subject Categories. The discussion is extended to include the mix of subjects with other orientations, such as Item, Mission-Project, Expertise and Data Bank Categories. Sample queries are…

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

PubMed Central

El Malti, Rajae; Liu, Hui; Doray, Bérénice; Thauvin, Christel; Maltret, Alice; Dauphin, Claire; Gonçalves-Rocha, Miguel; Teboul, Michel; Blanchet, Patricia; Roume, Joëlle; Gronier, Céline; Ducreux, Corinne; Veyrier, Magali; Marçon, François; Acar, Philippe; Lusson, Jean-René; Levy, Marilyne; Beyler, Constance; Vigneron, Jacqueline; Cordier-Alex, Marie-Pierre; Heitz, François; Sanlaville, Damien; Bonnet, Damien; Bouvagnet, Patrice

2016-01-01

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era. PMID:26014430

Crystallography of decahedral and icosahedral particles. II - High symmetry orientations

NASA Technical Reports Server (NTRS)

Yang, C. Y.; Yacaman, M. J.; Heinemann, K.

1979-01-01

Based on the exact crystal structure of decahedral and icosahedral particles, high energy electron diffraction patterns and image profiles have been derived for various high symmetry orientations of the particles with respect to the incident beam. These results form a basis for the identification of small metal particle structures with advanced methods of transmission electron microscopy.

Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

PubMed Central

Gupta, Saumya; Radhakrishnan, Aparna; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M.; Gagneur, Julien; Sinha, Himanshu

2015-01-01

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing

Implicit orientation toward family and school among bilingual Latino college students.

PubMed

Devos, Thierry; Blanco, Karla; Muñoz, Cynthia; Dunn, Roger; Ulloa, Emilio C

2008-08-01

The authors examined the associations that underlie the orientations of bilingual Latino college students toward family and school. Participants completed, in English or Spanish, 3 implicit association tests assessing their attitude toward family vs. school, identifications with these concepts, and self-esteem. Results revealed a more positive attitude toward, and stronger identification with, family than school. Identification with family was stronger among participants who completed the study in English, suggesting self-definition in terms of distinctions from the context. Last, the more participants valued family over school and identified with family rather than school, the higher was their self-esteem. These findings shed light on the subtle, yet crucial, mechanisms by which cultural knowledge is incorporated in the self-concept of bilingual Latino college students.

Implicit Orientation Toward Family and School Among Bilingual Latino College Students

PubMed Central

DEVOS, THIERRY; BLANCO, KARLA; MUÑOZ, CYNTHIA; DUNN, ROGER; ULLOA, EMILIO C.

2015-01-01

The authors examined the associations that underlie the orientations of bilingual Latino college students toward family and school. Participants completed, in English or Spanish, 3 implicit association tests assessing their attitude toward family vs. school, identifications with these concepts, and self-esteem. Results revealed a more positive attitude toward, and stronger identification with, family than school. Identification with family was stronger among participants who completed the study in English, suggesting self-definition in terms of distinctions from the context. Last, the more participants valued family over school and identified with family rather than school, the higher was their self-esteem. These findings shed light on the subtle, yet crucial, mechanisms by which cultural knowledge is incorporated in the self-concept of bilingual Latino college students. PMID:18807421

Cystic fibrosis newborn screening programs: implications of the CFTR variant spectrum in nonwhite patients.

PubMed

Pique, Lynn; Graham, Steve; Pearl, Michelle; Kharrazi, Martin; Schrijver, Iris

2017-01-01

Cystic fibrosis newborn screening (CFNBS) has been offered across the United States since 2010. However, as compared with white patients with CF, CFTR variant identification in nonwhite populations remains inequitable. Utilizing the recent characterization of the nonwhite CF variant spectrum, we examined the effectiveness of current CFNBS molecular panels in identifying affected nonwhite newborns. Based on a cross-sectional evaluation of genotyping data from the CF Foundation Patient Registry that compared 3,496 nonwhite with 22,206 white CF patients, the current CFNBS algorithms used in the 50 states and the District of Columbia were analyzed. We assessed the percentage of CF patients of Hispanic, African, Asian, and Native American heritage who would not be identified by the molecular panels most commonly used. Compared with whites, variant detection was significantly lower in Hispanic, black, and Asian newborns (P ≤ 0.0001 each), as well as in Native American newborns (P values ranged from 0.001 to 0.0003), for the most common CFNBS panels. This study provides a perspective on the applicability of current panels to a diverse population and enables CFNBS programs to consider more inclusive test approaches to facilitate diagnosis, timely clinical intervention, and enhanced prognosis for CF patients of nonwhite and mixed ethnicities.Genet Med 19 1, 36-44.

Proteomic analysis of hair shafts from monozygotic twins: Expression profiles and genetically variant peptides.

PubMed

Wu, Pei-Wen; Mason, Katelyn E; Durbin-Johnson, Blythe P; Salemi, Michelle; Phinney, Brett S; Rocke, David M; Parker, Glendon J; Rice, Robert H

2017-07-01

Forensic association of hair shaft evidence with individuals is currently assessed by comparing mitochondrial DNA haplotypes of reference and casework samples, primarily for exclusionary purposes. Present work tests and validates more recent proteomic approaches to extract quantitative transcriptional and genetic information from hair samples of monozygotic twin pairs, which would be predicted to partition away from unrelated individuals if the datasets contain identifying information. Protein expression profiles and polymorphic, genetically variant hair peptides were generated from ten pairs of monozygotic twins. Profiling using the protein tryptic digests revealed that samples from identical twins had typically an order of magnitude fewer protein expression differences than unrelated individuals. The data did not indicate that the degree of difference within twin pairs increased with age. In parallel, data from the digests were used to detect genetically variant peptides that result from common nonsynonymous single nucleotide polymorphisms in genes expressed in the hair follicle. Compilation of the variants permitted sorting of the samples by hierarchical clustering, permitting accurate matching of twin pairs. The results demonstrate that genetic differences are detectable by proteomic methods and provide a framework for developing quantitative statistical estimates of personal identification that increase the value of hair shaft evidence. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Object-oriented Bayesian networks for paternity cases with allelic dependencies

PubMed Central

Hepler, Amanda B.; Weir, Bruce S.

2008-01-01

This study extends the current use of Bayesian networks by incorporating the effects of allelic dependencies in paternity calculations. The use of object-oriented networks greatly simplify the process of building and interpreting forensic identification models, allowing researchers to solve new, more complex problems. We explore two paternity examples: the most common scenario where DNA evidence is available from the alleged father, the mother and the child; a more complex casewhere DNA is not available from the alleged father, but is available from the alleged father’s brother. Object-oriented networks are built, using HUGIN, for each example which incorporate the effects of allelic dependence caused by evolutionary relatedness. PMID:19079769

Growth mechanism of extension twin variants during annealing of pure magnesium: An ‘ex situ’ electron backscattered diffraction investigation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sabat, R.K.

Pure magnesium was subjected to plastic deformation through CSM (continuous stiffness measurement) indentation followed by annealing at 200 °C for 30 min. Nucleation of no new grains was observed neither at the twin–twin intersections nor at the multiple twin variants of a grain after annealing. Significant growth of off-basal twin orientation compared to basal twin orientation was observed in the sample after annealing and is attributed to the partial coherent nature of twin boundary in the later case. Further, growth of twins was independent of the strain distribution between parent and twinned grains. - Highlights: • An ‘ex situ’ EBSDmore » of pure Mg during annealing was investigated. • Nucleation of no new grains was observed. • Significant growth of off-basal twin orientation was observed. • Growth of twins may be attributed to the partial coherent nature of twin boundary.« less

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing

PubMed Central

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

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

PubMed Central

Buitrago, Lorena; Rendon, Augusto; Liang, Yupu; Simeoni, Ilenia; Negri, Ana; Filizola, Marta; Ouwehand, Willem H.; Coller, Barry S.; Alessi, Marie-Christine; Ballmaier, Matthias; Bariana, Tadbir; Bellissimo, Daniel; Bertoli, Marta; Bray, Paul; Bury, Loredana; Carrell, Robin; Cattaneo, Marco; Collins, Peter; French, Deborah; Favier, Remi; Freson, Kathleen; Furie, Bruce; Germeshausen, Manuela; Ghevaert, Cedric; Gomez, Keith; Goodeve, Anne; Gresele, Paolo; Guerrero, Jose; Hampshire, Dan J.; Hadinnapola, Charaka; Heemskerk, Johan; Henskens, Yvonne; Hill, Marian; Hogg, Nancy; Johnsen, Jill; Kahr, Walter; Kerr, Ron; Kunishima, Shinji; Laffan, Michael; Natwani, Amit; Neerman-Arbez, Marguerite; Nurden, Paquita; Nurden, Alan; Ormiston, Mark; Othman, Maha; Ouwehand, Willem; Perry, David; Vilk, Shoshana Ravel; Reitsma, Pieter; Rondina, Matthew; Simeoni, Ilenia; Smethurst, Peter; Stephens, Jonathan; Stevenson, William; Szkotak, Artur; Turro, Ernest; Van Geet, Christel; Vries, Minka; Ward, June; Waye, John; Westbury, Sarah; Whiteheart, Sidney; Wilcox, David; Zhang, Bi

2015-01-01

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID:25827233

Variant Interpretation: Functional Assays to the Rescue.

PubMed

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.

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

PubMed Central

van Leeuwen, Elisabeth M; Sabo, Aniko; Bis, Joshua C; Huffman, Jennifer E; Manichaikul, Ani; Smith, Albert V; Feitosa, Mary F; Demissie, Serkalem; Joshi, Peter K; Duan, Qing; Marten, Jonathan; van Klinken, Jan B; Surakka, Ida; Nolte, Ilja M; Zhang, Weihua; Mbarek, Hamdi; Li-Gao, Ruifang; Trompet, Stella; Verweij, Niek; Evangelou, Evangelos; Lyytikäinen, Leo-Pekka; Tayo, Bamidele O; Deelen, Joris; van der Most, Peter J; van der Laan, Sander W; Arking, Dan E; Morrison, Alanna; Dehghan, Abbas; Franco, Oscar H; Hofman, Albert; Rivadeneira, Fernando; Sijbrands, Eric J; Uitterlinden, Andre G; Mychaleckyj, Josyf C; Campbell, Archie; Hocking, Lynne J; Padmanabhan, Sandosh; Brody, Jennifer A; Rice, Kenneth M; White, Charles C; Harris, Tamara; Isaacs, Aaron; Campbell, Harry; Lange, Leslie A; Rudan, Igor; Kolcic, Ivana; Navarro, Pau; Zemunik, Tatijana; Salomaa, Veikko; Kooner, Angad S; Kooner, Jaspal S; Lehne, Benjamin; Scott, William R; Tan, Sian-Tsung; de Geus, Eco J; Milaneschi, Yuri; Penninx, Brenda W J H; Willemsen, Gonneke; de Mutsert, Renée; Ford, Ian; Gansevoort, Ron T; Segura-Lepe, Marcelo P; Raitakari, Olli T; Viikari, Jorma S; Nikus, Kjell; Forrester, Terrence; McKenzie, Colin A; de Craen, Anton J M; de Ruijter, Hester M; Pasterkamp, Gerard; Snieder, Harold; Oldehinkel, Albertine J; Slagboom, P Eline; Cooper, Richard S; Kähönen, Mika; Lehtimäki, Terho; Elliott, Paul; van der Harst, Pim; Jukema, J Wouter; Mook-Kanamori, Dennis O; Boomsma, Dorret I; Chambers, John C; Swertz, Morris; Ripatti, Samuli; Willems van Dijk, Ko; Vitart, Veronique; Polasek, Ozren; Hayward, Caroline; Wilson, James G; Wilson, James F; Gudnason, Vilmundur; Rich, Stephen S; Psaty, Bruce M; Borecki, Ingrid B; Boerwinkle, Eric; Rotter, Jerome I; Cupples, L Adrienne; van Duijn, Cornelia M

2016-01-01

Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels. PMID:27036123

Predicting helix orientation for coiled-coil dimers

PubMed Central

Apgar, James R.; Gutwin, Karl N.; Keating, Amy E.

2008-01-01

The alpha-helical coiled coil is a structurally simple protein oligomerization or interaction motif consisting of two or more alpha helices twisted into a supercoiled bundle. Coiled coils can differ in their stoichiometry, helix orientation and axial alignment. Because of the near degeneracy of many of these variants, coiled coils pose a challenge to fold recognition methods for structure prediction. Whereas distinctions between some protein folds can be discriminated on the basis of hydrophobic/polar patterning or secondary structure propensities, the sequence differences that encode important details of coiled-coil structure can be subtle. This is emblematic of a larger problem in the field of protein structure and interaction prediction: that of establishing specificity between closely similar structures. We tested the behavior of different computational models on the problem of recognizing the correct orientation - parallel vs. antiparallel - of pairs of alpha helices that can form a dimeric coiled coil. For each of 131 examples of known structure, we constructed a large number of both parallel and antiparallel structural models and used these to asses the ability of five energy functions to recognize the correct fold. We also developed and tested three sequenced-based approaches that make use of varying degrees of implicit structural information. The best structural methods performed similarly to the best sequence methods, correctly categorizing ∼81% of dimers. Steric compatibility with the fold was important for some coiled coils we investigated. For many examples, the correct orientation was determined by smaller energy differences between parallel and antiparallel structures distributed over many residues and energy components. Prediction methods that used structure but incorporated varying approximations and assumptions showed quite different behaviors when used to investigate energetic contributions to orientation preference. Sequence based methods were

Rotation-invariant features for multi-oriented text detection in natural images.

PubMed

Yao, Cong; Zhang, Xin; Bai, Xiang; Liu, Wenyu; Ma, Yi; Tu, Zhuowen

2013-01-01

Texts in natural scenes carry rich semantic information, which can be used to assist a wide range of applications, such as object recognition, image/video retrieval, mapping/navigation, and human computer interaction. However, most existing systems are designed to detect and recognize horizontal (or near-horizontal) texts. Due to the increasing popularity of mobile-computing devices and applications, detecting texts of varying orientations from natural images under less controlled conditions has become an important but challenging task. In this paper, we propose a new algorithm to detect texts of varying orientations. Our algorithm is based on a two-level classification scheme and two sets of features specially designed for capturing the intrinsic characteristics of texts. To better evaluate the proposed method and compare it with the competing algorithms, we generate a comprehensive dataset with various types of texts in diverse real-world scenes. We also propose a new evaluation protocol, which is more suitable for benchmarking algorithms for detecting texts in varying orientations. Experiments on benchmark datasets demonstrate that our system compares favorably with the state-of-the-art algorithms when handling horizontal texts and achieves significantly enhanced performance on variant texts in complex natural scenes.

