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

Ciuca, Razvan; Hernández, Oscar F., E-mail: razvan.ciuca@mail.mcgill.ca, E-mail: oscarh@physics.mcgill.ca

There exists various proposals to detect cosmic strings from Cosmic Microwave Background (CMB) or 21 cm temperature maps. Current proposals do not aim to find the location of strings on sky maps, all of these approaches can be thought of as a statistic on a sky map. We propose a Bayesian interpretation of cosmic string detection and within that framework, we derive a connection between estimates of cosmic string locations and cosmic string tension G μ. We use this Bayesian framework to develop a machine learning framework for detecting strings from sky maps and outline how to implement this frameworkmore » with neural networks. The neural network we trained was able to detect and locate cosmic strings on noiseless CMB temperature map down to a string tension of G μ=5 ×10{sup −9} and when analyzing a CMB temperature map that does not contain strings, the neural network gives a 0.95 probability that G μ≤2.3×10{sup −9}.« less

Rapid Gynogenetic Mapping of Xenopus tropicalis Mutations to Chromosomes

PubMed Central

Khokha, Mustafa K.; Krylov, Vladimir; Reilly, Michael J.; Gall, Joseph G.; Bhattacharya, Dipankan; Cheung, Chung Yan J.; Kaufman, Sarah; Lam, Dang Khoa; Macha, Jaroslav; Ngo, Catherine; Prakash, Neha; Schmidt, Philip; Tlapakova, Tereza; Trivedi, Toral; Tumova, Lucie; Abu-Daya, Anita; Geach, Timothy; Vendrell, Elisenda; Ironfield, Holly; Sinzelle, Ludivine; Sater, Amy K.; Wells, Dan E.; Harland, Richard M.; Zimmerman, Lyle B.

2010-01-01

Pilot forward genetic screens in Xenopus tropicalis have isolated over 60 recessive mutations (Grammer et al., 2005; Noramly et al., 2005; Goda et al., 2006). Here we present a simple method for mapping mutations to chromosomes using gynogenesis and centromeric markers. When coupled with available genomic resources, gross mapping facilitates evaluation of candidate genes as well as higher resolution linkage studies. Using gynogenesis, we have mapped the genetic locations of the 10 X. tropicalis centromeres, and performed Fluorescence In Situ Hybridization to validate these locations cytologically. We demonstrate the use of this very small set of centromeric markers to map mutations efficiently to specific chromosomes. PMID:19441086

Efficient Posterior Probability Mapping Using Savage-Dickey Ratios

PubMed Central

Penny, William D.; Ridgway, Gerard R.

2013-01-01

Statistical Parametric Mapping (SPM) is the dominant paradigm for mass-univariate analysis of neuroimaging data. More recently, a Bayesian approach termed Posterior Probability Mapping (PPM) has been proposed as an alternative. PPM offers two advantages: (i) inferences can be made about effect size thus lending a precise physiological meaning to activated regions, (ii) regions can be declared inactive. This latter facility is most parsimoniously provided by PPMs based on Bayesian model comparisons. To date these comparisons have been implemented by an Independent Model Optimization (IMO) procedure which separately fits null and alternative models. This paper proposes a more computationally efficient procedure based on Savage-Dickey approximations to the Bayes factor, and Taylor-series approximations to the voxel-wise posterior covariance matrices. Simulations show the accuracy of this Savage-Dickey-Taylor (SDT) method to be comparable to that of IMO. Results on fMRI data show excellent agreement between SDT and IMO for second-level models, and reasonable agreement for first-level models. This Savage-Dickey test is a Bayesian analogue of the classical SPM-F and allows users to implement model comparison in a truly interactive manner. PMID:23533640

Evidence of major genes affecting stress response in rainbow trout using Bayesian methods of complex segregation analysis

USDA-ARS?s Scientific Manuscript database

As a first step towards the genetic mapping of quantitative trait loci (QTL) affecting stress response variation in rainbow trout, we performed complex segregation analyses (CSA) fitting mixed inheritance models of plasma cortisol using Bayesian methods in large full-sib families of rainbow trout. ...

Snake River Plain Geothermal Play Fairway Analysis - Phase 1 Raster Files

DOE Data Explorer

John Shervais

2015-10-09

Snake River Plain Play Fairway Analysis - Phase 1 CRS Raster Files. This dataset contains raster files created in ArcGIS. These raster images depict Common Risk Segment (CRS) maps for HEAT, PERMEABILITY, AND SEAL, as well as selected maps of Evidence Layers. These evidence layers consist of either Bayesian krige functions or kernel density functions, and include: (1) HEAT: Heat flow (Bayesian krige map), Heat flow standard error on the krige function (data confidence), volcanic vent distribution as function of age and size, groundwater temperature (equivalue interval and natural breaks bins), and groundwater T standard error. (2) PERMEABILTY: Fault and lineament maps, both as mapped and as kernel density functions, processed for both dilational tendency (TD) and slip tendency (ST), along with data confidence maps for each data type. Data types include mapped surface faults from USGS and Idaho Geological Survey data bases, as well as unpublished mapping; lineations derived from maximum gradients in magnetic, deep gravity, and intermediate depth gravity anomalies. (3) SEAL: Seal maps based on presence and thickness of lacustrine sediments and base of SRP aquifer. Raster size is 2 km. All files generated in ArcGIS.

Radiation dose reduction in computed tomography perfusion using spatial-temporal Bayesian methods

NASA Astrophysics Data System (ADS)

Fang, Ruogu; Raj, Ashish; Chen, Tsuhan; Sanelli, Pina C.

2012-03-01

In current computed tomography (CT) examinations, the associated X-ray radiation dose is of significant concern to patients and operators, especially CT perfusion (CTP) imaging that has higher radiation dose due to its cine scanning technique. A simple and cost-effective means to perform the examinations is to lower the milliampere-seconds (mAs) parameter as low as reasonably achievable in data acquisition. However, lowering the mAs parameter will unavoidably increase data noise and degrade CT perfusion maps greatly if no adequate noise control is applied during image reconstruction. To capture the essential dynamics of CT perfusion, a simple spatial-temporal Bayesian method that uses a piecewise parametric model of the residual function is used, and then the model parameters are estimated from a Bayesian formulation of prior smoothness constraints on perfusion parameters. From the fitted residual function, reliable CTP parameter maps are obtained from low dose CT data. The merit of this scheme exists in the combination of analytical piecewise residual function with Bayesian framework using a simpler prior spatial constrain for CT perfusion application. On a dataset of 22 patients, this dynamic spatial-temporal Bayesian model yielded an increase in signal-tonoise-ratio (SNR) of 78% and a decrease in mean-square-error (MSE) of 40% at low dose radiation of 43mA.

A Gaussian random field model for similarity-based smoothing in Bayesian disease mapping.

PubMed

Baptista, Helena; Mendes, Jorge M; MacNab, Ying C; Xavier, Miguel; Caldas-de-Almeida, José

2016-08-01

Conditionally specified Gaussian Markov random field (GMRF) models with adjacency-based neighbourhood weight matrix, commonly known as neighbourhood-based GMRF models, have been the mainstream approach to spatial smoothing in Bayesian disease mapping. In the present paper, we propose a conditionally specified Gaussian random field (GRF) model with a similarity-based non-spatial weight matrix to facilitate non-spatial smoothing in Bayesian disease mapping. The model, named similarity-based GRF, is motivated for modelling disease mapping data in situations where the underlying small area relative risks and the associated determinant factors do not vary systematically in space, and the similarity is defined by "similarity" with respect to the associated disease determinant factors. The neighbourhood-based GMRF and the similarity-based GRF are compared and accessed via a simulation study and by two case studies, using new data on alcohol abuse in Portugal collected by the World Mental Health Survey Initiative and the well-known lip cancer data in Scotland. In the presence of disease data with no evidence of positive spatial correlation, the simulation study showed a consistent gain in efficiency from the similarity-based GRF, compared with the adjacency-based GMRF with the determinant risk factors as covariate. This new approach broadens the scope of the existing conditional autocorrelation models. © The Author(s) 2016.