Identification of Genes and Genetic Variants Associated with Poor Treatment Response in Patients with Prostate Cancer

DTIC Science & Technology

2013-10-01

collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources...gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate...variants which explain much more than a small amount of risk for prostate cancer among a small population of men. Even less progress has been made

RareVariantVis: new tool for visualization of causative variants in rare monogenic disorders using whole genome sequencing data.

PubMed

Stokowy, Tomasz; Garbulowski, Mateusz; Fiskerstrand, Torunn; Holdhus, Rita; Labun, Kornel; Sztromwasser, Pawel; Gilissen, Christian; Hoischen, Alexander; Houge, Gunnar; Petersen, Kjell; Jonassen, Inge; Steen, Vidar M

2016-10-01

The search for causative genetic variants in rare diseases of presumed monogenic inheritance has been boosted by the implementation of whole exome (WES) and whole genome (WGS) sequencing. In many cases, WGS seems to be superior to WES, but the analysis and visualization of the vast amounts of data is demanding. To aid this challenge, we have developed a new tool-RareVariantVis-for analysis of genome sequence data (including non-coding regions) for both germ line and somatic variants. It visualizes variants along their respective chromosomes, providing information about exact chromosomal position, zygosity and frequency, with point-and-click information regarding dbSNP IDs, gene association and variant inheritance. Rare variants as well as de novo variants can be flagged in different colors. We show the performance of the RareVariantVis tool in the Genome in a Bottle WGS data set. https://www.bioconductor.org/packages/3.3/bioc/html/RareVariantVis.html tomasz.stokowy@k2.uib.no Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Swine Influenza/Variant Influenza Viruses

MedlinePlus

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

STAG3 truncating variant as the cause of primary ovarian insufficiency

PubMed Central

Le Quesne Stabej, Polona; Williams, Hywel J; James, Chela; Tekman, Mehmet; Stanescu, Horia C; Kleta, Robert; Ocaka, Louise; Lescai, Francesco; Storr, Helen L; Bitner-Glindzicz, Maria; Bacchelli, Chiara; Conway, Gerard S

2016-01-01

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI. PMID:26059840

Determination of a novel integron-located variant (blaOXA -320 ) of Class D β-lactamase in Proteus mirabilis.

PubMed

Cicek, Aysegul Copur; Duzgun, Azer Ozad; Saral, Aysegul; Sandalli, Cemal

2014-10-01

Proteus mirabilis (P. mirabilis) is one of Gram-negative pathogens encountered in clinical specimens. A clinical isolate (TRP41) of P. mirabilis was isolated from a Turkish patient in Turkey. The isolate was identified using the API 32GN system and 16S rRNA gene sequencing and it was found resistant to ampicillin/sulbactam, piperacillin, tetracycline, and trimethoprim/sulfamethoxazole. This isolate was harboring a Class 1 integron gene cassette and its DNA sequence analysis revealed a novel blaOXA variant exhibiting one amino acid substitution (Asn266Ile) from blaOXA-1 . This new variant of OXA was located on Class 1 integron together with aadA1 gene encoding aminoglycoside-modifying enzymes. According to sequence records, the new variant was named as blaOXA-320 . Cassette array and size of integron were found as blaOXA-320 -aadA1 and 2086 bp, respectively. The blaOXA-320 gene is not transferable according to conjugation experiment. In this study, we report the first identification of blaOXA-320 -aadA1 gene cassette, a novel variant of Class D β-lactamase, in P. mirabilis from Turkey. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

PubMed Central

Courcet, Jean- Benoît; Elalaoui, Siham Chafai; Duplomb, Laurence; Tajir, Mariam; Rivière, Jean-Baptiste; Thevenon, Julien; Gigot, Nadège; Marle, Nathalie; Aral, Bernard; Duffourd, Yannis; Sarasin, Alain; Naim, Valeria; Courcet-Degrolard, Emilie; Aubriot-Lorton, Marie- Hélène; Martin, Laurent; Abrid, Jamal Eddin; Thauvin, Christel; Sefiani, Abdelaziz; Vabres, Pierre; Faivre, Laurence

2015-01-01

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer. PMID:25315659

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

PubMed

Courcet, Jean-Benoît; Elalaoui, Siham Chafai; Duplomb, Laurence; Tajir, Mariam; Rivière, Jean-Baptiste; Thevenon, Julien; Gigot, Nadège; Marle, Nathalie; Aral, Bernard; Duffourd, Yannis; Sarasin, Alain; Naim, Valeria; Courcet-Degrolard, Emilie; Aubriot-Lorton, Marie-Hélène; Martin, Laurent; Abrid, Jamal Eddin; Thauvin, Christel; Sefiani, Abdelaziz; Vabres, Pierre; Faivre, Laurence

2015-07-01

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.

Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains

PubMed Central

Cronin, Thomas C; DiNitto, Jonathan P; Czech, Michael P; Lambright, David G

2004-01-01

The pleckstrin homology (PH) domains of the homologous proteins Grp1 (general receptor for phosphoinositides), ARNO (Arf nucleotide binding site opener), and Cytohesin-1 bind phosphatidylinositol (PtdIns) 3,4,5-trisphosphate with unusually high selectivity. Remarkably, splice variants that differ only by the insertion of a single glycine residue in the β1/β2 loop exhibit dual specificity for PtdIns(3,4,5)P3 and PtdIns(4,5)P2. The structural basis for this dramatic specificity switch is not apparent from the known modes of phosphoinositide recognition. Here, we report crystal structures for dual specificity variants of the Grp1 and ARNO PH domains in either the unliganded form or in complex with the head groups of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Loss of contacts with the β1/β2 loop with no significant change in head group orientation accounts for the significant decrease in PtdIns(3,4,5)P3 affinity observed for the dual specificity variants. Conversely, a small increase rather than decrease in affinity for PtdIns(4,5)P2 is explained by a novel binding mode, in which the glycine insertion alleviates unfavorable interactions with the β1/β2 loop. These observations are supported by a systematic mutational analysis of the determinants of phosphoinositide recognition. PMID:15359279

Beta-glucosidase variants and polynucleotides encoding same

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wogulis, Mark; Harris, Paul; Osborn, David

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.

Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data

PubMed Central

Watson, Christopher M.; Crinnion, Laura A.; Gurgel‐Gianetti, Juliana; Harrison, Sally M.; Daly, Catherine; Antanavicuite, Agne; Lascelles, Carolina; Markham, Alexander F.; Pena, Sergio D. J.; Bonthron, David T.

2015-01-01

ABSTRACT Autozygosity mapping is a powerful technique for the identification of rare, autosomal recessive, disease‐causing genes. The ease with which this category of disease gene can be identified has greatly increased through the availability of genome‐wide SNP genotyping microarrays and subsequently of exome sequencing. Although these methods have simplified the generation of experimental data, its analysis, particularly when disparate data types must be integrated, remains time consuming. Moreover, the huge volume of sequence variant data generated from next generation sequencing experiments opens up the possibility of using these data instead of microarray genotype data to identify disease loci. To allow these two types of data to be used in an integrated fashion, we have developed AgileVCFMapper, a program that performs both the mapping of disease loci by SNP genotyping and the analysis of potentially deleterious variants using exome sequence variant data, in a single step. This method does not require microarray SNP genotype data, although analysis with a combination of microarray and exome genotype data enables more precise delineation of disease loci, due to superior marker density and distribution. PMID:26037133

Automated correction of improperly rotated diffusion gradient orientations in diffusion weighted MRI.

PubMed

Jeurissen, Ben; Leemans, Alexander; Sijbers, Jan

2014-10-01

Ensuring one is using the correct gradient orientations in a diffusion MRI study can be a challenging task. As different scanners, file formats and processing tools use different coordinate frame conventions, in practice, users can end up with improperly oriented gradient orientations. Using such wrongly oriented gradient orientations for subsequent diffusion parameter estimation will invalidate all rotationally variant parameters and fiber tractography results. While large misalignments can be detected by visual inspection, small rotations of the gradient table (e.g. due to angulation of the acquisition plane), are much more difficult to detect. In this work, we propose an automated method to align the coordinate frame of the gradient orientations with that of the corresponding diffusion weighted images, using a metric based on whole brain fiber tractography. By transforming the gradient table and measuring the average fiber trajectory length, we search for the transformation that results in the best global 'connectivity'. To ensure a fast calculation of the metric we included a range of algorithmic optimizations in our tractography routine. To make the optimization routine robust to spurious local maxima, we use a stochastic optimization routine that selects a random set of seed points on each evaluation. Using simulations, we show that our method can recover the correct gradient orientations with high accuracy and precision. In addition, we demonstrate that our technique can successfully recover rotated gradient tables on a wide range of clinically realistic data sets. As such, our method provides a practical and robust solution to an often overlooked pitfall in the processing of diffusion MRI. Copyright © 2014 Elsevier B.V. All rights reserved.

Gender variance in childhood and sexual orientation in adulthood: a prospective study.

PubMed

Steensma, Thomas D; van der Ende, Jan; Verhulst, Frank C; Cohen-Kettenis, Peggy T

2013-11-01

Several retrospective and prospective studies have reported on the association between childhood gender variance and sexual orientation and gender discomfort in adulthood. In most of the retrospective studies, samples were drawn from the general population. The samples in the prospective studies consisted of clinically referred children. In understanding the extent to which the association applies for the general population, prospective studies using random samples are needed. This prospective study examined the association between childhood gender variance, and sexual orientation and gender discomfort in adulthood in the general population. In 1983, we measured childhood gender variance, in 406 boys and 473 girls. In 2007, sexual orientation and gender discomfort were assessed. Childhood gender variance was measured with two items from the Child Behavior Checklist/4-18. Sexual orientation was measured for four parameters of sexual orientation (attraction, fantasy, behavior, and identity). Gender discomfort was assessed by four questions (unhappiness and/or uncertainty about one's gender, wish or desire to be of the other gender, and consideration of living in the role of the other gender). For both men and women, the presence of childhood gender variance was associated with homosexuality for all four parameters of sexual orientation, but not with bisexuality. The report of adulthood homosexuality was 8 to 15 times higher for participants with a history of gender variance (10.2% to 12.2%), compared to participants without a history of gender variance (1.2% to 1.7%). The presence of childhood gender variance was not significantly associated with gender discomfort in adulthood. This study clearly showed a significant association between childhood gender variance and a homosexual sexual orientation in adulthood in the general population. In contrast to the findings in clinically referred gender-variant children, the presence of a homosexual sexual orientation in

An AI-based approach to structural damage identification by modal analysis

NASA Technical Reports Server (NTRS)

Glass, B. J.; Hanagud, S.

1990-01-01

Flexible-structure damage is presently addressed by a combined model- and parameter-identification approach which employs the AI methodologies of classification, heuristic search, and object-oriented model knowledge representation. The conditions for model-space search convergence to the best model are discussed in terms of search-tree organization and initial model parameter error. In the illustrative example of a truss structure presented, the use of both model and parameter identification is shown to lead to smaller parameter corrections than would be required by parameter identification alone.

Object-oriented fault tree models applied to system diagnosis

NASA Technical Reports Server (NTRS)

Iverson, David L.; Patterson-Hine, F. A.

1990-01-01

When a diagnosis system is used in a dynamic environment, such as the distributed computer system planned for use on Space Station Freedom, it must execute quickly and its knowledge base must be easily updated. Representing system knowledge as object-oriented augmented fault trees provides both features. The diagnosis system described here is based on the failure cause identification process of the diagnostic system described by Narayanan and Viswanadham. Their system has been enhanced in this implementation by replacing the knowledge base of if-then rules with an object-oriented fault tree representation. This allows the system to perform its task much faster and facilitates dynamic updating of the knowledge base in a changing diagnosis environment. Accessing the information contained in the objects is more efficient than performing a lookup operation on an indexed rule base. Additionally, the object-oriented fault trees can be easily updated to represent current system status. This paper describes the fault tree representation, the diagnosis algorithm extensions, and an example application of this system. Comparisons are made between the object-oriented fault tree knowledge structure solution and one implementation of a rule-based solution. Plans for future work on this system are also discussed.

Precise detection of de novo single nucleotide variants in human genomes.

PubMed

Gómez-Romero, Laura; Palacios-Flores, Kim; Reyes, José; García, Delfino; Boege, Margareta; Dávila, Guillermo; Flores, Margarita; Schatz, Michael C; Palacios, Rafael

2018-05-22

The precise determination of de novo genetic variants has enormous implications across different fields of biology and medicine, particularly personalized medicine. Currently, de novo variations are identified by mapping sample reads from a parent-offspring trio to a reference genome, allowing for a certain degree of differences. While widely used, this approach often introduces false-positive (FP) results due to misaligned reads and mischaracterized sequencing errors. In a previous study, we developed an alternative approach to accurately identify single nucleotide variants (SNVs) using only perfect matches. However, this approach could be applied only to haploid regions of the genome and was computationally intensive. In this study, we present a unique approach, coverage-based single nucleotide variant identification (COBASI), which allows the exploration of the entire genome using second-generation short sequence reads without extensive computing requirements. COBASI identifies SNVs using changes in coverage of exactly matching unique substrings, and is particularly suited for pinpointing de novo SNVs. Unlike other approaches that require population frequencies across hundreds of samples to filter out any methodological biases, COBASI can be applied to detect de novo SNVs within isolated families. We demonstrate this capability through extensive simulation studies and by studying a parent-offspring trio we sequenced using short reads. Experimental validation of all 58 candidate de novo SNVs and a selection of non-de novo SNVs found in the trio confirmed zero FP calls. COBASI is available as open source at https://github.com/Laura-Gomez/COBASI for any researcher to use. Copyright © 2018 the Author(s). Published by PNAS.

Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

PubMed Central

Höglinger, Günter U.; Melhem, Nadine M.; Dickson, Dennis W.; Sleiman, Patrick M.A.; Wang, Li-San; Klei, Lambertus; Rademakers, Rosa; de Silva, Rohan; Litvan, Irene; Riley, David E.; van Swieten, John C.; Heutink, Peter; Wszolek, Zbigniew K.; Uitti, Ryan J.; Vandrovcova, Jana; Hurtig, Howard I.; Gross, Rachel G.; Maetzler, Walter; Goldwurm, Stefano; Tolosa, Eduardo; Borroni, Barbara; Pastor, Pau; Cantwell, Laura B.; Han, Mi Ryung; Dillman, Allissa; van der Brug, Marcel P.; Gibbs, J Raphael; Cookson, Mark R.; Hernandez, Dena G.; Singleton, Andrew B.; Farrer, Matthew J.; Yu, Chang-En; Golbe, Lawrence I.; Revesz, Tamas; Hardy, John; Lees, Andrew J.; Devlin, Bernie; Hakonarson, Hakon; Müller, Ulrich; Schellenberg, Gerard D.

2011-01-01

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component. PMID:21685912

High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.

PubMed

Kelleher, Raymond J; Geigenmüller, Ute; Hovhannisyan, Hayk; Trautman, Edwin; Pinard, Robert; Rathmell, Barbara; Carpenter, Randall; Margulies, David

2012-01-01

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism.

High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism

PubMed Central

Hovhannisyan, Hayk; Trautman, Edwin; Pinard, Robert; Rathmell, Barbara; Carpenter, Randall; Margulies, David

2012-01-01

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism. PMID:22558107

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

PubMed Central

Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

2016-01-01

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). PMID:27379672

Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans.

PubMed

Franceschini, Nora; Carty, Cara L; Lu, Yingchang; Tao, Ran; Sung, Yun Ju; Manichaikul, Ani; Haessler, Jeff; Fornage, Myriam; Schwander, Karen; Zubair, Niha; Bien, Stephanie; Hindorff, Lucia A; Guo, Xiuqing; Bielinski, Suzette J; Ehret, Georg; Kaufman, Joel D; Rich, Stephen S; Carlson, Christopher S; Bottinger, Erwin P; North, Kari E; Rao, D C; Chakravarti, Aravinda; Barrett, Paula Q; Loos, Ruth J F; Buyske, Steven; Kooperberg, Charles

2016-01-01

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans-populations that are understudied for hypertension genetic risk factors.

Variant Humicola grisea CBH1.1

DOEpatents

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

2013-02-19

Disclosed are variants of Humicola grisea Cel7A (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.

Variant Humicola grisea CBH1.1

DOEpatents

Goedegebuur, Frits [Vlaardingen, NL; Gualfetti, Peter [San Francisco, CA; Mitchinson, Colin [Half Moon Bay, CA; Larenas, Edmund [Moss Beach, CA

2011-05-31

Disclosed are variants of Humicola grisea Cel7A (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.

Variant humicola grisea CBH1.1

DOEpatents

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

2014-09-09

Disclosed are variants of Humicola grisea Cel7A (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.

Variant Humicola grisea CBH1.1

DOEpatents

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

2014-03-18

Disclosed are variants of Humicola grisea Cel7A (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.

Variant Humicola grisea CBH1.1

DOEpatents

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.

Variant Humicola grisea CBH1.1

DOEpatents

Goedegebuur, Frits [Vlaardingen, NL; Gualfetti, Peter [San Francisco, CA; Mitchinson, Colin [Half Moon Bay, CA; Larenas, Edmund [Moss Beach, CA

2011-08-16

Disclosed are variants of Humicola grisea Cel7A (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.

Variant Humicola grisea CBH1.1

DOEpatents

Goedegebuur, Frits [Vlaardingen, NL; Gualfetti, Peter [San Francisco, CA; Mitchinson, Colin [Half Moon Bay, CA; Larenas, Edmund [Moss Beach, CA

2012-08-07

Disclosed are variants of Humicola grisea Cel7A (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.

Variant Humicola grisea CBH1.1

DOEpatents

Goedegebuur, Frits [Vlaardingen, NL; Gualfetti, Peter [San Francisco, CA; Mitchinson, Colin [Half Moon Bay, CA; Larenas, Edmund [Moss Beach, CA

2008-12-02

Disclosed are variants of Humicola grisea Cel7A (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.

Determining the orientation of a chiral substrate using full-hemisphere angle-resolved photoelectron spectroscopy.

PubMed

Tadich, A; Riley, J; Thomsen, L; Cowie, B C C; Gladys, M J

2011-10-21

Chiral interfaces and substrates are of increasing importance in the field of enantioselective chemistry. To fully understand the enantiospecific interactions between chiral adsorbate molecules and the chiral substrate, it is vital that the chiral orientation of the substrate is known. In this Letter we demonstrate that full-hemisphere angle-resolved photoemission permits straightforward identification of the orientation of a chiral surface. The technique can be applied to any solid state system for which photoemission measurements are possible. © 2011 American Physical Society

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry

PubMed Central

Ward, Robyn L.; Dobbins, Timothy; Lindor, Noralane M.; Rapkins, Robert W.; Hitchins, Megan P.

2013-01-01

Purpose: Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome–associated cancers. This study investigated their frequency and inheritance. Methods: A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals. Results: Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays. Conclusion: Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor. PMID:22878509

Patterns and Trajectories in Williams Syndrome: The Case of Visual Orientation Discrimination

ERIC Educational Resources Information Center

Palomares, Melanie; Englund, Julia A.; Ahlers, Stephanie

2011-01-01

Williams Syndrome (WS) is a developmental disorder typified by deficits in visuospatial cognition. To understand the nature of this deficit, we characterized how people with WS perceive visual orientation, a fundamental ability related to object identification. We compared WS participants to typically developing children (3-6 years of age) and…

Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease.

PubMed

Kelsen, Judith R; Dawany, Noor; Moran, Christopher J; Petersen, Britt-Sabina; Sarmady, Mahdi; Sasson, Ariella; Pauly-Hubbard, Helen; Martinez, Alejandro; Maurer, Kelly; Soong, Joanne; Rappaport, Eric; Franke, Andre; Keller, Andreas; Winter, Harland S; Mamula, Petar; Piccoli, David; Artis, David; Sonnenberg, Gregory F; Daly, Mark; Sullivan, Kathleen E; Baldassano, Robert N; Devoto, Marcella

2015-11-01

identification of previously unidentified IBD-associated variants. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease

PubMed Central

Kelsen, Judith R.; Dawany, Noor; Moran, Christopher J.; Petersen, Britt-Sabina; Sarmady, Mahdi; Sasson, Ariella; Pauly-Hubbard, Helen; Martinez, Alejandro; Maurer, Kelly; Soong, Joanne; Rappaport, Eric; Franke, Andre; Keller, Andreas; Winter, Harland S.; Mamula, Petar; Piccoli, David; Artis, David; Sonnenberg, Gregory F.; Daly, Mark; Sullivan, Kathleen E.; Baldassano, Robert N.; Devoto, Marcella

2016-01-01

identification of previously unidentified IBD-associated variants. PMID:26193622

Social dominance orientation and gender: the moderating role of gender identity.

PubMed

Wilson, Marc Stewart; Liu, James H

2003-06-01

The aim of this research was to investigate the claim that gender differences in levels of social dominance orientation (SDO; Pratto, Sidanius, Stallworth, & Malle, 1994), a personality variable measuring a general predisposition towards anti-egalitarianism, are essentially invariant (Sidanius & Pratto, 1999). Previous findings have indicated that (regardless of covariate) males display higher levels of SDO than females. Two studies were conducted to test the expectation (derived from social identity theory) that the gender-SDO relationship would be moderated by strength of gender group identification. Both samples (150 non-students and 163 students) completed the full SDO(6) measure, and measures of gender group identification. Consistent with predictions, strength of gender identification was found to moderate the gender-SDO relationship, such that increasing group identification was associated with increasing SDO scores for males, and decreasing SDO for females. This result raises questions concerning the theoretical basis of social dominance theory, and whether gender group membership should be accorded a different status from other 'arbitrary-set' group memberships.

In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features.

PubMed

Ibáñez-Costa, Alejandro; Gahete, Manuel D; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D; Dieguez, Carlos; Castaño, Justo P; Luque, Raúl M

2015-03-04

Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas compared with normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24-72 h) increased GH and ACTH secretion, Ca(2+) and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors.

In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features

PubMed Central

Ibáñez-Costa, Alejandro; Gahete, Manuel D.; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A.; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D.; Dieguez, Carlos; Castaño, Justo P.; Luque, Raúl M.

2015-01-01

Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas comparedwith normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24–72 h) increased GH and ACTH secretion, Ca2+ and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors. PMID:25737012

[Analysis of bacterial small-colony variants isolated from clinical specimens].

PubMed

Matsumoto, Takehisa

2014-07-01

There is a slow-growing subpopulation of bacteria with distinctive phenotypic and pathogenic traits called bacterial small-colony variants (SCVs). Phenotypically, SCVs show a slow growth rate, atypical colony morphology, and unusual biochemical characteristics. SCV strains often grow on blood agar or Drigalski agar as non-pigmented or pinpoint pigmented colonies, and key biochemical tests for them are often non-reactive. This review describes analyses of hemin-dependent Escherichia coli SCV and Staphylococcus aureus thymidine-dependent SCVs based on our case reports. Because SCVs exhibit fastidious growth characteristics, clinical microbiologists may easily miss or misidentify them in the clinical laboratory. Therefore, we must elucidate the cause of SCVs, and improve laboratory methods for the identification and assessment of the susceptibility of SCVs in the clinical laboratory.

Histopathologic risk factors in oral and oropharyngeal squamous cell carcinoma variants: An update with special reference to HPV-related carcinomas

PubMed Central

2014-01-01

Accurate identification of the microscopic risk factors of oral and oropharyngeal (OP) squamous cell carcinomas (SCC) and their morphologic variants is of at most importance, as these generally determine treatment modalities, prognosis and overall patient outcome. The great majority of oral and oropharyngeal squamous cell carcinomas are microscopically described as kerartinizing squamous cell carcinoma (KSCC). They bear certain resemblance to keratinizing stratified squamous epithelium. Tobacco habits and excessive consumption of alcoholic beverages have been considered to be the main etiologic agents in these carcinomas. The tumors occurred in older patients more commonly affected the oral tongue and floor of the mouth with well established morphologic risk factors including tumor grade, pattern of invasion and perineural involvement. Within the last 30 years however, the advent and expanding prevalence of high risk human papillomavirus (HPV) as an important etiologic agent for head and neck squamous cell carcinoma, particularly in the OP, has resulted in a significant change in the established morphologic criteria for risk assessment. The majority of HPV relate carcinomas of the OP are nonkeratinizing squamous cell carcinoma (NKSCC). These tumors are found to be more responsive to treatment with a favorable patient outcome and good prognosis. Consequently, alterations in treatment protocols aimed at de-escalation are currently being evaluated. More recently, other morphologic variants that are HPV positive are reported with increasing frequency in the OP and other head and neck sites. As a result, several clinical and pathologic questions have emerged. Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in the HPV-related variants. Examples of HPV-related squamous cell carcinoma variants that will be addressed here are

The skylight gradient of luminance helps sandhoppers in sun and moon identification.

PubMed

Ugolini, Alberto; Galanti, Giuditta; Mercatelli, Luca

2012-08-15

To return to the ecologically optimal zone of the beach, the sandhopper Talitrus saltator (Montagu) maintains a constant sea-land direction based on the sun and moon compasses. In this study, we investigated the role of the skylight gradient of luminance in sun and moon identification under natural and artificial conditions of illumination. Clock-shifted (inverted) sandhoppers tested under the sun (during their subjective night) and under the full moon (during their subjective day) exhibit orientation in accordance with correct identification of the sun and the moon at night. Tested in artificial conditions of illumination at night without the artificial gradient of luminance, the artificial astronomical cue is identified as the moon even when the conditions of illumination allow sun compass orientation during the day. When the artificial gradient of luminance is added, the artificial astronomical cue is identified as the sun. The role of the sky gradient of luminance in sun and moon identification is discussed on the basis of present and past findings.

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

PubMed Central

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Seielstad, Mark; Wilson, James G.; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L.; Doney, Alex S. F.; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E.; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D.; Morris, Andrew D.; Palmer, Colin N. A.; Collins, Francis S.; Mohlke, Karen L.; Bergman, Richard N.; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M.; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C.; Morris, Andrew P.; Altshuler, David; Meigs, James B.; Boehnke, Michael; McCarthy, Mark I.; Lindgren, Cecilia M.; Gloyn, Anna L.

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights. PMID:25625282

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

PubMed

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heather M; Locke, Adam E; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J; Teslovich, Tanya M; Rayner, N William; Robertson, Neil R; Beer, Nicola L; Rundle, Jana K; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Hanis, Craig L; Seielstad, Mark; Wilson, James G; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L; Doney, Alex S F; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D; Morris, Andrew D; Palmer, Colin N A; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C; Morris, Andrew P; Altshuler, David; Meigs, James B; Boehnke, Michael; McCarthy, Mark I; Lindgren, Cecilia M; Gloyn, Anna L

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

DHAD variants and methods of screening

DOEpatents

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.

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

PubMed Central

Hauke, Jan; Heitz, Florian; Reuss, Alexander; Kommoss, Stefan; Marmé, Frederik; Heimbach, André; Prieske, Katharina; Richters, Lisa; Burges, Alexander; Neidhardt, Guido; de Gregorio, Nikolaus; El-Balat, Ahmed; Hilpert, Felix; Meier, Werner; Kimmig, Rainer; Kast, Karin; Sehouli, Jalid; Baumann, Klaus; Jackisch, Christian; Park-Simon, Tjoung-Won; Hanker, Lars; Kröber, Sandra; Pfisterer, Jacobus; Gevensleben, Heidrun; Schnelzer, Andreas; Dietrich, Dimo; Neunhöffer, Tanja; Krockenberger, Mathias; Brucker, Sara Y.; Nürnberg, Peter; Thiele, Holger; Altmüller, Janine; Lamla, Josefin; Elser, Gabriele; du Bois, Andreas; Hahnen, Eric; Schmutzler, Rita

2017-01-01

Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of

Cellobiohydrolase variants and polynucleotides encoding the same

DOEpatents

Wogulis, Mark

2014-09-09

The present invention relates to variants of a parent cellobiohydrolase. The present invention also relates to polynucleotides encoding the cellobiohydrolase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the cellobiohydrolase variants.