Large-scale mapping of mutations affecting zebrafish development.

PubMed

Geisler, Robert; Rauch, Gerd-Jörg; Geiger-Rudolph, Silke; Albrecht, Andrea; van Bebber, Frauke; Berger, Andrea; Busch-Nentwich, Elisabeth; Dahm, Ralf; Dekens, Marcus P S; Dooley, Christopher; Elli, Alexandra F; Gehring, Ines; Geiger, Horst; Geisler, Maria; Glaser, Stefanie; Holley, Scott; Huber, Matthias; Kerr, Andy; Kirn, Anette; Knirsch, Martina; Konantz, Martina; Küchler, Axel M; Maderspacher, Florian; Neuhauss, Stephan C; Nicolson, Teresa; Ober, Elke A; Praeg, Elke; Ray, Russell; Rentzsch, Brit; Rick, Jens M; Rief, Eva; Schauerte, Heike E; Schepp, Carsten P; Schönberger, Ulrike; Schonthaler, Helia B; Seiler, Christoph; Sidi, Samuel; Söllner, Christian; Wehner, Anja; Weiler, Christian; Nüsslein-Volhard, Christiane

2007-01-09

Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations.

F-MAP: A Bayesian approach to infer the gene regulatory network using external hints

PubMed Central

Shahdoust, Maryam; Mahjub, Hossein; Sadeghi, Mehdi

2017-01-01

The Common topological features of related species gene regulatory networks suggest reconstruction of the network of one species by using the further information from gene expressions profile of related species. We present an algorithm to reconstruct the gene regulatory network named; F-MAP, which applies the knowledge about gene interactions from related species. Our algorithm sets a Bayesian framework to estimate the precision matrix of one species microarray gene expressions dataset to infer the Gaussian Graphical model of the network. The conjugate Wishart prior is used and the information from related species is applied to estimate the hyperparameters of the prior distribution by using the factor analysis. Applying the proposed algorithm on six related species of drosophila shows that the precision of reconstructed networks is improved considerably compared to the precision of networks constructed by other Bayesian approaches. PMID:28938012

Bayesian component separation: The Planck experience

NASA Astrophysics Data System (ADS)

Wehus, Ingunn Kathrine; Eriksen, Hans Kristian

2018-05-01

Bayesian component separation techniques have played a central role in the data reduction process of Planck. The most important strength of this approach is its global nature, in which a parametric and physical model is fitted to the data. Such physical modeling allows the user to constrain very general data models, and jointly probe cosmological, astrophysical and instrumental parameters. This approach also supports statistically robust goodness-of-fit tests in terms of data-minus-model residual maps, which are essential for identifying residual systematic effects in the data. The main challenges are high code complexity and computational cost. Whether or not these costs are justified for a given experiment depends on its final uncertainty budget. We therefore predict that the importance of Bayesian component separation techniques is likely to increase with time for intensity mapping experiments, similar to what has happened in the CMB field, as observational techniques mature, and their overall sensitivity improves.

Exploiting the extraordinary genetic polymorphism of ciona for developmental genetics with whole genome sequencing.

PubMed

Abdul-Wajid, Sarah; Veeman, Michael T; Chiba, Shota; Turner, Thomas L; Smith, William C

2014-05-01

Studies in tunicates such as Ciona have revealed new insights into the evolutionary origins of chordate development. Ciona populations are characterized by high levels of natural genetic variation, between 1 and 5%. This variation has provided abundant material for forward genetic studies. In the current study, we make use of deep sequencing and homozygosity mapping to map spontaneous mutations in outbred populations. With this method we have mapped two spontaneous developmental mutants. In Ciona intestinalis we mapped a short-tail mutation with strong phenotypic similarity to a previously identified mutant in the related species Ciona savignyi. Our bioinformatic approach mapped the mutation to a narrow interval containing a single mutated gene, α-laminin3,4,5, which is the gene previously implicated in C. savignyi. In addition, we mapped a novel genetic mutation disrupting neural tube closure in C. savignyi to a T-type Ca(2+) channel gene. The high efficiency and unprecedented mapping resolution of our study is a powerful advantage for developmental genetics in Ciona, and may find application in other outbred species.

XID+: Next generation XID development

NASA Astrophysics Data System (ADS)

Hurley, Peter

2017-04-01

XID+ is a prior-based source extraction tool which carries out photometry in the Herschel SPIRE (Spectral and Photometric Imaging Receiver) maps at the positions of known sources. It uses a probabilistic Bayesian framework that provides a natural framework in which to include prior information, and uses the Bayesian inference tool Stan to obtain the full posterior probability distribution on flux estimates.

A Measure of Systems Engineering Effectiveness in Government Acquisition of Complex Information Systems: A Bayesian Belief Network-Based Approach

ERIC Educational Resources Information Center

Doskey, Steven Craig

2014-01-01

This research presents an innovative means of gauging Systems Engineering effectiveness through a Systems Engineering Relative Effectiveness Index (SE REI) model. The SE REI model uses a Bayesian Belief Network to map causal relationships in government acquisitions of Complex Information Systems (CIS), enabling practitioners to identify and…

Bayesian QTL mapping using genome-wide SSR markers and segregating population derived from a cross of two commercial F1 hybrids of tomato.

PubMed

Ohyama, Akio; Shirasawa, Kenta; Matsunaga, Hiroshi; Negoro, Satomi; Miyatake, Koji; Yamaguchi, Hirotaka; Nunome, Tsukasa; Iwata, Hiroyoshi; Fukuoka, Hiroyuki; Hayashi, Takeshi

2017-08-01

Using newly developed euchromatin-derived genomic SSR markers and a flexible Bayesian mapping method, 13 significant agricultural QTLs were identified in a segregating population derived from a four-way cross of tomato. So far, many QTL mapping studies in tomato have been performed for progeny obtained from crosses between two genetically distant parents, e.g., domesticated tomatoes and wild relatives. However, QTL information of quantitative traits related to yield (e.g., flower or fruit number, and total or average weight of fruits) in such intercross populations would be of limited use for breeding commercial tomato cultivars because individuals in the populations have specific genetic backgrounds underlying extremely different phenotypes between the parents such as large fruit in domesticated tomatoes and small fruit in wild relatives, which may not be reflective of the genetic variation in tomato breeding populations. In this study, we constructed F 2 population derived from a cross between two commercial F 1 cultivars in tomato to extract QTL information practical for tomato breeding. This cross corresponded to a four-way cross, because the four parental lines of the two F 1 cultivars were considered to be the founders. We developed 2510 new expressed sequence tag (EST)-based (euchromatin-derived) genomic SSR markers and selected 262 markers from these new SSR markers and publicly available SSR markers to construct a linkage map. QTL analysis for ten agricultural traits of tomato was performed based on the phenotypes and marker genotypes of F 2 plants using a flexible Bayesian method. As results, 13 QTL regions were detected for six traits by the Bayesian method developed in this study.