Brain calcifications and PCDH12 variants

PubMed Central

Nicolas, Gaël; Sanchez-Contreras, Monica; Ramos, Eliana Marisa; Lemos, Roberta R.; Ferreira, Joana; Moura, Denis; Sobrido, Maria J.; Richard, Anne-Claire; Lopez, Alma Rosa; Legati, Andrea; Deleuze, Jean-François; Boland, Anne; Quenez, Olivier; Krystkowiak, Pierre; Favrole, Pascal; Geschwind, Daniel H.; Aran, Adi; Segel, Reeval; Levy-Lahad, Ephrat; Dickson, Dennis W.; Coppola, Giovanni; Rademakers, Rosa

2017-01-01

Objective: To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications. Methods: We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC). Results: We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available. Conclusions: Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC. PMID:28804758

Why Learner-Centered New Faculty Orientations Matter: Organizational Culture and Faculty Retention

ERIC Educational Resources Information Center

Scott, Whitney; Lemus, Daisy; Knotts, Greg; Oh, Janet

2016-01-01

A learner-centered New Faculty Orientation (NFO) can be a powerful way to immediately engage new faculty and develop their organizational identification to the institution and its values. Unfortunately, some NFOs do not model a learner-centered philosophy and miss opportunities to establish a collaborative and celebratory tone. In this paper, we…

Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis.

PubMed

Wyatt, Emma E; Galloway, Warren R J D; Thomas, Gemma L; Welch, Martin; Loiseleur, Olivier; Plowright, Alleyn T; Spring, David R

2008-10-28

The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.

An integrative computational approach for prioritization of genomic variants

DOE PAGES

Dubchak, Inna; Balasubramanian, Sandhya; Wang, Sheng; ...

2014-12-15

An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidatemore » genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. This study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.« less

Rare genetic variants and the risk of cancer.

PubMed

Bodmer, Walter; Tomlinson, Ian

2010-06-01

There are good reasons to expect that common genetic variants do not explain all of the inherited risk of the common cancers, not least of these being the relatively low proportion of familial relative risk that common cancer SNPs currently explain. One promising source of the unexplained risk is rare, low-penetrance genetic variants, a class that ranges from low-frequency polymorphisms (allele frequency < 5%) through subpolymorphic variants (frequency 0.1-1.0%) to very low frequency or 'private' variants with frequencies of 0.1% or less. Examples of rare cancer variants include breast cancer susceptibility loci CHEK2, BRIP1 and PALB2. There are considerable challenges associated with the discovery and testing of rare predisposition alleles, many of which are illustrated by the issues associated with variants of unknown significance in the Mendelian cancer predisposition genes. However, whilst cost constraints remain, the technological barriers to rare variant discovery and large-scale genotyping no longer exist. If each individual carries many disease-causing rare variants, the so-called missing heritability of cancer might largely be explained. Whether or not rare variants do end up filling the heritability gap, it is imperative to look for them along side common variants.

A service-oriented data access control model

NASA Astrophysics Data System (ADS)

Meng, Wei; Li, Fengmin; Pan, Juchen; Song, Song; Bian, Jiali

2017-01-01

The development of mobile computing, cloud computing and distributed computing meets the growing individual service needs. Facing with complex application system, it's an urgent problem to ensure real-time, dynamic, and fine-grained data access control. By analyzing common data access control models, on the basis of mandatory access control model, the paper proposes a service-oriented access control model. By regarding system services as subject and data of databases as object, the model defines access levels and access identification of subject and object, and ensures system services securely to access databases.

The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants.

PubMed

Zhang, J; Kuehl, P; Green, E D; Touchman, J W; Watkins, P B; Daly, A; Hall, S D; Maurel, P; Relling, M; Brimer, C; Yasuda, K; Wrighton, S A; Hancock, M; Kim, R B; Strom, S; Thummel, K; Russell, C G; Hudson, J R; Schuetz, E G; Boguski, M S

2001-10-01

The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.

OVA: integrating molecular and physical phenotype data from multiple biomedical domain ontologies with variant filtering for enhanced variant prioritization.

PubMed

Antanaviciute, Agne; Watson, Christopher M; Harrison, Sally M; Lascelles, Carolina; Crinnion, Laura; Markham, Alexander F; Bonthron, David T; Carr, Ian M

2015-12-01

Exome sequencing has become a de facto standard method for Mendelian disease gene discovery in recent years, yet identifying disease-causing mutations among thousands of candidate variants remains a non-trivial task. Here we describe a new variant prioritization tool, OVA (ontology variant analysis), in which user-provided phenotypic information is exploited to infer deeper biological context. OVA combines a knowledge-based approach with a variant-filtering framework. It reduces the number of candidate variants by considering genotype and predicted effect on protein sequence, and scores the remainder on biological relevance to the query phenotype.We take advantage of several ontologies in order to bridge knowledge across multiple biomedical domains and facilitate computational analysis of annotations pertaining to genes, diseases, phenotypes, tissues and pathways. In this way, OVA combines information regarding molecular and physical phenotypes and integrates both human and model organism data to effectively prioritize variants. By assessing performance on both known and novel disease mutations, we show that OVA performs biologically meaningful candidate variant prioritization and can be more accurate than another recently published candidate variant prioritization tool. OVA is freely accessible at http://dna2.leeds.ac.uk:8080/OVA/index.jsp. Supplementary data are available at Bioinformatics online. umaan@leeds.ac.uk. © The Author 2015. Published by Oxford University Press.

Aversive learning shapes neuronal orientation tuning in human visual cortex.

PubMed

McTeague, Lisa M; Gruss, L Forest; Keil, Andreas

2015-07-28

The responses of sensory cortical neurons are shaped by experience. As a result perceptual biases evolve, selectively facilitating the detection and identification of sensory events that are relevant for adaptive behaviour. Here we examine the involvement of human visual cortex in the formation of learned perceptual biases. We use classical aversive conditioning to associate one out of a series of oriented gratings with a noxious sound stimulus. After as few as two grating-sound pairings, visual cortical responses to the sound-paired grating show selective amplification. Furthermore, as learning progresses, responses to the orientations with greatest similarity to the sound-paired grating are increasingly suppressed, suggesting inhibitory interactions between orientation-selective neuronal populations. Changes in cortical connectivity between occipital and fronto-temporal regions mirror the changes in visuo-cortical response amplitudes. These findings suggest that short-term behaviourally driven retuning of human visual cortical neurons involves distal top-down projections as well as local inhibitory interactions.

Interactions of form and orientation

NASA Technical Reports Server (NTRS)

Mittelstaedt, Horst

1989-01-01

It is well known that the orientation of an optical pattern relative to egocentric or extraneous references affects its figural quality, that is, alters its perceived form and concomitantly delays or quickens its identification (Rock 1973). A square presented in the frontal plane to an upright person (S), for instance, changes from a box to a diamond when it is rotated with respect to the S's median plane by 45 deg. This angle, that is, the angle between the orientations of the pattern in which the two apparent figures (Gestalten) attain a summit of purity and distinctness, will be called the figural disparity of the pattern. If, as in this case, the S is upright, the retinal meridian and the subjective vertical (SV) are both in the viewer's median plane. The question arises with respect to which of these orientation references the two figures are identified. The answer may be found when the pattern and the S are oriented in such a way that the projections of the retinal meridian and the SV into the plane of the pattern diverge by the pattern's figural disparity or its periodic multiples: that is, in this case of a square by 45 or 135 deg, respectively. Similarly, which reference determines whether an equilateral triangle is seen as a pyramid or a traffic warning sign may be revealed at a divergence of SV and retinal meridian of 60 or 180 deg, respectively. It is generally found that for head roll tilts (Rho) and figural disparities of up to 90 deg, the figure whose axis coincides with the SV is seen. At head tilts of Rho=180 deg, however, the retinal reference dominates, as a rule independently of the figural disparity.

High-resolution genetic mapping of allelic variants associated with cell wall chemistry in Populus

DOE PAGES

Muchero, Wellington; Guo, Jianjun; Difazio, Stephen P.; ...

2015-01-23

We report the identification of six genetic loci and the allelic-variants associated with Populus cell wall phenotypes determined independently using pyrolysis Molecular Beam Mass Spectrometry (pyMBMS), saccharification assay and wet chemistry in two partially overlapping populations of P. trichocarpa genotypes sampled from multiple environments in the Pacific Northwest of North America. All 6 variants co-located with a quantitative trait locus (QTL) hotspot on chromosome XIV for lignin content, syringyl to guaiacyl (S/G) ratio, 5- and 6- carbon sugars identified in an interspecific P. trichocarpa x P. deltoides pseudo-backcross mapping pedigree. Genomic intervals containing an amino acid transporter, a MYB transcriptionmore » factor, an angustifolia CtBP transcription factor, a copper transport protein ATOX1-related, a Ca 2+ transporting ATPase and a protein kinase were identified within 5 QTL regions. Each interval contained single nucleotide polymorphisms (SNPs) that were significantly associated to cell-wall phenotypes, with associations exceeding the chromosome-wise Bonferroni-adjusted p-values in at least one environment. cDNA sequencing for allelic variants of 3 of the 6 genes identified polymorphisms leading to premature stop codons in the MYB transcription factor and protein kinase. On the other hand, variants of the Angustifolia CtBP transcription factor exhibited a polyglutamine (PolyQ) length polymorphism. Results from transient protoplast assays suggested that each of the polymorphisms conferred allelic differences in activation of cellulose, hemicelluloses and lignin pathway marker genes, with truncated and short PolyQ alleles exhibiting significantly reduced marker gene activation. Genes identified in this study represent novel targets for reducing cell wall recalcitrance for lignocellulosic biofuels production using plant biomass.« less

The curation of genetic variants: difficulties and possible solutions.

PubMed

Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

2012-12-01

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. Copyright © 2012. Published by Elsevier Ltd.

The Curation of Genetic Variants: Difficulties and Possible Solutions

PubMed Central

Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

2012-01-01

The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. PMID:23317699

Rare Variant Association Test with Multiple Phenotypes

PubMed Central

Lee, Selyeong; Won, Sungho; Kim, Young Jin; Kim, Yongkang; Kim, Bong-Jo; Park, Taesung

2016-01-01

Although genome-wide association studies (GWAS) have now discovered thousands of genetic variants associated with common traits, such variants cannot explain the large degree of “missing heritability,” likely due to rare variants. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait. Although multiply correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used. However, few existing multi-variant analyses can identify rare variants for assessing multiple phenotypes. Here, we propose Multivariate Association Analysis using Score Statistics (MAAUSS), to identify rare variants associated with multiple phenotypes, based on the widely used Sequence Kernel Association Test (SKAT) for a single phenotype. We applied MAAUSS to Whole Exome Sequencing (WES) data from a Korean population of 1,058 subjects, to discover genes associated with multiple traits of liver function. We then assessed validation of those genes by a replication study, using an independent dataset of 3,445 individuals. Notably, we detected the gene ZNF620 among five significant genes. We then performed a simulation study to compare MAAUSS's performance with existing methods. Overall, MAAUSS successfully conserved type 1 error rates and in many cases, had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability. PMID:28039885

Crystal Structure of an Activated Variant of Small Heat Shock Protein Hsp16.5

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mchaourab, Hassane S.; Lin, Yi-Lun; Spiller, Benjamin W.

How does the sequence of a single small heat shock protein (sHSP) assemble into oligomers of different sizes? To gain insight into the underlying structural mechanism, we determined the crystal structure of an engineered variant of Methanocaldococcus jannaschii Hsp16.5 wherein a 14 amino acid peptide from human heat shock protein 27 (Hsp27) was inserted at the junction of the N-terminal region and the {alpha}-crystallin domain. In response to this insertion, the oligomer shell expands from 24 to 48 subunits while maintaining octahedral symmetry. Oligomer rearrangement does not alter the fold of the conserved {alpha}-crystallin domain nor does it disturb themore » interface holding the dimeric building block together. Rather, the flexible C-terminal tail of Hsp16.5 changes its orientation relative to the {alpha}-crystallin domain which enables alternative packing of dimers. This change in orientation preserves a peptide-in-groove interaction of the C-terminal tail with an adjacent {beta}-sandwich, thereby holding the assembly together. The interior of the expanded oligomer, where substrates presumably bind, retains its predominantly nonpolar character relative to the outside surface. New large windows in the outer shell provide increased access to these substrate-binding regions, thus accounting for the higher affinity of this variant to substrates. Oligomer polydispersity regulates sHSPs chaperone activity in vitro and has been implicated in their physiological roles. The structural mechanism of Hsp16.5 oligomer flexibility revealed here, which is likely to be highly conserved across the sHSP superfamily, explains the relationship between oligomer expansion observed in disease-linked mutants and changes in chaperone activity.« less

Crystal structure of an activated variant of small heat shock protein Hsp16.5.

PubMed

McHaourab, Hassane S; Lin, Yi-Lun; Spiller, Benjamin W

2012-06-26

How does the sequence of a single small heat shock protein (sHSP) assemble into oligomers of different sizes? To gain insight into the underlying structural mechanism, we determined the crystal structure of an engineered variant of Methanocaldococcus jannaschii Hsp16.5 wherein a 14 amino acid peptide from human heat shock protein 27 (Hsp27) was inserted at the junction of the N-terminal region and the α-crystallin domain. In response to this insertion, the oligomer shell expands from 24 to 48 subunits while maintaining octahedral symmetry. Oligomer rearrangement does not alter the fold of the conserved α-crystallin domain nor does it disturb the interface holding the dimeric building block together. Rather, the flexible C-terminal tail of Hsp16.5 changes its orientation relative to the α-crystallin domain which enables alternative packing of dimers. This change in orientation preserves a peptide-in-groove interaction of the C-terminal tail with an adjacent β-sandwich, thereby holding the assembly together. The interior of the expanded oligomer, where substrates presumably bind, retains its predominantly nonpolar character relative to the outside surface. New large windows in the outer shell provide increased access to these substrate-binding regions, thus accounting for the higher affinity of this variant to substrates. Oligomer polydispersity regulates sHSPs chaperone activity in vitro and has been implicated in their physiological roles. The structural mechanism of Hsp16.5 oligomer flexibility revealed here, which is likely to be highly conserved across the sHSP superfamily, explains the relationship between oligomer expansion observed in disease-linked mutants and changes in chaperone activity.

Rare variants and cardiovascular disease.

PubMed

Wain, Louise V

2014-09-01

Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the Western world. Large genome-wide association studies (GWASs) of coronary artery disease, myocardial infarction, stroke and dilated cardiomyopathy have identified a number of common genetic variants with modest effects on disease risk. Similarly, studies of important modifiable risk factors of CVD have identified a large number of predominantly common variant associations, for example, with blood pressure and blood lipid levels. In each case, despite the often large numbers of loci identified, only a small proportion of the phenotypic variance is explained. It has been hypothesised that rare variants with large effects may account for some of the missing variance but large-scale studies of rare variation are in their infancy for cardiovascular traits and have yet to produce fruitful results. Studies of monogenic CVDs, inherited disorders believed to be entirely driven by individual rare mutations, have highlighted genes that play a key role in disease aetiology. In this review, we discuss how findings from studies of rare variants in monogenic disease and GWAS of predominantly common variants are converging to provide further insight into biological disease mechanisms. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

TREM2 Variants in Alzheimer's Disease

PubMed Central

Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

2013-01-01

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

Inverse modeling of rainfall infiltration with a dual permeability approach using different matrix-fracture coupling variants.

NASA Astrophysics Data System (ADS)

Blöcher, Johanna; Kuraz, Michal

2017-04-01

In this contribution we propose implementations of the dual permeability model with different inter-domain exchange descriptions and metaheuristic optimization algorithms for parameter identification and mesh optimization. We compare variants of the coupling term with different numbers of parameters to test if a reduction of parameters is feasible. This can reduce parameter uncertainty in inverse modeling, but also allow for different conceptual models of the domain and matrix coupling. The different variants of the dual permeability model are implemented in the open-source objective library DRUtES written in FORTRAN 2003/2008 in 1D and 2D. For parameter identification we use adaptations of the particle swarm optimization (PSO) and Teaching-learning-based optimization (TLBO), which are population-based metaheuristics with different learning strategies. These are high-level stochastic-based search algorithms that don't require gradient information or a convex search space. Despite increasing computing power and parallel processing, an overly fine mesh is not feasible for parameter identification. This creates the need to find a mesh that optimizes both accuracy and simulation time. We use a bi-objective PSO algorithm to generate a Pareto front of optimal meshes to account for both objectives. The dual permeability model and the optimization algorithms were tested on virtual data and field TDR sensor readings. The TDR sensor readings showed a very steep increase during rapid rainfall events and a subsequent steep decrease. This was theorized to be an effect of artificial macroporous envelopes surrounding TDR sensors creating an anomalous region with distinct local soil hydraulic properties. One of our objectives is to test how well the dual permeability model can describe this infiltration behavior and what coupling term would be most suitable.

Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases.

PubMed

Vail, Paris J; Morris, Brian; van Kan, Aric; Burdett, Brianna C; Moyes, Kelsey; Theisen, Aaron; Kerr, Iain D; Wenstrup, Richard J; Eggington, Julie M

2015-10-01

Genetic variants of uncertain clinical significance (VUSs) are a common outcome of clinical genetic testing. Locus-specific variant databases (LSDBs) have been established for numerous disease-associated genes as a research tool for the interpretation of genetic sequence variants to facilitate variant interpretation via aggregated data. If LSDBs are to be used for clinical practice, consistent and transparent criteria regarding the deposition and interpretation of variants are vital, as variant classifications are often used to make important and irreversible clinical decisions. In this study, we performed a retrospective analysis of 2017 consecutive BRCA1 and BRCA2 genetic variants identified from 24,650 consecutive patient samples referred to our laboratory to establish an unbiased dataset representative of the types of variants seen in the US patient population, submitted by clinicians and researchers for BRCA1 and BRCA2 testing. We compared the clinical classifications of these variants among five publicly accessible BRCA1 and BRCA2 variant databases: BIC, ClinVar, HGMD (paid version), LOVD, and the UMD databases. Our results show substantial disparity of variant classifications among publicly accessible databases. Furthermore, it appears that discrepant classifications are not the result of a single outlier but widespread disagreement among databases. This study also shows that databases sometimes favor a clinical classification when current best practice guidelines (ACMG/AMP/CAP) would suggest an uncertain classification. Although LSDBs have been well established for research applications, our results suggest several challenges preclude their wider use in clinical practice.

ANTIGENIC VARIANTS OF INFLUENZA A VIRUS (PR8 STRAIN)

PubMed Central

Hamre, Dorothy; Loosli, Clayton G.; Gerber, Paul

1958-01-01

Seven variant strains of influenza A PR8-S virus, each derived from the previous one by serial passage in the lungs of mice immunized with the homologous agent have been produced. With the H.I. and neutralization procedures these variants showed a progressive serological deviation from the parent PR8-S virus. The seven variants provoked antibodies in varying titers to the preceding variants and the parent virus but not in relation to their position in the series. Thus, the seventh variant provoked significantly more antibody to the PR8-S virus than did the fifth variant. A possible explanation for this is presented. The first four variant viruses showed progressively less ability to react with antisera of the preceding variants and the PR8-S virus, and the three most recently derived variants showed essentially no ability to react with PR8-S and first variant antisera. The variant viruses remained antigenically stable through numerous lung passages in normal mice. Cross absorption tests revealed common antigenic components among the variant viruses and also individual characteristics which classify them as being different from one another. The implications of these findings in relation to studies by others have been discussed. PMID:13539308

Characteristics of MUTYH variants in Japanese colorectal polyposis patients.

PubMed

Takao, Misato; Yamaguchi, Tatsuro; Eguchi, Hidetaka; Tada, Yuhki; Kohda, Masakazu; Koizumi, Koichi; Horiguchi, Shin-Ichiro; Okazaki, Yasushi; Ishida, Hideyuki

2018-06-01

The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis. After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH. Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants 'pathogenic' were lacking. Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods

PubMed Central

Arora, Sanjeevani; Huwe, Peter J.; Sikder, Rahmat; Shah, Manali; Browne, Amanda J.; Lesh, Randy; Nicolas, Emmanuelle; Deshpande, Sanat; Hall, Michael J.; Dunbrack, Roland L.; Golemis, Erica A.

2017-01-01

ABSTRACT The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6, and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes. We evaluated the performance of multiple predictive programs in the context of functional biologic data for 15 VUS in MLH1, MSH2, and PMS2. Using cell line models, we characterized VUS predicted to range from neutral to pathogenic on mRNA and protein expression, basal cellular viability, viability following treatment with a panel of DNA-damaging agents, and functionality in DNA damage response (DDR) signaling, benchmarking to wild-type MMR proteins. Our results suggest that the MMR gene-specific classifiers do not always align with the experimental phenotypes related to DDR. Our study highlights the importance of complementary experimental and computational assessment to develop future predictors for the assessment of VUS. PMID:28494185

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

PubMed

Reijnders, Margot R F; Miller, Kerry A; Alvi, Mohsan; Goos, Jacqueline A C; Lees, Melissa M; de Burca, Anna; Henderson, Alex; Kraus, Alison; Mikat, Barbara; de Vries, Bert B A; Isidor, Bertrand; Kerr, Bronwyn; Marcelis, Carlo; Schluth-Bolard, Caroline; Deshpande, Charu; Ruivenkamp, Claudia A L; Wieczorek, Dagmar; Baralle, Diana; Blair, Edward M; Engels, Hartmut; Lüdecke, Hermann-Josef; Eason, Jacqueline; Santen, Gijs W E; Clayton-Smith, Jill; Chandler, Kate; Tatton-Brown, Katrina; Payne, Katelyn; Helbig, Katherine; Radtke, Kelly; Nugent, Kimberly M; Cremer, Kirsten; Strom, Tim M; Bird, Lynne M; Sinnema, Margje; Bitner-Glindzicz, Maria; van Dooren, Marieke F; Alders, Marielle; Koopmans, Marije; Brick, Lauren; Kozenko, Mariya; Harline, Megan L; Klaassens, Merel; Steinraths, Michelle; Cooper, Nicola S; Edery, Patrick; Yap, Patrick; Terhal, Paulien A; van der Spek, Peter J; Lakeman, Phillis; Taylor, Rachel L; Littlejohn, Rebecca O; Pfundt, Rolph; Mercimek-Andrews, Saadet; Stegmann, Alexander P A; Kant, Sarina G; McLean, Scott; Joss, Shelagh; Swagemakers, Sigrid M A; Douzgou, Sofia; Wall, Steven A; Küry, Sébastien; Calpena, Eduardo; Koelling, Nils; McGowan, Simon J; Twigg, Stephen R F; Mathijssen, Irene M J; Nellaker, Christoffer; Brunner, Han G; Wilkie, Andrew O M

2018-06-07

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

CoVaCS: a consensus variant calling system.

PubMed

Chiara, Matteo; Gioiosa, Silvia; Chillemi, Giovanni; D'Antonio, Mattia; Flati, Tiziano; Picardi, Ernesto; Zambelli, Federico; Horner, David Stephen; Pesole, Graziano; Castrignanò, Tiziana

2018-02-05

The advent and ongoing development of next generation sequencing technologies (NGS) has led to a rapid increase in the rate of human genome re-sequencing data, paving the way for personalized genomics and precision medicine. The body of genome resequencing data is progressively increasing underlining the need for accurate and time-effective bioinformatics systems for genotyping - a crucial prerequisite for identification of candidate causal mutations in diagnostic screens. Here we present CoVaCS, a fully automated, highly accurate system with a web based graphical interface for genotyping and variant annotation. Extensive tests on a gold standard benchmark data-set -the NA12878 Illumina platinum genome- confirm that call-sets based on our consensus strategy are completely in line with those attained by similar command line based approaches, and far more accurate than call-sets from any individual tool. Importantly our system exhibits better sensitivity and higher specificity than equivalent commercial software. CoVaCS offers optimized pipelines integrating state of the art tools for variant calling and annotation for whole genome sequencing (WGS), whole-exome sequencing (WES) and target-gene sequencing (TGS) data. The system is currently hosted at Cineca, and offers the speed of a HPC computing facility, a crucial consideration when large numbers of samples must be analysed. Importantly, all the analyses are performed automatically allowing high reproducibility of the results. As such, we believe that CoVaCS can be a valuable tool for the analysis of human genome resequencing studies. CoVaCS is available at: https://bioinformatics.cineca.it/covacs .

Detection of influenza antigenic variants directly from clinical samples using polyclonal antibody based proximity ligation assays

PubMed Central

Martin, Brigitte E.; Jia, Kun; Sun, Hailiang; Ye, Jianqiang; Hall, Crystal; Ware, Daphne; Wan, Xiu-Feng

2016-01-01

Identification of antigenic variants is the key to a successful influenza vaccination program. The empirical serological methods to determine influenza antigenic properties require viral propagation. Here a novel quantitative PCR-based antigenic characterization method using polyclonal antibody and proximity ligation assays, or so-called polyPLA, was developed and validated. This method can detect a viral titer that is less than 1000 TCID50/mL. Not only can this method differentiate between different HA subtypes of influenza viruses but also effectively identify antigenic drift events within the same HA subtype of influenza viruses. Applications in H3N2 seasonal influenza data showed that the results from this novel method are consistent with those from the conventional serological assays. This method is not limited to the detection of antigenic variants in influenza but also other pathogens. It has the potential to be applied through a large-scale platform in disease surveillance requiring minimal biosafety and directly using clinical samples. PMID:25546251

Promising Variants of Initiation of Martensitic γ - α Transformation in Iron Alloys by a Couple of Elastic Waves

NASA Astrophysics Data System (ADS)

Kashchenko, M. P.; Chashchina, V. G.

2016-01-01

Variants of initiation of growth of crystals of α-martensite by couples of elastic waves propagating in directions <001>γ and <110>γ in singles crystals of Fe31Ni are suggested. The dynamic theory is used to show that the expected orientations of habit planes {110}γ, {001}γ and {559}γ differ from the typical {31015}γ. Possible features of tetragonality of martensite crystals are discussed. The power of the sources of ultrasound required for initiation of γ - α martensitic transformation is estimated.

Identification of new TSGA10 transcript variants in human testis with conserved regulatory RNA elements in 5'untranslated region and distinct expression in breast cancer.

PubMed

Salehipour, Pouya; Nematzadeh, Mahsa; Mobasheri, Maryam Beigom; Afsharpad, Mandana; Mansouri, Kamran; Modarressi, Mohammad Hossein

2017-09-01

Testis specific gene antigen 10 (TSGA10) is a cancer testis antigen involved in the process of spermatogenesis. TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α. Although it has been shown that TSGA10 messenger RNA (mRNA) is mainly expressed in testis and some tumors, the transcription pattern and regulatory mechanisms of this gene remain largely unknown. Here, we report that human TSGA10 comprises at least 22 exons and generates four different transcript variants. It was identified that using two distinct promoters and splicing of exons 4 and 7 produced these transcript variants, which have the same coding sequence, but the sequence of 5'untanslated region (5'UTR) is different between them. This is significant because conserved regulatory RNA elements like upstream open reading frame (uORF) and putative internal ribosome entry site (IRES) were found in this region which have different combinations in each transcript variant and it may influence translational efficiency of them in normal or unusual environmental conditions like hypoxia. To indicate the transcription pattern of TSGA10 in breast cancer, expression of identified transcript variants was analyzed in 62 breast cancer samples. We found that TSGA10 tends to express variants with shorter 5'UTR and fewer uORF elements in breast cancer tissues. Our study demonstrates for the first time the expression of different TSGA10 transcript variants in testis and breast cancer tissues and provides a first clue to a role of TSGA10 5'UTR in regulation of translation in unusual environmental conditions like hypoxia. Copyright © 2017. Published by Elsevier B.V.