Mapping Challenging Mutations by Whole-Genome Sequencing

PubMed Central

Smith, Harold E.; Fabritius, Amy S.; Jaramillo-Lambert, Aimee; Golden, Andy

2016-01-01

Whole-genome sequencing provides a rapid and powerful method for identifying mutations on a global scale, and has spurred a renewed enthusiasm for classical genetic screens in model organisms. The most commonly characterized category of mutation consists of monogenic, recessive traits, due to their genetic tractability. Therefore, most of the mapping methods for mutation identification by whole-genome sequencing are directed toward alleles that fulfill those criteria (i.e., single-gene, homozygous variants). However, such approaches are not entirely suitable for the characterization of a variety of more challenging mutations, such as dominant and semidominant alleles or multigenic traits. Therefore, we have developed strategies for the identification of those classes of mutations, using polymorphism mapping in Caenorhabditis elegans as our model for validation. We also report an alternative approach for mutation identification from traditional recombinant crosses, and a solution to the technical challenge of sequencing sterile or terminally arrested strains where population size is limiting. The methods described herein extend the applicability of whole-genome sequencing to a broader spectrum of mutations, including classes that are difficult to map by traditional means. PMID:26945029

Mutated Genes in Schizophrenia Map to Brain Networks

MedlinePlus

... Research Matters August 12, 2013 Mutated Genes in Schizophrenia Map to Brain Networks Schizophrenia networks in the prefrontal cortex area of the ... University of Washington Researchers found that people with schizophrenia have a high number of spontaneous mutations in ...

Endometrial cancer and somatic G>T KRAS transversion in patients with constitutional MUTYH biallelic mutations.

PubMed

Tricarico, Rossella; Bet, Paola; Ciambotti, Benedetta; Di Gregorio, Carmela; Gatteschi, Beatrice; Gismondi, Viviana; Toschi, Benedetta; Tonelli, Francesco; Varesco, Liliana; Genuardi, Maurizio

2009-02-18

MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for PTEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis.

Bayesian Estimation of the Spatially Varying Completeness Magnitude of Earthquake Catalogs

NASA Astrophysics Data System (ADS)

Mignan, A.; Werner, M.; Wiemer, S.; Chen, C.; Wu, Y.

2010-12-01

Assessing the completeness magnitude Mc of earthquake catalogs is an essential prerequisite for any seismicity analysis. We employ a simple model to compute Mc in space, based on the proximity to seismic stations in a network. We show that a relationship of the form Mcpred(d) = ad^b+c, with d the distance to the 5th nearest seismic station, fits the observations well. We then propose a new Mc mapping approach, the Bayesian Magnitude of Completeness (BMC) method, based on a 2-step procedure: (1) a spatial resolution optimization to minimize spatial heterogeneities and uncertainties in Mc estimates and (2) a Bayesian approach that merges prior information about Mc based on the proximity to seismic stations with locally observed values weighted by their respective uncertainties. This new methodology eliminates most weaknesses associated with current Mc mapping procedures: the radius that defines which earthquakes to include in the local magnitude distribution is chosen according to an objective criterion and there are no gaps in the spatial estimation of Mc. The method solely requires the coordinates of seismic stations. Here, we investigate the Taiwan Central Weather Bureau (CWB) earthquake catalog by computing a Mc map for the period 1994-2010.

Mapping marine habitat suitability and uncertainty of Bayesian networks: a case study using Pacific benthic macrofauna

Treesearch

Andrea Havron; Chris Goldfinger; Sarah Henkel; Bruce G. Marcot; Chris Romsos; Lisa Gilbane

2017-01-01

Resource managers increasingly use habitat suitability map products to inform risk management and policy decisions. Modeling habitat suitability of data-poor species over large areas requires careful attention to assumptions and limitations. Resulting habitat suitability maps can harbor uncertainties from data collection and modeling processes; yet these limitations...

Maximum entropy perception-action space: a Bayesian model of eye movement selection

NASA Astrophysics Data System (ADS)

Colas, Francis; Bessière, Pierre; Girard, Benoît

2011-03-01

In this article, we investigate the issue of the selection of eye movements in a free-eye Multiple Object Tracking task. We propose a Bayesian model of retinotopic maps with a complex logarithmic mapping. This model is structured in two parts: a representation of the visual scene, and a decision model based on the representation. We compare different decision models based on different features of the representation and we show that taking into account uncertainty helps predict the eye movements of subjects recorded in a psychophysics experiment. Finally, based on experimental data, we postulate that the complex logarithmic mapping has a functional relevance, as the density of objects in this space in more uniform than expected. This may indicate that the representation space and control strategies are such that the object density is of maximum entropy.

Empirical Bayesian Geographical Mapping of Occupational Accidents among Iranian Workers.

PubMed

Vahabi, Nasim; Kazemnejad, Anoshirvan; Datta, Somnath

2017-05-01

Work-related accidents are believed to be a serious preventable cause of mortality and disability worldwide. This study aimed to provide Bayesian geographical maps of occupational injury rates among workers insured by the Iranian Social Security Organization. The participants included all insured workers in the Iranian Social Security Organization database in 2012. One of the applications of the Bayesian approach called the Poisson-Gamma model was applied to estimate the relative risk of occupational accidents. Data analysis and mapping were performed using R 3.0.3, Open-Bugs 3.2.3 rev 1012 and ArcMap9.3. The majority of all 21,484 investigated occupational injury victims were male (98.3%) including 16,443 (76.5%) single workers aged 20 - 29 years. The accidents were more frequent in basic metal, electric, and non-electric machining jobs. About 0.4% (96) of work-related accidents led to death, 2.2% (457) led to disability (partial and total), 4.6% (980) led to fixed compensation, and 92.8% (19,951) of the injured victims recovered completely. The geographical maps of estimated relative risk of occupational accidents were also provided. The results showed that the highest estimations pertained to provinces which were mostly located along mountain chains, some of which are categorized as deprived provinces in Iran. The study revealed the need for further investigation of the role of economic and climatic factors in high risk areas. The application of geographical mapping together with statistical approaches can provide more accurate tools for policy makers to make better decisions in order to prevent and reduce the risks and adverse outcomes of work-related accidents.

A glycogene mutation map for discovery of diseases of glycosylation

PubMed Central

Hansen, Lars; Lind-Thomsen, Allan; Joshi, Hiren J; Pedersen, Nis Borbye; Have, Christian Theil; Kong, Yun; Wang, Shengjun; Sparso, Thomas; Grarup, Niels; Vester-Christensen, Malene Bech; Schjoldager, Katrine; Freeze, Hudson H; Hansen, Torben; Pedersen, Oluf; Henrissat, Bernard; Mandel, Ulla; Clausen, Henrik; Wandall, Hans H; Bennett, Eric P

2015-01-01

Glycosylation of proteins and lipids involves over 200 known glycosyltransferases (GTs), and deleterious defects in many of the genes encoding these enzymes cause disorders collectively classified as congenital disorders of glycosylation (CDGs). Most known CDGs are caused by defects in glycogenes that affect glycosylation globally. Many GTs are members of homologous isoenzyme families and deficiencies in individual isoenzymes may not affect glycosylation globally. In line with this, there appears to be an underrepresentation of disease-causing glycogenes among these larger isoenzyme homologous families. However, genome-wide association studies have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole-exome sequencing (WES) provides access to mutations in, for example, GT genes in populations, which can be used to predict and/or analyze functional deleterious mutations. Here, we constructed a draft of a functional mutational map of glycogenes, GlyMAP, from WES of a rather homogenous population of 2000 Danes. We cataloged all missense mutations and used prediction algorithms, manual inspection and in case of carbohydrate-active enzymes family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP (http://glymap.glycomics.ku.dk) provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs. PMID:25267602

Functional Multi-Locus QTL Mapping of Temporal Trends in Scots Pine Wood Traits

PubMed Central

Li, Zitong; Hallingbäck, Henrik R.; Abrahamsson, Sara; Fries, Anders; Gull, Bengt Andersson; Sillanpää, Mikko J.; García-Gil, M. Rosario

2014-01-01

Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals. PMID:25305041

Functional multi-locus QTL mapping of temporal trends in Scots pine wood traits.