Influence of Hydrogen and Number of Particle Variants on Ordinary and Two-Way Shape Memory Effects in Ti-Ni Single Crystals

NASA Astrophysics Data System (ADS)

Kireeva, I. V.; Platonova, Yu. N.; Chumlyakov, Yu. I.

2017-02-01

The ordinary and two-way shape memory effects (SMEs) are investigated for [ overline{1} 12] single crystals of Ti-51.3Ni (at.%) alloy aged at 823 K for 1.5 h in free state and under tensile stress of 150 MPa without hydrogen and after saturation by hydrogen. It is established that without hydrogen in [ overline{1} 12] single crystals with one and four variants of Ti3Ni4 particles the maximum magnitude of the ordinary SME is 1.9-2.6% under the external stress σext = 250 MPa. Under σext > 250 MPa, crystals are destroyed. The magnitude of the two-way SME caused by the B2- R- B19' MT equal to 1.1% at σext = 0 is observed in [ overline{1} 12] single crystals with one variant of Ti3Ni4 particles. The physical reason for the observed two-way SME is the internal compressive stresses oriented along the [ overline{1} 12] directions arising from one variant of Ti3Ni4 particles as a result of aging under tensile stress of 150 MPa. It is established that hydrogen does not influence the TR temperature, reduces the plasticity, and suppresses the two-way SME. The suppression of two-way SME in the [ overline{1} 12] single crystals of the Ti-51.3Ni (at.%) alloy with one variant of Ti3Ni4 particles is caused by shielding of stress fields from one variant of Ti3Ni4 particles and multiple nucleation of R- and B19' martensite variants under loading with saturation by hydrogen.

Fiber orientation interpolation for the multiscale analysis of short fiber reinforced composite parts

NASA Astrophysics Data System (ADS)

Köbler, Jonathan; Schneider, Matti; Ospald, Felix; Andrä, Heiko; Müller, Ralf

2018-06-01

For short fiber reinforced plastic parts the local fiber orientation has a strong influence on the mechanical properties. To enable multiscale computations using surrogate models we advocate a two-step identification strategy. Firstly, for a number of sample orientations an effective model is derived by numerical methods available in the literature. Secondly, to cover a general orientation state, these effective models are interpolated. In this article we develop a novel and effective strategy to carry out this interpolation. Firstly, taking into account symmetry arguments, we reduce the fiber orientation phase space to a triangle in R^2 . For an associated triangulation of this triangle we furnish each node with an surrogate model. Then, we use linear interpolation on the fiber orientation triangle to equip each fiber orientation state with an effective stress. The proposed approach is quite general, and works for any physically nonlinear constitutive law on the micro-scale, as long as surrogate models for single fiber orientation states can be extracted. To demonstrate the capabilities of our scheme we study the viscoelastic creep behavior of short glass fiber reinforced PA66, and use Schapery's collocation method together with FFT-based computational homogenization to derive single orientation state effective models. We discuss the efficient implementation of our method, and present results of a component scale computation on a benchmark component by using ABAQUS ®.

Fiber orientation interpolation for the multiscale analysis of short fiber reinforced composite parts

NASA Astrophysics Data System (ADS)

Köbler, Jonathan; Schneider, Matti; Ospald, Felix; Andrä, Heiko; Müller, Ralf

2018-04-01

For short fiber reinforced plastic parts the local fiber orientation has a strong influence on the mechanical properties. To enable multiscale computations using surrogate models we advocate a two-step identification strategy. Firstly, for a number of sample orientations an effective model is derived by numerical methods available in the literature. Secondly, to cover a general orientation state, these effective models are interpolated. In this article we develop a novel and effective strategy to carry out this interpolation. Firstly, taking into account symmetry arguments, we reduce the fiber orientation phase space to a triangle in R^2 . For an associated triangulation of this triangle we furnish each node with an surrogate model. Then, we use linear interpolation on the fiber orientation triangle to equip each fiber orientation state with an effective stress. The proposed approach is quite general, and works for any physically nonlinear constitutive law on the micro-scale, as long as surrogate models for single fiber orientation states can be extracted. To demonstrate the capabilities of our scheme we study the viscoelastic creep behavior of short glass fiber reinforced PA66, and use Schapery's collocation method together with FFT-based computational homogenization to derive single orientation state effective models. We discuss the efficient implementation of our method, and present results of a component scale computation on a benchmark component by using ABAQUS ®.

A Bioinformatics Approach to the Identification of Variants Associated with Type 1 and Type 2 Diabetes Mellitus that Reside in Functionally Validated miRNAs Binding Sites.

PubMed

Ghaedi, Hamid; Bastami, Milad; Jahani, Mohammad Mehdi; Alipoor, Behnam; Tabasinezhad, Maryam; Ghaderi, Omar; Nariman-Saleh-Fam, Ziba; Mirfakhraie, Reza; Movafagh, Abolfazl; Omrani, Mir Davood; Masotti, Andrea

2016-06-01

The present work is aimed at finding variants associated with Type 1 and Type 2 diabetes mellitus (DM) that reside in functionally validated miRNAs binding sites and that can have a functional role in determining diabetes and related pathologies. Using bioinformatics analyses we obtained a database of validated polymorphic miRNA binding sites which has been intersected with genes related to DM or to variants associated and/or in linkage disequilibrium (LD) with it and is reported in genome-wide association studies (GWAS). The workflow we followed allowed us to find variants associated with DM that also reside in functional miRNA binding sites. These data have been demonstrated to have a functional role by impairing the functions of genes implicated in biological processes linked to DM. In conclusion, our work emphasized the importance of SNPs located in miRNA binding sites. The results discussed in this work may constitute the basis of further works aimed at finding functional candidates and variants affecting protein structure and function, transcription factor binding sites, and non-coding epigenetic variants, contributing to widen the knowledge about the pathogenesis of this important disease.

Automatic identification of agricultural terraces through object-oriented analysis of very high resolution DSMs and multispectral imagery obtained from an unmanned aerial vehicle.

PubMed

Diaz-Varela, R A; Zarco-Tejada, P J; Angileri, V; Loudjani, P

2014-02-15

Agricultural terraces are features that provide a number of ecosystem services. As a result, their maintenance is supported by measures established by the European Common Agricultural Policy (CAP). In the framework of CAP implementation and monitoring, there is a current and future need for the development of robust, repeatable and cost-effective methodologies for the automatic identification and monitoring of these features at farm scale. This is a complex task, particularly when terraces are associated to complex vegetation cover patterns, as happens with permanent crops (e.g. olive trees). In this study we present a novel methodology for automatic and cost-efficient identification of terraces using only imagery from commercial off-the-shelf (COTS) cameras on board unmanned aerial vehicles (UAVs). Using state-of-the-art computer vision techniques, we generated orthoimagery and digital surface models (DSMs) at 11 cm spatial resolution with low user intervention. In a second stage, these data were used to identify terraces using a multi-scale object-oriented classification method. Results show the potential of this method even in highly complex agricultural areas, both regarding DSM reconstruction and image classification. The UAV-derived DSM had a root mean square error (RMSE) lower than 0.5 m when the height of the terraces was assessed against field GPS data. The subsequent automated terrace classification yielded an overall accuracy of 90% based exclusively on spectral and elevation data derived from the UAV imagery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Histone H3 Variants in Trichomonas vaginalis

PubMed Central

Zubáčová, Zuzana; Hostomská, Jitka

2012-01-01

The parabasalid protist Trichomonas vaginalis is a widespread parasite that affects humans, frequently causing vaginitis in infected women. Trichomonad mitosis is marked by the persistence of the nuclear membrane and the presence of an asymmetric extranuclear spindle with no obvious direct connection to the chromosomes. No centromeric markers have been described in T. vaginalis, which has prevented a detailed analysis of mitotic events in this organism. In other eukaryotes, nucleosomes of centromeric chromatin contain the histone H3 variant CenH3. The principal aim of this work was to identify a CenH3 homolog in T. vaginalis. We performed a screen of the T. vaginalis genome to retrieve sequences of canonical and variant H3 histones. Three variant histone H3 proteins were identified, and the subcellular localization of their epitope-tagged variants was determined. The localization of the variant TVAG_185390 could not be distinguished from that of the canonical H3 histone. The sequence of the variant TVAG_087830 closely resembled that of histone H3. The tagged protein colocalized with sites of active transcription, indicating that the variant TVAG_087830 represented H3.3 in T. vaginalis. The third H3 variant (TVAG_224460) was localized to 6 or 12 distinct spots at the periphery of the nucleus, corresponding to the number of chromosomes in G1 phase and G2 phase, respectively. We propose that this variant represents the centromeric marker CenH3 and thus can be employed as a tool to study mitosis in T. vaginalis. Furthermore, we suggest that the peripheral distribution of CenH3 within the nucleus results from the association of centromeres with the nuclear envelope throughout the cell cycle. PMID:22408228

False discovery rates in spectral identification.

PubMed

Jeong, Kyowon; Kim, Sangtae; Bandeira, Nuno

2012-01-01

Automated database search engines are one of the fundamental engines of high-throughput proteomics enabling daily identifications of hundreds of thousands of peptides and proteins from tandem mass (MS/MS) spectrometry data. Nevertheless, this automation also makes it humanly impossible to manually validate the vast lists of resulting identifications from such high-throughput searches. This challenge is usually addressed by using a Target-Decoy Approach (TDA) to impose an empirical False Discovery Rate (FDR) at a pre-determined threshold x% with the expectation that at most x% of the returned identifications would be false positives. But despite the fundamental importance of FDR estimates in ensuring the utility of large lists of identifications, there is surprisingly little consensus on exactly how TDA should be applied to minimize the chances of biased FDR estimates. In fact, since less rigorous TDA/FDR estimates tend to result in more identifications (at higher 'true' FDR), there is often little incentive to enforce strict TDA/FDR procedures in studies where the major metric of success is the size of the list of identifications and there are no follow up studies imposing hard cost constraints on the number of reported false positives. Here we address the problem of the accuracy of TDA estimates of empirical FDR. Using MS/MS spectra from samples where we were able to define a factual FDR estimator of 'true' FDR we evaluate several popular variants of the TDA procedure in a variety of database search contexts. We show that the fraction of false identifications can sometimes be over 10× higher than reported and may be unavoidably high for certain types of searches. In addition, we further report that the two-pass search strategy seems the most promising database search strategy. While unavoidably constrained by the particulars of any specific evaluation dataset, our observations support a series of recommendations towards maximizing the number of resulting

The effect of grain orientation on nanoindentation behavior of model austenitic alloy Fe-20Cr-25Ni

DOE PAGES

Chen, Tianyi; Tan, Lizhen; Lu, Zizhe; ...

2017-07-26

Instrumented nanoindentation was used in this paper to investigate the hardness, elastic modulus, and creep behavior of an austenitic Fe-20Cr-25Ni model alloy at room temperature, with the indented grain orientation being the variant. The samples indented close to the {111} surfaces exhibited the highest hardness and modulus. However, nanoindentation creep tests showed the greatest tendency for creep in the {111} indented samples, compared with the samples indented close to the {001} and {101} surfaces. Scanning electron microscopy and cross-sectional transmission electron microscopy revealed slip bands and dislocations in all samples. The slip band patterns on the indented surfaces were influencedmore » by the grain orientations. Deformation twinning was observed only under the {001} indented surfaces. Finally, microstructural analysis and molecular dynamics modeling correlated the anisotropic nanoindentation-creep behavior with the different dislocation substructures formed during indentation, which resulted from the dislocation reactions of certain active slip systems that are determined by the indented grain orientations.« less

A particle swarm optimization variant with an inner variable learning strategy.

PubMed

Wu, Guohua; Pedrycz, Witold; Ma, Manhao; Qiu, Dishan; Li, Haifeng; Liu, Jin

2014-01-01

Although Particle Swarm Optimization (PSO) has demonstrated competitive performance in solving global optimization problems, it exhibits some limitations when dealing with optimization problems with high dimensionality and complex landscape. In this paper, we integrate some problem-oriented knowledge into the design of a certain PSO variant. The resulting novel PSO algorithm with an inner variable learning strategy (PSO-IVL) is particularly efficient for optimizing functions with symmetric variables. Symmetric variables of the optimized function have to satisfy a certain quantitative relation. Based on this knowledge, the inner variable learning (IVL) strategy helps the particle to inspect the relation among its inner variables, determine the exemplar variable for all other variables, and then make each variable learn from the exemplar variable in terms of their quantitative relations. In addition, we design a new trap detection and jumping out strategy to help particles escape from local optima. The trap detection operation is employed at the level of individual particles whereas the trap jumping out strategy is adaptive in its nature. Experimental simulations completed for some representative optimization functions demonstrate the excellent performance of PSO-IVL. The effectiveness of the PSO-IVL stresses a usefulness of augmenting evolutionary algorithms by problem-oriented domain knowledge.

Sexual Orientation Self-Presentation Among Bisexual-Identified Women and Men: Patterns and Predictors.

PubMed

Mohr, Jonathan J; Jackson, Skyler D; Sheets, Raymond L

2017-07-01

Writing on the experiences of bisexual-identified people has highlighted the potential complexity of the ongoing process of deciding when and how to present one's sexual orientation identity to others (Rust, 2002). The two studies presented here were designed to contribute basic knowledge regarding self-presentation of sexual orientation among bisexual people. In Study 1, bisexual participants (N = 147) were less likely than their lesbian and gay (LG) peers (N = 191) to present their actual orientation to others, and more likely to present themselves as having a sexual orientation different from their actual orientation. These sexual orientation differences were explained by gender of romantic partner and uncertainty about one's sexual orientation. Sexual orientation differences also emerged in links between self-presentation and outness level. For example, bisexual participants who presented themselves as LG had relatively high everyday outness levels; in contrast, LG participants who presented themselves as bisexual had relatively low everyday outness levels. In Study 2, 240 bisexual women and men indicated their levels of outness as a sexual minority person (potentially including identification as gay, lesbian, queer) and specifically as bisexual. Outness was higher with respect to status as a sexual minority compared to status as bisexual; the magnitude of this difference was predicted by gender of romantic partner and uncertainty about one's sexual orientation. Moreover, even controlling for outness as a sexual minority person, well-being was predicted by outness as bisexual to family members.

Variant adrenal venous anatomy in 546 laparoscopic adrenalectomies.

PubMed

Scholten, Anouk; Cisco, Robin M; Vriens, Menno R; Shen, Wen T; Duh, Quan-Yang

2013-04-01

Knowing the types and frequency of adrenal vein variants would help surgeons identify and control the adrenal vein during laparoscopic adrenalectomy. To establish the surgical anatomy of the main vein and its variants for laparoscopic adrenalectomy and to analyze the relationship between variant adrenal venous anatomy and tumor size, pathologic diagnosis, and operative outcomes. In a retrospective review of patients at a tertiary referral hospital, 506 patients underwent 546 consecutive laparoscopic adrenalectomies between April 22, 1993, and October 21, 2011. Patients with variant adrenal venous anatomy were compared with patients with normal adrenal venous anatomy regarding preoperative variables (patient and tumor characteristics [size and location] and clinical diagnosis), intraoperative variables (details on the main adrenal venous drainage, any variant venous anatomy, duration of operation, rate of conversion to hand-assisted or open procedure, and estimated blood loss), and postoperative variables (transfusion requirement, reoperation for bleeding, duration of hospital stay, and histologic diagnosis). Laparoscopic adrenalectomy. Prevalence of variant adrenal venous anatomy and its relationship to tumor characteristics, pathologic diagnosis, and operative outcomes. Variant venous anatomy was encountered in 70 of 546 adrenalectomies (13%). Variants included no main adrenal vein identifiable (n = 18), 1 main adrenal vein with additional small veins (n = 11), 2 adrenal veins (n = 20), more than 2 adrenal veins (n = 14), and variants of the adrenal vein drainage to the inferior vena cava and hepatic vein or of the inferior phrenic vein (n = 7). Variants occurred more often on the right side than on the left side (42 of 250 glands [17%] vs. 28 of 296 glands [9%], respectively; P = .02). Patients with variant anatomy compared with those with normal anatomy had larger tumors (mean, 5.1 vs 3.3 cm, respectively; P < .001), more pheochromocytomas (24 of 70 [35%] vs

How preserved is episodic memory in behavioral variant frontotemporal dementia?

PubMed

Hornberger, M; Piguet, O; Graham, A J; Nestor, P J; Hodges, J R

2010-02-09

Studies have shown variable memory performance in patients with behavioral variant frontotemporal dementia (bvFTD). Our study investigated whether this variability is due to the admixture of patients with true bvFTD and phenocopy patients. We also sought to compare performance of patients with bvFTD and patients with Alzheimer disease (AD). We analyzed neuropsychological memory performance in patients with a clinical diagnosis of bvFTD divided into those who progressed (n = 50) and those who remained stable (n = 39), patients with AD (n = 64), and healthy controls (n = 64). Patients with progressive bvFTD were impaired on most memory tests to a similar level to that of patients with early AD. Findings from a subset of patients with progressive bvFTD with confirmed FTLD pathology (n = 10) corroborated these findings. By contrast, patients with phenocopy bvFTD performed significantly better than progressors and patients with AD. Logistic regression revealed that patients with bvFTD can be distinguished to a high degree (85%) on the immediate recall score of a word list learning test (Rey Auditory Verbal Learning Test). Our results provide evidence for an underlying memory deficit in "real" or progressive behavioral variant frontotemporal dementia (bvFTD) similar to Alzheimer disease, though the groups differ in orientation scores, with patients with bvFTD being intact. Exclusion solely based on impaired neuropsychological memory performance can potentially lead to an underdiagnosis of FTD.

Rare variants and autoimmune disease.

PubMed

Massey, Jonathan; Eyre, Steve

2014-09-01

The study of rare variants in monogenic forms of autoimmune disease has offered insight into the aetiology of more complex pathologies. Research in complex autoimmune disease initially focused on sequencing candidate genes, with some early successes, notably in uncovering low-frequency variation associated with Type 1 diabetes mellitus. However, other early examples have proved difficult to replicate, and a recent study across six autoimmune diseases, re-sequencing 25 autoimmune disease-associated genes in large sample sizes, failed to find any associated rare variants. The study of rare and low-frequency variation in autoimmune diseases has been made accessible by the inclusion of such variants on custom genotyping arrays (e.g. Immunochip and Exome arrays). Whole-exome sequencing approaches are now also being utilised to uncover the contribution of rare coding variants to disease susceptibility, severity and treatment response. Other sequencing strategies are starting to uncover the role of regulatory rare variation. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Identification of a Latin American-specific BabA adhesin variant through whole genome sequencing of Helicobacter pylori patient isolates from Nicaragua

DOE PAGES

Thorell, Kaisa; Hosseini, Shaghayegh; Palacios Gonzales, Reyna Victoria Palacios; ...

2016-02-29

In this study, Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans and this infection can lead to gastric ulcers and gastric cancer. H. pylori is one of the most genetically variable human pathogens and the ability of the bacterium to bind to the host epithelium as well as the presence of different virulence factors and genetic variants within these genes have been associated with disease severity. Nicaragua has particularly high gastric cancer incidence and we therefore studied Nicaraguan clinical H. pylori isolates for factors that could contribute to cancer risk. The complete genomes ofmore » fifty-two Nicaraguan H. pylorii isolates were sequenced and assembled de novo, and phylogenetic and virulence factor analyses were performed. The Nicaraguan isolates showed phylogenetic relationship with West African isolates in whole-genome sequence comparisons and with Western and urban South-and Central American isolates using MLSA (Multi-locus sequence analysis). A majority, 77 % of the isolates carried the cancer-associated virulence gene cagA and also the s1/i1/m1 vacuolating cytotoxin, vacA allele combination, which is linked to increased severity of disease. Specifically, we also found that Nicaraguan isolates have a blood group-binding adhesin (BabA) variant highly similar to previously reported BabA sequences from Latin America, including from isolates belonging to other phylogenetic groups. These BabA sequences were found to be under positive selection at several amino acid positions that differed from the global collection of isolates. In conclusion, the discovery of a Latin American BabA variant, independent of overall phylogenetic background, suggests hitherto unknown host or environmental factors within the Latin American population giving H. pylori isolates carrying this adhesin variant a selective advantage, which could affect pathogenesis and risk for sequelae through specific adherence properties.« less

Seshat: A Web service for accurate annotation, validation, and analysis of TP53 variants generated by conventional and next-generation sequencing.

PubMed

Tikkanen, Tuomas; Leroy, Bernard; Fournier, Jean Louis; Risques, Rosa Ana; Malcikova, Jitka; Soussi, Thierry

2018-07-01

Accurate annotation of genomic variants in human diseases is essential to allow personalized medicine. Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL). Here, we present Seshat, a Web service for annotating TP53 information derived from sequencing data. A flexible framework allows the use of standard file formats such as Mutation Annotation Format (MAF) or Variant Call Format (VCF), as well as common TXT files. Seshat performs accurate variant annotations using the Human Genome Variation Society (HGVS) nomenclature and the stable TP53 genomic reference provided by the Locus Reference Genomic (LRG). In addition, using the 2017 release of the UMD_TP53 database, Seshat provides multiple statistical information for each TP53 variant including database frequency, functional activity, or pathogenicity. The information is delivered in standardized output tables that minimize errors and facilitate comparison of mutational data across studies. Seshat is a beneficial tool to interpret the ever-growing TP53 sequencing data generated by multiple sequencing platforms and it is freely available via the TP53 Website, http://p53.fr or directly at http://vps338341.ovh.net/. © 2018 Wiley Periodicals, Inc.

Variant Review with the Integrative Genomics Viewer.

PubMed

Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

2017-11-01

Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

Harnessing Omics Big Data in Nine Vertebrate Species by Genome-Wide Prioritization of Sequence Variants with the Highest Predicted Deleterious Effect on Protein Function.

PubMed

Rozman, Vita; Kunej, Tanja

2018-05-10

Harnessing the genomics big data requires innovation in how we extract and interpret biologically relevant variants. Currently, there is no established catalog of prioritized missense variants associated with deleterious protein function phenotypes. We report in this study, to the best of our knowledge, the first genome-wide prioritization of sequence variants with the most deleterious effect on protein function (potentially deleterious variants [pDelVars]) in nine vertebrate species: human, cattle, horse, sheep, pig, dog, rat, mouse, and zebrafish. The analysis was conducted using the Ensembl/BioMart tool. Genes comprising pDelVars in the highest number of examined species were identified using a Python script. Multiple genomic alignments of the selected genes were built to identify interspecies orthologous potentially deleterious variants, which we defined as the "ortho-pDelVars." Genome-wide prioritization revealed that in humans, 0.12% of the known variants are predicted to be deleterious. In seven out of nine examined vertebrate species, the genes encoding the multiple PDZ domain crumbs cell polarity complex component (MPDZ) and the transforming acidic coiled-coil containing protein 2 (TACC2) comprise pDelVars. Five interspecies ortho-pDelVars were identified in three genes. These findings offer new ways to harness genomics big data by facilitating the identification of functional polymorphisms in humans and animal models and thus provide a future basis for optimization of protocols for whole genome prioritization of pDelVars and screening of orthologous sequence variants. The approach presented here can inform various postgenomic applications such as personalized medicine and multiomics study of health interventions (iatromics).

Histological variants of cutaneous Kaposi sarcoma

PubMed Central

Grayson, Wayne; Pantanowitz, Liron

2008-01-01

This review provides a comprehensive overview of the broad clinicopathologic spectrum of cutaneous Kaposi sarcoma (KS) lesions. Variants discussed include: usual KS lesions associated with disease progression (i.e. patch, plaque and nodular stage); morphologic subtypes alluded to in the older literature such as anaplastic and telangiectatic KS, as well as several lymphedematous variants; and numerous recently described variants including hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS. Involuting lesions as a result of treatment related regression are also presented. PMID:18655700

A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity.

PubMed

Read, Timothy; Richmond, Phillip A; Dowell, Robin D

2016-01-01

Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ∑1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ∑1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ∑1278b counterpart. We conclude that ∑1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non-native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant.

SCN5A (NaV1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance.

PubMed

Kroncke, Brett M; Glazer, Andrew M; Smith, Derek K; Blume, Jeffrey D; Roden, Dan M

2018-05-01

Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein Na V 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance. From a comprehensive literature review, we quantified the number of carriers presenting with and without disease for 1712 reported SCN5A variants. For 356 variants, data were also available for 5 Na V 1.5 electrophysiological parameters: peak current, late/persistent current, steady-state V1/2 of activation and inactivation, and recovery from inactivation. We found that peak and late current significantly associate with Brugada syndrome ( P <0.001; ρ=-0.44; Spearman rank test) and long QT syndrome disease penetrance ( P <0.001; ρ=0.37). Steady-state V1/2 activation and recovery from inactivation associate significantly with Brugada syndrome and long QT syndrome penetrance, respectively. Continuous estimates of disease penetrance align with the current American College of Medical Genetics classification paradigm. Na V 1.5 in vitro electrophysiological parameters are correlated with Brugada syndrome and long QT syndrome disease risk. Our data emphasize the value of in vitro electrophysiological characterization and incorporating counts of affected and unaffected carriers to aid variant classification. This quantitative analysis of the electrophysiological literature should aid the interpretation of Na V 1.5 variant electrophysiological abnormalities and help improve Na V 1.5 variant classification. © 2018 American Heart Association, Inc.

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

PubMed

Renault, Anne-Laure; Mebirouk, Noura; Fuhrmann, Laetitia; Bataillon, Guillaume; Cavaciuti, Eve; Le Gal, Dorothée; Girard, Elodie; Popova, Tatiana; La Rosa, Philippe; Beauvallet, Juana; Eon-Marchais, Séverine; Dondon, Marie-Gabrielle; d'Enghien, Catherine Dubois; Laugé, Anthony; Chemlali, Walid; Raynal, Virginie; Labbé, Martine; Bièche, Ivan; Baulande, Sylvain; Bay, Jacques-Olivier; Berthet, Pascaline; Caron, Olivier; Buecher, Bruno; Faivre, Laurence; Fresnay, Marc; Gauthier-Villars, Marion; Gesta, Paul; Janin, Nicolas; Lejeune, Sophie; Maugard, Christine; Moutton, Sébastien; Venat-Bouvet, Laurence; Zattara, Hélène; Fricker, Jean-Pierre; Gladieff, Laurence; Coupier, Isabelle; Chenevix-Trench, Georgia; Hall, Janet; Vincent-Salomon, Anne; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Lesueur, Fabienne

2018-04-17

The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological

Pathogenic Germline Variants in 10,389 Adult Cancers.

PubMed

Huang, Kuan-Lin; Mashl, R Jay; Wu, Yige; Ritter, Deborah I; Wang, Jiayin; Oh, Clara; Paczkowska, Marta; Reynolds, Sheila; Wyczalkowski, Matthew A; Oak, Ninad; Scott, Adam D; Krassowski, Michal; Cherniack, Andrew D; Houlahan, Kathleen E; Jayasinghe, Reyka; Wang, Liang-Bo; Zhou, Daniel Cui; Liu, Di; Cao, Song; Kim, Young Won; Koire, Amanda; McMichael, Joshua F; Hucthagowder, Vishwanathan; Kim, Tae-Beom; Hahn, Abigail; Wang, Chen; McLellan, Michael D; Al-Mulla, Fahd; Johnson, Kimberly J; Lichtarge, Olivier; Boutros, Paul C; Raphael, Benjamin; Lazar, Alexander J; Zhang, Wei; Wendl, Michael C; Govindan, Ramaswamy; Jain, Sanjay; Wheeler, David; Kulkarni, Shashikant; Dipersio, John F; Reimand, Jüri; Meric-Bernstam, Funda; Chen, Ken; Shmulevich, Ilya; Plon, Sharon E; Chen, Feng; Ding, Li

2018-04-05

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

ScaffoldScaffolder: solving contig orientation via bidirected to directed graph reduction.