PubMed

Li, Zitong; Hallingbäck, Henrik R; Abrahamsson, Sara; Fries, Anders; Gull, Bengt Andersson; Sillanpää, Mikko J; García-Gil, M Rosario

2014-10-09

Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals. Copyright © 2014 Li et al.

A bayesian hierarchical model for spatio-temporal prediction and uncertainty assessment using repeat LiDAR acquisitions for the Kenai Peninsula, AK, USA

Treesearch

Chad Babcock; Hans Andersen; Andrew O. Finley; Bruce D. Cook

2015-01-01

Models leveraging repeat LiDAR and field collection campaigns may be one possible mechanism to monitor carbon flux in remote forested regions. Here, we look to the spatio-temporally data-rich Kenai Peninsula in Alaska, USA to examine the potential for Bayesian spatio-temporal mapping of terrestrial forest carbon storage and uncertainty.

Learning oncogenetic networks by reducing to mixed integer linear programming.

PubMed

Shahrabi Farahani, Hossein; Lagergren, Jens

2013-01-01

Cancer can be a result of accumulation of different types of genetic mutations such as copy number aberrations. The data from tumors are cross-sectional and do not contain the temporal order of the genetic events. Finding the order in which the genetic events have occurred and progression pathways are of vital importance in understanding the disease. In order to model cancer progression, we propose Progression Networks, a special case of Bayesian networks, that are tailored to model disease progression. Progression networks have similarities with Conjunctive Bayesian Networks (CBNs) [1],a variation of Bayesian networks also proposed for modeling disease progression. We also describe a learning algorithm for learning Bayesian networks in general and progression networks in particular. We reduce the hard problem of learning the Bayesian and progression networks to Mixed Integer Linear Programming (MILP). MILP is a Non-deterministic Polynomial-time complete (NP-complete) problem for which very good heuristics exists. We tested our algorithm on synthetic and real cytogenetic data from renal cell carcinoma. We also compared our learned progression networks with the networks proposed in earlier publications. The software is available on the website https://bitbucket.org/farahani/diprog.

Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer.

PubMed

Avivar-Valderas, Alvaro; McEwen, Robert; Taheri-Ghahfarokhi, Amir; Carnevalli, Larissa S; Hardaker, Elizabeth L; Maresca, Marcello; Hudson, Kevin; Harrington, Elizabeth A; Cruzalegui, Francisco

2018-04-20

The PI3Kα signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2 ), decreased function in tumor suppressors (e.g. PTEN ) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kα/δ(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC 50 increases, respectively) compared with parental control cell lines. In addition, mechanistic analysis revealed that MAP3K1 disruption enhances AKT phosphorylation and downstream signaling and reduces sensitivity to AZD5363-mediated pathway inhibition. This appears to be a consequence of deficient MAP3K1-JNK signaling increasing IRS1 stability and therefore promoting IRS1 binding to p85, resulting in enhanced PI3Kα activity. Using 3D-MCF10A-PI3Kα H1047R models, we found that MAP3K1 depletion increased overall acinar volume and counteracted AZD5363-mediated reduction of acinar growth due to enhanced proliferation and reduced apoptosis. Furthermore, in vivo efficacy studies revealed that MAP3K1-deficient MCF7 tumors were less sensitive to AKT inhibitor treatment, compared with parental MCF7 tumors. Our study provides mechanistic and in vivo evidence indicating a role for MAP3K1 as a tumor suppressor gene at least in the context of PIK3CA -mutant backgrounds. Further, our work predicts that MAP3K1 mutational status may be considered as a predictive biomarker for efficacy in PI3K pathway inhibitor trials.

Evolution in Mind: Evolutionary Dynamics, Cognitive Processes, and Bayesian Inference.

PubMed

Suchow, Jordan W; Bourgin, David D; Griffiths, Thomas L

2017-07-01

Evolutionary theory describes the dynamics of population change in settings affected by reproduction, selection, mutation, and drift. In the context of human cognition, evolutionary theory is most often invoked to explain the origins of capacities such as language, metacognition, and spatial reasoning, framing them as functional adaptations to an ancestral environment. However, evolutionary theory is useful for understanding the mind in a second way: as a mathematical framework for describing evolving populations of thoughts, ideas, and memories within a single mind. In fact, deep correspondences exist between the mathematics of evolution and of learning, with perhaps the deepest being an equivalence between certain evolutionary dynamics and Bayesian inference. This equivalence permits reinterpretation of evolutionary processes as algorithms for Bayesian inference and has relevance for understanding diverse cognitive capacities, including memory and creativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

A BAYESIAN SPATIAL AND TEMPORAL MODELING APPROACH TO MAPPING GEOGRAPHIC VARIATION IN MORTALITY RATES FOR SUBNATIONAL AREAS WITH R-INLA.

PubMed

Khana, Diba; Rossen, Lauren M; Hedegaard, Holly; Warner, Margaret

2018-01-01

Hierarchical Bayes models have been used in disease mapping to examine small scale geographic variation. State level geographic variation for less common causes of mortality outcomes have been reported however county level variation is rarely examined. Due to concerns about statistical reliability and confidentiality, county-level mortality rates based on fewer than 20 deaths are suppressed based on Division of Vital Statistics, National Center for Health Statistics (NCHS) statistical reliability criteria, precluding an examination of spatio-temporal variation in less common causes of mortality outcomes such as suicide rates (SRs) at the county level using direct estimates. Existing Bayesian spatio-temporal modeling strategies can be applied via Integrated Nested Laplace Approximation (INLA) in R to a large number of rare causes of mortality outcomes to enable examination of spatio-temporal variations on smaller geographic scales such as counties. This method allows examination of spatiotemporal variation across the entire U.S., even where the data are sparse. We used mortality data from 2005-2015 to explore spatiotemporal variation in SRs, as one particular application of the Bayesian spatio-temporal modeling strategy in R-INLA to predict year and county-specific SRs. Specifically, hierarchical Bayesian spatio-temporal models were implemented with spatially structured and unstructured random effects, correlated time effects, time varying confounders and space-time interaction terms in the software R-INLA, borrowing strength across both counties and years to produce smoothed county level SRs. Model-based estimates of SRs were mapped to explore geographic variation.

Identification of somatic mutations in cancer through Bayesian-based analysis of sequenced genome pairs

PubMed Central

2013-01-01

Background The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations – changes specific to a tumor and not within an individual’s germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific. Results We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity. Conclusion We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic. PMID:23642077

Identification of somatic mutations in cancer through Bayesian-based analysis of sequenced genome pairs.

PubMed

Christoforides, Alexis; Carpten, John D; Weiss, Glen J; Demeure, Michael J; Von Hoff, Daniel D; Craig, David W

2013-05-04

The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations--changes specific to a tumor and not within an individual's germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific. We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity. We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic.

Identification of BRCA1 and 2 Other Tumor Suppressor Genes on Chromosome 17 Through Positional Cloning

DTIC Science & Technology

2000-04-01

Genes, LOH Mapping, Chromosome 17, Physical Mapping, Genetic Mapping, CDNA Screening, Humans, Anatomical 81 Samples, Mutation Detection, Breast Cancer...According to the established model for LOH involving tumor suppressor genes, the allele remaining in the tumor sample would harbor the deleterious mutation ...sequencing on an AB1373A sequencer (Applied Biosystems, Foster City, CA). As none of the samples we have sequenced have revealed any mutations , we have

A Bayesian approach to traffic light detection and mapping

NASA Astrophysics Data System (ADS)

Hosseinyalamdary, Siavash; Yilmaz, Alper

2017-03-01

Automatic traffic light detection and mapping is an open research problem. The traffic lights vary in color, shape, geolocation, activation pattern, and installation which complicate their automated detection. In addition, the image of the traffic lights may be noisy, overexposed, underexposed, or occluded. In order to address this problem, we propose a Bayesian inference framework to detect and map traffic lights. In addition to the spatio-temporal consistency constraint, traffic light characteristics such as color, shape and height is shown to further improve the accuracy of the proposed approach. The proposed approach has been evaluated on two benchmark datasets and has been shown to outperform earlier studies. The results show that the precision and recall rates for the KITTI benchmark are 95.78 % and 92.95 % respectively and the precision and recall rates for the LARA benchmark are 98.66 % and 94.65 % .

Advanced obstacle avoidance for a laser based wheelchair using optimised Bayesian neural networks.

PubMed

Trieu, Hoang T; Nguyen, Hung T; Willey, Keith

2008-01-01

In this paper we present an advanced method of obstacle avoidance for a laser based intelligent wheelchair using optimized Bayesian neural networks. Three neural networks are designed for three separate sub-tasks: passing through a door way, corridor and wall following and general obstacle avoidance. The accurate usable accessible space is determined by including the actual wheelchair dimensions in a real-time map used as inputs to each networks. Data acquisitions are performed separately to collect the patterns required for specified sub-tasks. Bayesian frame work is used to determine the optimal neural network structure in each case. Then these networks are trained under the supervision of Bayesian rule. Experiment results showed that compare to the VFH algorithm our neural networks navigated a smoother path following a near optimum trajectory.

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis.

PubMed

Azorsa, David O; Lee, David W; Wai, Daniel H; Bista, Ranjan; Patel, Apurvi R; Aleem, Eiman; Henry, Michael M; Arceci, Robert J

2018-05-16

Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance. © 2018 Wiley Periodicals, Inc.

A Bayesian framework based on a Gaussian mixture model and radial-basis-function Fisher discriminant analysis (BayGmmKda V1.1) for spatial prediction of floods

NASA Astrophysics Data System (ADS)

Tien Bui, Dieu; Hoang, Nhat-Duc

2017-09-01

In this study, a probabilistic model, named as BayGmmKda, is proposed for flood susceptibility assessment in a study area in central Vietnam. The new model is a Bayesian framework constructed by a combination of a Gaussian mixture model (GMM), radial-basis-function Fisher discriminant analysis (RBFDA), and a geographic information system (GIS) database. In the Bayesian framework, GMM is used for modeling the data distribution of flood-influencing factors in the GIS database, whereas RBFDA is utilized to construct a latent variable that aims at enhancing the model performance. As a result, the posterior probabilistic output of the BayGmmKda model is used as flood susceptibility index. Experiment results showed that the proposed hybrid framework is superior to other benchmark models, including the adaptive neuro-fuzzy inference system and the support vector machine. To facilitate the model implementation, a software program of BayGmmKda has been developed in MATLAB. The BayGmmKda program can accurately establish a flood susceptibility map for the study region. Accordingly, local authorities can overlay this susceptibility map onto various land-use maps for the purpose of land-use planning or management.

Disease Mapping for Stomach Cancer in Libya Based on Besag– York– Mollié (BYM) Model

PubMed

Alhdiri, Maryam Ahmed Salem; Samat, Nor Azah; Mohamed, Zulkifley

2017-06-25

Globally, Cancer is the ever-increasing health problem and most common cause of medical deaths. In Libya, it is an important health concern, especially in the setting of an aging population and limited healthcare facilities. Therefore, the goal of this research is to map of the county’ cancer incidence rate using the Bayesian method and identify the high-risk regions (for the first time in a decade). In the field of disease mapping, very little has been done to address the issue of analyzing sparse cancer diseases in Libya. Standardized Morbidity Ratio or SMR is known as a traditional approach to measure the relative risk of the disease, which is the ratio of observed and expected number of accounts in a region that has the greatest uncertainty if the disease is rare or small geographical region. Therefore, to solve some of SMR’s problems, we used statistical smoothing or Bayesian models to estimate the relative risk for stomach cancer incidence in Libya in 2007 based on the BYM model. This research begins with a short offer of the SMR and Bayesian model with BYM model, which we applied to stomach cancer incidence in Libya. We compared all of the results using maps and tables. We found that BYM model is potentially beneficial, because it gives better relative risk estimates compared to SMR method. As well as, it has can overcome the classical method problem when there is no observed stomach cancer in a region. Creative Commons Attribution License

No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men.

PubMed

Chaillon, Antoine; Nakazawa, Masato; Wertheim, Joel O; Little, Susan J; Smith, Davey M; Mehta, Sanjay R; Gianella, Sara

2017-11-01

During primary HIV infection, the presence of minority drug resistance mutations (DRM) may be a consequence of sexual transmission, de novo mutations, or technical errors in identification. Baseline blood samples were collected from 24 HIV-infected antiretroviral-naive, genetically and epidemiologically linked source and recipient partners shortly after the recipient's estimated date of infection. An additional 32 longitudinal samples were available from 11 recipients. Deep sequencing of HIV reverse transcriptase (RT) was performed (Roche/454), and the sequences were screened for nucleoside and nonnucleoside RT inhibitor DRM. The likelihood of sexual transmission and persistence of DRM was assessed using Bayesian-based statistical modeling. While the majority of DRM (>20%) were consistently transmitted from source to recipient, the probability of detecting a minority DRM in the recipient was not increased when the same minority DRM was detected in the source (Bayes factor [BF] = 6.37). Longitudinal analyses revealed an exponential decay of DRM (BF = 0.05) while genetic diversity increased. Our analysis revealed no substantial evidence for sexual transmission of minority DRM (BF = 0.02). The presence of minority DRM during early infection, followed by a rapid decay, is consistent with the "mutation-selection balance" hypothesis, in which deleterious mutations are more efficiently purged later during HIV infection when the larger effective population size allows more efficient selection. Future studies using more recent sequencing technologies that are less prone to single-base errors should confirm these results by applying a similar Bayesian framework in other clinical settings. IMPORTANCE The advent of sensitive sequencing platforms has led to an increased identification of minority drug resistance mutations (DRM), including among antiretroviral therapy-naive HIV-infected individuals. While transmission of DRM may impact future therapy options for newly infected individuals, the clinical significance of the detection of minority DRM remains controversial. In the present study, we applied deep-sequencing techniques within a Bayesian hierarchical framework to a cohort of 24 transmission pairs to investigate whether minority DRM detected shortly after transmission were the consequence of (i) sexual transmission from the source, (ii) de novo emergence shortly after infection followed by viral selection and evolution, or (iii) technical errors/limitations of deep-sequencing methods. We found no clear evidence to support the sexual transmission of minority resistant variants, and our results suggested that minor resistant variants may emerge de novo shortly after transmission, when the small effective population size limits efficient purge by natural selection. Copyright © 2017 American Society for Microbiology.