PubMed

Bodily, Paul M; Fujimoto, M Stanley; Snell, Quinn; Ventura, Dan; Clement, Mark J

2016-01-01

The contig orientation problem, which we formally define as the MAX-DIR problem, has at times been addressed cursorily and at times using various heuristics. In setting forth a linear-time reduction from the MAX-CUT problem to the MAX-DIR problem, we prove the latter is NP-complete. We compare the relative performance of a novel greedy approach with several other heuristic solutions. Our results suggest that our greedy heuristic algorithm not only works well but also outperforms the other algorithms due to the nature of scaffold graphs. Our results also demonstrate a novel method for identifying inverted repeats and inversion variants, both of which contradict the basic single-orientation assumption. Such inversions have previously been noted as being difficult to detect and are directly involved in the genetic mechanisms of several diseases. http://bioresearch.byu.edu/scaffoldscaffolder. paulmbodily@gmail.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.

Visualizing the geography of genetic variants.

PubMed

Marcus, Joseph H; Novembre, John

2017-02-15

One of the key characteristics of any genetic variant is its geographic distribution. The geographic distribution can shed light on where an allele first arose, what populations it has spread to, and in turn on how migration, genetic drift, and natural selection have acted. The geographic distribution of a genetic variant can also be of great utility for medical/clinical geneticists and collectively many genetic variants can reveal population structure. Here we develop an interactive visualization tool for rapidly displaying the geographic distribution of genetic variants. Through a REST API and dynamic front-end, the Geography of Genetic Variants (GGV) browser ( http://popgen.uchicago.edu/ggv/ ) provides maps of allele frequencies in populations distributed across the globe. GGV is implemented as a website ( http://popgen.uchicago.edu/ggv/ ) which employs an API to access frequency data ( http://popgen.uchicago.edu/freq_api/ ). Python and javascript source code for the website and the API are available at: http://github.com/NovembreLab/ggv/ and http://github.com/NovembreLab/ggv-api/ . jnovembre@uchicago.edu. Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Persons with Multiple Disabilities Use Orientation Technology to Find Room Entrances during Indoor Traveling

ERIC Educational Resources Information Center

Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Alberti, Gloria; Scigliuzzo, Francesca; Signorino, Mario; Oliva, Doretta; Smaldone, Angela; La Martire, Maria L.

2010-01-01

These two studies assessed adapted orientation technology for promoting correct direction and room identification during indoor traveling by persons with multiple (e.g., sensory, motor and intellectual/adaptive) disabilities. In Study I, two adults were included who had severe visual impairment or total blindness and deafness and used a wheelchair…

Variants of glycoside hydrolases

DOEpatents

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

2013-02-26

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.

Variants of glycoside hydrolases

DOEpatents

Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

2011-04-26

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.

Variants of glycoside hydrolases

DOEpatents

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.

A fiber orientation-adapted integration scheme for computing the hyperelastic Tucker average for short fiber reinforced composites

NASA Astrophysics Data System (ADS)

Goldberg, Niels; Ospald, Felix; Schneider, Matti

2017-10-01

In this article we introduce a fiber orientation-adapted integration scheme for Tucker's orientation averaging procedure applied to non-linear material laws, based on angular central Gaussian fiber orientation distributions. This method is stable w.r.t. fiber orientations degenerating into planar states and enables the construction of orthotropic hyperelastic energies for truly orthotropic fiber orientation states. We establish a reference scenario for fitting the Tucker average of a transversely isotropic hyperelastic energy, corresponding to a uni-directional fiber orientation, to microstructural simulations, obtained by FFT-based computational homogenization of neo-Hookean constituents. We carefully discuss ideas for accelerating the identification process, leading to a tremendous speed-up compared to a naive approach. The resulting hyperelastic material map turns out to be surprisingly accurate, simple to integrate in commercial finite element codes and fast in its execution. We demonstrate the capabilities of the extracted model by a finite element analysis of a fiber reinforced chain link.

Variants of Phosphotriesterase for the Enhanced Detoxification of the Chemical Warfare Agent VR.

PubMed

Bigley, Andrew N; Mabanglo, Mark F; Harvey, Steven P; Raushel, Frank M

2015-09-08

The V-type organophosphorus nerve agents are among the most hazardous compounds known. Previous efforts to evolve the bacterial enzyme phosphotriesterase (PTE) for the hydrolytic decontamination of VX resulted in the identification of the variant L7ep-3a, which has a kcat value more than 2 orders of magnitude higher than that of wild-type PTE for the hydrolysis of VX. Because of the relatively small size of the O-ethyl, methylphosphonate center in VX, stereoselectivity is not a major concern. However, the Russian V-agent, VR, contains a larger O-isobutyl, methylphosphonate center, making stereoselectivity a significant issue since the SP-enantiomer is expected to be significantly more toxic than the RP-enantiomer. The three-dimensional structure of the L7ep-3a variant was determined to a resolution of 2.01 Å (PDB id: 4ZST ). The active site of the L7ep-3a mutant has revealed a network of hydrogen bonding interactions between Asp-301, Tyr-257, Gln-254, and the hydroxide that bridges the two metal ions. A series of new analogues that mimic VX and VR has helped to identify critical structural features for the development of new enzyme variants that are further enhanced for the catalytic detoxification of VR and VX. The best of these mutants has been shown to have a reversed stereochemical preference for the hydrolysis of VR-chiral center analogues. This mutant hydrolyzes the two enantiomers of VR 160- and 600-fold faster than wild-type PTE hydrolyzes the SP-enantiomer of VR.

Analysis of association of gene variants with obesity traits in New Zealand European children at 6 years of age.

PubMed

Krishnan, Mohanraj; Thompson, John M D; Mitchell, Edwin A; Murphy, Rinki; McCowan, Lesley M E; Shelling, Andrew N; On Behalf Of The Children Of Scope Study Group, G

2017-07-25

Childhood obesity is a public health problem, which is associated with a long-term increased risk of cardiovascular disease and premature mortality. Several gene variants have previously been identified that have provided novel insights into biological factors that contribute to the development of obesity. As obesity tracks through childhood into adulthood, identification of the genetic factors for obesity in early life is important. The objective of this study was to identify putative associations between genetic variants and obesity traits in children at 6 years of age. We recruited 1208 children of mothers from the New Zealand centre of the international Screening for Pregnancy Endpoints (SCOPE) study. Eighty common genetic variants associated with obesity traits were evaluated by the Sequenom assay. Body mass index standardised scores (BMI z-scores) and percentage body fat (PBF; measured by bio-impedance assay (BIA)) were used as anthropometric measures of obesity. A positive correlation was found between BMI z-scores and PBF (p < 0.001, r = 0.756). Two subsets of gene variants were associated with BMI z-scores (HOXB5-rs9299, SH2B1-rs7498665, NPC1-rs1805081 and MSRA-rs545854) and PBF (TMEM18-rs6548238, NPY-rs17149106, ETV-rs7647305, NPY-rs16139, TIMELESS-rs4630333, FTO-rs9939609, UCP2-rs659366, MAP2K5-rs2241423 and FAIM2-rs7138803) in the genotype models. However, there was an absence of overlapping association between any of the gene variants with BMI z-scores and PBF. A further five variants were associated with BMI z-scores (TMEM18-rs6548238, FTO-rs9939609 and MC4R-rs17782313) and PBF (SH2B1-rs7498665 and FTO-rs1421085) once separated by genetic models (additive, recessive and dominant) of inheritance. This study has identified significant associations between numerous gene variants selected on the basis of prior association with obesity and obesity traits in New Zealand European children.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.

PubMed

Elsayed, Liena E O; Mohammed, Inaam N; Hamed, Ahlam A A; Elseed, Maha A; Johnson, Adam; Mairey, Mathilde; Mohamed, Hassab Elrasoul S A; Idris, Mohamed N; Salih, Mustafa A M; El-Sadig, Sarah M; Koko, Mahmoud E; Mohamed, Ashraf Y O; Raymond, Laure; Coutelier, Marie; Darios, Frédéric; Siddig, Rayan A; Ahmed, Ahmed K M A; Babai, Arwa M A; Malik, Hiba M O; Omer, Zulfa M B M; Mohamed, Eman O E; Eltahir, Hanan B; Magboul, Nasr Aldin A; Bushara, Elfatih E; Elnour, Abdelrahman; Rahim, Salah M Abdel; Alattaya, Abdelmoneim; Elbashir, Mustafa I; Ibrahim, Muntaser E; Durr, Alexandra; Audhya, Anjon; Brice, Alexis; Ahmed, Ammar E; Stevanin, Giovanni

2016-01-01

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

PubMed Central

Elsayed, Liena E O; Mohammed, Inaam N; Hamed, Ahlam A A; Elseed, Maha A; Johnson, Adam; Mairey, Mathilde; Mohamed, Hassab Elrasoul S A; Idris, Mohamed N; Salih, Mustafa A M; El-sadig, Sarah M; Koko, Mahmoud E; Mohamed, Ashraf Y O; Raymond, Laure; Coutelier, Marie; Darios, Frédéric; Siddig, Rayan A; Ahmed, Ahmed K M A; Babai, Arwa M A; Malik, Hiba M O; Omer, Zulfa M B M; Mohamed, Eman O E; Eltahir, Hanan B; Magboul, Nasr Aldin A; Bushara, Elfatih E; Elnour, Abdelrahman; Rahim, Salah M Abdel; Alattaya, Abdelmoneim; Elbashir, Mustafa I; Ibrahim, Muntaser E; Durr, Alexandra; Audhya, Anjon; Brice, Alexis; Ahmed, Ammar E; Stevanin, Giovanni

2017-01-01

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance. PMID:27601211

Two Variants of a High-Throughput Fluorescent Microplate Assay of Polysaccharide Endotransglycosylases.

PubMed

Kováčová, Kristína; Farkaš, Vladimír

2016-04-01

Polysaccharide endotransglycosylases (PETs) are the cell wall-modifying enzymes of fungi and plants. They catalyze random endo-splitting of the polysaccharide donor molecule and transfer of the newly formed reducing sugar residue to the nonreducing end of an acceptor molecule which can be a polysaccharide or an oligosaccharide. Owing to their important role in the cell wall formation, the inhibition of PETs represents an attractive strategy in the fight against fungal infections. We have elaborated two variants of a versatile high-throughput microplate fluorimetric assay that could be used for effective identification of PETs and screening of their inhibitors. Both assays use the respective polysaccharides as the donors and sulforhodamine-labeled oligosaccharides as the acceptors but differ from each other by mode of how the labeled polysaccharide products of transglycosylation are separated from the unreacted oligosaccharide acceptors. In the first variant, the reactions take place in a layer of agar gel laid on the bottoms of the wells of a microtitration plate. After the reaction, the high-Mr transglycosylation products are precipitated with 66 % ethanol and retained within the gel while the low-Mr products and the unreacted acceptors are washed out. In the second variant, the donor polysaccharides are adsorbed to the surface of a microplate well and remain adsorbed there also after becoming labeled in the course of the transglycosylation reaction whereas the unused low-Mr acceptors are washed out. As a proof of versatility, assays of heterologously expressed transglycosylases ScGas1, ScCrh1, and ScCrh2 from the yeast Saccharomyces cerevisiae, CaPhr1 and CaPhr2 from Candida albicans, and of a plant xyloglucan endotransglycosylase (XET) are demonstrated.

Detection of alternative splice variants at the proteome level in Aspergillus flavus.

PubMed

Chang, Kung-Yen; Georgianna, D Ryan; Heber, Steffen; Payne, Gary A; Muddiman, David C

2010-03-05

Identification of proteins from proteolytic peptides or intact proteins plays an essential role in proteomics. Researchers use search engines to match the acquired peptide sequences to the target proteins. However, search engines depend on protein databases to provide candidates for consideration. Alternative splicing (AS), the mechanism where the exon of pre-mRNAs can be spliced and rearranged to generate distinct mRNA and therefore protein variants, enable higher eukaryotic organisms, with only a limited number of genes, to have the requisite complexity and diversity at the proteome level. Multiple alternative isoforms from one gene often share common segments of sequences. However, many protein databases only include a limited number of isoforms to keep minimal redundancy. As a result, the database search might not identify a target protein even with high quality tandem MS data and accurate intact precursor ion mass. We computationally predicted an exhaustive list of putative isoforms of Aspergillus flavus proteins from 20 371 expressed sequence tags to investigate whether an alternative splicing protein database can assign a greater proportion of mass spectrometry data. The newly constructed AS database provided 9807 new alternatively spliced variants in addition to 12 832 previously annotated proteins. The searches of the existing tandem MS spectra data set using the AS database identified 29 new proteins encoded by 26 genes. Nine fungal genes appeared to have multiple protein isoforms. In addition to the discovery of splice variants, AS database also showed potential to improve genome annotation. In summary, the introduction of an alternative splicing database helps identify more proteins and unveils more information about a proteome.

Moon orientation in adult and young sandhoppers under artificial light.

PubMed

Ugolini, Alberto; Boddi, Vieri; Mercatelli, Luca; Castellini, Carlo

2005-10-22

Our experiments, carried out at night and during the day on adults and laboratory-born young of the sandhopper Talitrus saltator, deal with the identification and use of the moon as an orientating factor. Sandhoppers were released in an apparatus (a Plexiglas dome) that produced a scenario similar to the natural one (with artificial sky, moon or sun illuminated at different intensities). When tested at night, the adult and young sandhoppers used the artificial moon like the natural one, independently of the intensity of illumination of the artificial sky and moon. In other words, sandhoppers tested at night always identified the artificial moon as the moon and never as the sun. In daytime releases, the seaward orientation failed at low intensities of artificial sky and sun illumination (3.07 and 1.55 microW cm2, respectively), whereas the sun compass was used effectively at higher levels of artificial sun and sky illumination. The innate ability of moon compass orientation in inexpert young sandhoppers was demonstrated even under artificial light.

Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls.

PubMed

Park, Ji Soo; Nam, Eun Ji; Park, Hyung Seok; Han, Jung Woo; Lee, Jung-Yun; Kim, Jieun; Kim, Tae Il; Lee, Seung-Tae

2017-10-01

Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants. Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls. We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients. Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.

The CIP Battery: Identification of Depression in a Juvenile Delinquent Population.

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