Empirically-based modeling and mapping to consider the co-occurrence of ecological receptors and stressors

EPA Science Inventory

Part of the ecological risk assessment process involves examining the potential for environmental stressors and ecological receptors to co-occur across a landscape. In this study, we introduce a Bayesian joint modeling framework for use in evaluating and mapping the co-occurrence...

Spatial mapping and prediction of Plasmodium falciparum infection risk among school-aged children in Côte d'Ivoire.

PubMed

Houngbedji, Clarisse A; Chammartin, Frédérique; Yapi, Richard B; Hürlimann, Eveline; N'Dri, Prisca B; Silué, Kigbafori D; Soro, Gotianwa; Koudou, Benjamin G; Assi, Serge-Brice; N'Goran, Eliézer K; Fantodji, Agathe; Utzinger, Jürg; Vounatsou, Penelope; Raso, Giovanna

2016-09-07

In Côte d'Ivoire, malaria remains a major public health issue, and thus a priority to be tackled. The aim of this study was to identify spatially explicit indicators of Plasmodium falciparum infection among school-aged children and to undertake a model-based spatial prediction of P. falciparum infection risk using environmental predictors. A cross-sectional survey was conducted, including parasitological examinations and interviews with more than 5,000 children from 93 schools across Côte d'Ivoire. A finger-prick blood sample was obtained from each child to determine Plasmodium species-specific infection and parasitaemia using Giemsa-stained thick and thin blood films. Household socioeconomic status was assessed through asset ownership and household characteristics. Children were interviewed for preventive measures against malaria. Environmental data were gathered from satellite images and digitized maps. A Bayesian geostatistical stochastic search variable selection procedure was employed to identify factors related to P. falciparum infection risk. Bayesian geostatistical logistic regression models were used to map the spatial distribution of P. falciparum infection and to predict the infection prevalence at non-sampled locations via Bayesian kriging. Complete data sets were available from 5,322 children aged 5-16 years across Côte d'Ivoire. P. falciparum was the predominant species (94.5 %). The Bayesian geostatistical variable selection procedure identified land cover and socioeconomic status as important predictors for infection risk with P. falciparum. Model-based prediction identified high P. falciparum infection risk in the north, central-east, south-east, west and south-west of Côte d'Ivoire. Low-risk areas were found in the south-eastern area close to Abidjan and the south-central and west-central part of the country. The P. falciparum infection risk and related uncertainty estimates for school-aged children in Côte d'Ivoire represent the most up-to-date malaria risk maps. These tools can be used for spatial targeting of malaria control interventions.

Applications of Bayesian spectrum representation in acoustics

NASA Astrophysics Data System (ADS)

Botts, Jonathan M.

This dissertation utilizes a Bayesian inference framework to enhance the solution of inverse problems where the forward model maps to acoustic spectra. A Bayesian solution to filter design inverts a acoustic spectra to pole-zero locations of a discrete-time filter model. Spatial sound field analysis with a spherical microphone array is a data analysis problem that requires inversion of spatio-temporal spectra to directions of arrival. As with many inverse problems, a probabilistic analysis results in richer solutions than can be achieved with ad-hoc methods. In the filter design problem, the Bayesian inversion results in globally optimal coefficient estimates as well as an estimate the most concise filter capable of representing the given spectrum, within a single framework. This approach is demonstrated on synthetic spectra, head-related transfer function spectra, and measured acoustic reflection spectra. The Bayesian model-based analysis of spatial room impulse responses is presented as an analogous problem with equally rich solution. The model selection mechanism provides an estimate of the number of arrivals, which is necessary to properly infer the directions of simultaneous arrivals. Although, spectrum inversion problems are fairly ubiquitous, the scope of this dissertation has been limited to these two and derivative problems. The Bayesian approach to filter design is demonstrated on an artificial spectrum to illustrate the model comparison mechanism and then on measured head-related transfer functions to show the potential range of application. Coupled with sampling methods, the Bayesian approach is shown to outperform least-squares filter design methods commonly used in commercial software, confirming the need for a global search of the parameter space. The resulting designs are shown to be comparable to those that result from global optimization methods, but the Bayesian approach has the added advantage of a filter length estimate within the same unified framework. The application to reflection data is useful for representing frequency-dependent impedance boundaries in finite difference acoustic simulations. Furthermore, since the filter transfer function is a parametric model, it can be modified to incorporate arbitrary frequency weighting and account for the band-limited nature of measured reflection spectra. Finally, the model is modified to compensate for dispersive error in the finite difference simulation, from the filter design process. Stemming from the filter boundary problem, the implementation of pressure sources in finite difference simulation is addressed in order to assure that schemes properly converge. A class of parameterized source functions is proposed and shown to offer straightforward control of residual error in the simulation. Guided by the notion that the solution to be approximated affects the approximation error, sources are designed which reduce residual dispersive error to the size of round-off errors. The early part of a room impulse response can be characterized by a series of isolated plane waves. Measured with an array of microphones, plane waves map to a directional response of the array or spatial intensity map. Probabilistic inversion of this response results in estimates of the number and directions of image source arrivals. The model-based inversion is shown to avoid ambiguities associated with peak-finding or inspection of the spatial intensity map. For this problem, determining the number of arrivals in a given frame is critical for properly inferring the state of the sound field. This analysis is effectively compression of the spatial room response, which is useful for analysis or encoding of the spatial sound field. Parametric, model-based formulations of these problems enhance the solution in all cases, and a Bayesian interpretation provides a principled approach to model comparison and parameter estimation. v

AlignerBoost: A Generalized Software Toolkit for Boosting Next-Gen Sequencing Mapping Accuracy Using a Bayesian-Based Mapping Quality Framework.

PubMed

Zheng, Qi; Grice, Elizabeth A

2016-10-01

Accurate mapping of next-generation sequencing (NGS) reads to reference genomes is crucial for almost all NGS applications and downstream analyses. Various repetitive elements in human and other higher eukaryotic genomes contribute in large part to ambiguously (non-uniquely) mapped reads. Most available NGS aligners attempt to address this by either removing all non-uniquely mapping reads, or reporting one random or "best" hit based on simple heuristics. Accurate estimation of the mapping quality of NGS reads is therefore critical albeit completely lacking at present. Here we developed a generalized software toolkit "AlignerBoost", which utilizes a Bayesian-based framework to accurately estimate mapping quality of ambiguously mapped NGS reads. We tested AlignerBoost with both simulated and real DNA-seq and RNA-seq datasets at various thresholds. In most cases, but especially for reads falling within repetitive regions, AlignerBoost dramatically increases the mapping precision of modern NGS aligners without significantly compromising the sensitivity even without mapping quality filters. When using higher mapping quality cutoffs, AlignerBoost achieves a much lower false mapping rate while exhibiting comparable or higher sensitivity compared to the aligner default modes, therefore significantly boosting the detection power of NGS aligners even using extreme thresholds. AlignerBoost is also SNP-aware, and higher quality alignments can be achieved if provided with known SNPs. AlignerBoost's algorithm is computationally efficient, and can process one million alignments within 30 seconds on a typical desktop computer. AlignerBoost is implemented as a uniform Java application and is freely available at https://github.com/Grice-Lab/AlignerBoost.

System Analysis by Mapping a Fault-tree into a Bayesian-network

NASA Astrophysics Data System (ADS)

Sheng, B.; Deng, C.; Wang, Y. H.; Tang, L. H.

2018-05-01

In view of the limitations of fault tree analysis in reliability assessment, Bayesian Network (BN) has been studied as an alternative technology. After a brief introduction to the method for mapping a Fault Tree (FT) into an equivalent BN, equations used to calculate the structure importance degree, the probability importance degree and the critical importance degree are presented. Furthermore, the correctness of these equations is proved mathematically. Combining with an aircraft landing gear’s FT, an equivalent BN is developed and analysed. The results show that richer and more accurate information have been achieved through the BN method than the FT, which demonstrates that the BN is a superior technique in both reliability assessment and fault diagnosis.

Bayesian depth estimation from monocular natural images.

PubMed

Su, Che-Chun; Cormack, Lawrence K; Bovik, Alan C

2017-05-01

Estimating an accurate and naturalistic dense depth map from a single monocular photographic image is a difficult problem. Nevertheless, human observers have little difficulty understanding the depth structure implied by photographs. Two-dimensional (2D) images of the real-world environment contain significant statistical information regarding the three-dimensional (3D) structure of the world that the vision system likely exploits to compute perceived depth, monocularly as well as binocularly. Toward understanding how this might be accomplished, we propose a Bayesian model of monocular depth computation that recovers detailed 3D scene structures by extracting reliable, robust, depth-sensitive statistical features from single natural images. These features are derived using well-accepted univariate natural scene statistics (NSS) models and recent bivariate/correlation NSS models that describe the relationships between 2D photographic images and their associated depth maps. This is accomplished by building a dictionary of canonical local depth patterns from which NSS features are extracted as prior information. The dictionary is used to create a multivariate Gaussian mixture (MGM) likelihood model that associates local image features with depth patterns. A simple Bayesian predictor is then used to form spatial depth estimates. The depth results produced by the model, despite its simplicity, correlate well with ground-truth depths measured by a current-generation terrestrial light detection and ranging (LIDAR) scanner. Such a strong form of statistical depth information could be used by the visual system when creating overall estimated depth maps incorporating stereopsis, accommodation, and other conditions. Indeed, even in isolation, the Bayesian predictor delivers depth estimates that are competitive with state-of-the-art "computer vision" methods that utilize highly engineered image features and sophisticated machine learning algorithms.

Variational Bayesian Learning for Wavelet Independent Component Analysis

NASA Astrophysics Data System (ADS)

Roussos, E.; Roberts, S.; Daubechies, I.

2005-11-01

In an exploratory approach to data analysis, it is often useful to consider the observations as generated from a set of latent generators or "sources" via a generally unknown mapping. For the noisy overcomplete case, where we have more sources than observations, the problem becomes extremely ill-posed. Solutions to such inverse problems can, in many cases, be achieved by incorporating prior knowledge about the problem, captured in the form of constraints. This setting is a natural candidate for the application of the Bayesian methodology, allowing us to incorporate "soft" constraints in a natural manner. The work described in this paper is mainly driven by problems in functional magnetic resonance imaging of the brain, for the neuro-scientific goal of extracting relevant "maps" from the data. This can be stated as a `blind' source separation problem. Recent experiments in the field of neuroscience show that these maps are sparse, in some appropriate sense. The separation problem can be solved by independent component analysis (ICA), viewed as a technique for seeking sparse components, assuming appropriate distributions for the sources. We derive a hybrid wavelet-ICA model, transforming the signals into a domain where the modeling assumption of sparsity of the coefficients with respect to a dictionary is natural. We follow a graphical modeling formalism, viewing ICA as a probabilistic generative model. We use hierarchical source and mixing models and apply Bayesian inference to the problem. This allows us to perform model selection in order to infer the complexity of the representation, as well as automatic denoising. Since exact inference and learning in such a model is intractable, we follow a variational Bayesian mean-field approach in the conjugate-exponential family of distributions, for efficient unsupervised learning in multi-dimensional settings. The performance of the proposed algorithm is demonstrated on some representative experiments.

Methods for Measuring the Influence of Concept Mapping on Student Information Literacy.

ERIC Educational Resources Information Center

Gordon, Carol A.

2002-01-01

Discusses research traditions in education and in information retrieval and explores the theory of expected information which uses formulas derived from the Fano measure and Bayesian statistics. Demonstrates its application in a study on the effects of concept mapping on the search behavior of tenth-grade biology students. (Author/LRW)

DAFNE: A Matlab toolbox for Bayesian multi-source remote sensing and ancillary data fusion, with application to flood mapping

NASA Astrophysics Data System (ADS)

D'Addabbo, Annarita; Refice, Alberto; Lovergine, Francesco P.; Pasquariello, Guido

2018-03-01

High-resolution, remotely sensed images of the Earth surface have been proven to be of help in producing detailed flood maps, thanks to their synoptic overview of the flooded area and frequent revisits. However, flood scenarios can be complex situations, requiring the integration of different data in order to provide accurate and robust flood information. Several processing approaches have been recently proposed to efficiently combine and integrate heterogeneous information sources. In this paper, we introduce DAFNE, a Matlab®-based, open source toolbox, conceived to produce flood maps from remotely sensed and other ancillary information, through a data fusion approach. DAFNE is based on Bayesian Networks, and is composed of several independent modules, each one performing a different task. Multi-temporal and multi-sensor data can be easily handled, with the possibility of following the evolution of an event through multi-temporal output flood maps. Each DAFNE module can be easily modified or upgraded to meet different user needs. The DAFNE suite is presented together with an example of its application.

Genetic basis of climatic adaptation in scots pine by bayesian quantitative trait locus analysis.

PubMed Central

Hurme, P; Sillanpää, M J; Arjas, E; Repo, T; Savolainen, O

2000-01-01

We examined the genetic basis of large adaptive differences in timing of bud set and frost hardiness between natural populations of Scots pine. As a mapping population, we considered an "open-pollinated backcross" progeny by collecting seeds of a single F(1) tree (cross between trees from southern and northern Finland) growing in southern Finland. Due to the special features of the design (no marker information available on grandparents or the father), we applied a Bayesian quantitative trait locus (QTL) mapping method developed previously for outcrossed offspring. We found four potential QTL for timing of bud set and seven for frost hardiness. Bayesian analyses detected more QTL than ANOVA for frost hardiness, but the opposite was true for bud set. These QTL included alleles with rather large effects, and additionally smaller QTL were supported. The largest QTL for bud set date accounted for about a fourth of the mean difference between populations. Thus, natural selection during adaptation has resulted in selection of at least some alleles of rather large effect. PMID:11063704

Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells

PubMed Central

Eid, Mohammed Mansour Abbas; Shimoda, Mayuko; Singh, Shailendra Kumar; Almofty, Sarah Ameen; Pham, Phuong; Goodman, Myron F.; Maeda, Kazuhiko; Sakaguchi, Nobuo

2017-01-01

Abstract Immunoglobulin affinity maturation depends on somatic hypermutation (SHM) in immunoglobulin variable (IgV) regions initiated by activation-induced cytidine deaminase (AID). AID induces transition mutations by C→U deamination on both strands, causing C:G→T:A. Error-prone repairs of U by base excision and mismatch repairs (MMRs) create transversion mutations at C/G and mutations at A/T sites. In Neuberger’s model, it remained to be clarified how transition/transversion repair is regulated. We investigate the role of AID-interacting GANP (germinal center-associated nuclear protein) in the IgV SHM profile. GANP enhances transition mutation of the non-transcribed strand G and reduces mutation at A, restricted to GYW of the AID hotspot motif. It reduces DNA polymerase η hotspot mutations associated with MMRs followed by uracil-DNA glycosylase. Mutation comparison between IgV complementary and framework regions (FWRs) by Bayesian statistical estimation demonstrates that GANP supports the preservation of IgV FWR genomic sequences. GANP works to maintain antibody structure by reducing drastic changes in the IgV FWR in affinity maturation. PMID:28541550

Innate immunity and the new forward genetics.

PubMed

Beutler, Bruce

2016-12-01

As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps. First, a genetic mapping step was used to show that a given phenotype emanated from a circumscribed region of the genome. Second, a physical mapping step was undertaken, in which all of the region was cloned and its gene content determined. Finally, a concerted search for the mutation was performed. Such projects usually lasted for several years, but could produce breakthroughs in our understanding of biological processes. Publication of the annotated mouse genome sequence in 2002 made physical mapping unnecessary. More recently we devised a new technology for automated genetic mapping, which eliminated both genetic mapping and the search for mutations among candidate genes. The cause of phenotype can now be determined instantaneously. We have created more than 100,000 coding/splicing mutations. And by screening for defects of innate and adaptive immunity we have discovered many "new" proteins needed for innate immune function. Copyright © 2016 Elsevier Ltd. All rights reserved.

Innate immunity and the new forward genetics

PubMed Central

Beutler, Bruce

2016-01-01

As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps. First, a genetic mapping step was used to show that a given phenotype emanated from a circumscribed region of the genome. Second, a physical mapping step was undertaken, in which all of the region was cloned and its gene content determined. Finally, a concerted search for the mutation was performed. Such projects usually lasted for several years, but could produce breakthroughs in our understanding of biological processes. Publication of the annotated mouse genome sequence in 2002 made physical mapping unnecessary. More recently we devised a new technology for automated genetic mapping, which eliminated both genetic mapping and the search for mutations among candidate genes. The cause of phenotype can now be determined instantaneously. We have created more than 100,000 coding/splicing mutations. And by screening for defects of innate and adaptive immunity we have discovered many “new” proteins needed for innate immune function. PMID:27890263

Hierarchical Bayesian method for mapping biogeochemical hot spots using induced polarization imaging

DOE PAGES

Wainwright, Haruko M.; Flores Orozco, Adrian; Bucker, Matthias; ...

2016-01-29

In floodplain environments, a naturally reduced zone (NRZ) is considered to be a common biogeochemical hot spot, having distinct microbial and geochemical characteristics. Although important for understanding their role in mediating floodplain biogeochemical processes, mapping the subsurface distribution of NRZs over the dimensions of a floodplain is challenging, as conventional wellbore data are typically spatially limited and the distribution of NRZs is heterogeneous. In this work, we present an innovative methodology for the probabilistic mapping of NRZs within a three-dimensional (3-D) subsurface domain using induced polarization imaging, which is a noninvasive geophysical technique. Measurements consist of surface geophysical surveys andmore » drilling-recovered sediments at the U.S. Department of Energy field site near Rifle, CO (USA). Inversion of surface time domain-induced polarization (TDIP) data yielded 3-D images of the complex electrical resistivity, in terms of magnitude and phase, which are associated with mineral precipitation and other lithological properties. By extracting the TDIP data values colocated with wellbore lithological logs, we found that the NRZs have a different distribution of resistivity and polarization from the other aquifer sediments. To estimate the spatial distribution of NRZs, we developed a Bayesian hierarchical model to integrate the geophysical and wellbore data. In addition, the resistivity images were used to estimate hydrostratigraphic interfaces under the floodplain. Validation results showed that the integration of electrical imaging and wellbore data using a Bayesian hierarchical model was capable of mapping spatially heterogeneous interfaces and NRZ distributions thereby providing a minimally invasive means to parameterize a hydrobiogeochemical model of the floodplain.« less

Simple summation rule for optimal fixation selection in visual search.

PubMed

Najemnik, Jiri; Geisler, Wilson S

2009-06-01

When searching for a known target in a natural texture, practiced humans achieve near-optimal performance compared to a Bayesian ideal searcher constrained with the human map of target detectability across the visual field [Najemnik, J., & Geisler, W. S. (2005). Optimal eye movement strategies in visual search. Nature, 434, 387-391]. To do so, humans must be good at choosing where to fixate during the search [Najemnik, J., & Geisler, W.S. (2008). Eye movement statistics in humans are consistent with an optimal strategy. Journal of Vision, 8(3), 1-14. 4]; however, it seems unlikely that a biological nervous system would implement the computations for the Bayesian ideal fixation selection because of their complexity. Here we derive and test a simple heuristic for optimal fixation selection that appears to be a much better candidate for implementation within a biological nervous system. Specifically, we show that the near-optimal fixation location is the maximum of the current posterior probability distribution for target location after the distribution is filtered by (convolved with) the square of the retinotopic target detectability map. We term the model that uses this strategy the entropy limit minimization (ELM) searcher. We show that when constrained with human-like retinotopic map of target detectability and human search error rates, the ELM searcher performs as well as the Bayesian ideal searcher, and produces fixation statistics similar to human.

EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII)

PubMed Central

Midha, Anita; Dearden, Simon; McCormack, Rose

2015-01-01

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC), particularly in tumors of adenocarcinoma (ADC) histology (NSCLC/ADC). Robust data exist regarding the prevalence of EGFR mutations in Western and Asian patients with NSCLC/ADC, yet there is a lack of data for patients of other ethnicities. This review collated available data with the aim of creating a complete, global picture of EGFR mutation frequency in patients with NSCLC/ADC by ethnicity. Worldwide literature reporting EGFR mutation frequency in patients with NSCLC/ADC was reviewed, to create a map of the world populated with EGFR mutation frequency by country (a ‘global EGFR mutMap’). A total of 151 worldwide studies (n=33162 patients with NSCLC/ADC, of which 9749 patients had EGFR mutation-positive NSCLC/ADC) were included. There was substantial variation in EGFR mutation frequency between studies, even when grouped by geographic region or individual country. As expected, the Asia-Pacific NSCLC/ADC subgroup had the highest EGFR mutation frequency (47% [5958/12819; 87 studies; range 20%-76%]) and the lowest EGFR mutation frequency occurred in the Oceania NSCLC/ADC subgroup (12% [69/570; 4 studies; range 7%-36%]); however, comparisons between regions were limited due to the varying sizes of the patient populations studied. In all regional (geographic) subgroups where data were available, EGFR mutation frequency in NSCLC/ADC was higher in women compared with men, and in never-compared with ever-smokers. This review provides the foundation for a global map of EGFR mutation frequency in patients with NSCLC/ADC. The substantial lack of data from several large geographic regions of the world, notably Africa, the Middle East, Central Asia, and Central and South America, highlights a potential lack of routine mutation testing and the need for further investigations in these regions. PMID:26609494

Homozygosity mapping in albinism patients using a novel panel of 13 STR markers inside the nonsyndromic OCA genes: introducing 5 novel mutations.

PubMed

Khordadpoor-Deilamani, Faravareh; Akbari, Mohammad Taghi; Karimipoor, Morteza; Javadi, Gholam Reza

2016-05-01

Albinism is a heterogeneous genetic disorder of melanin synthesis that results in hypopigmented hair, skin and eyes. It is associated with decreased visual acuity, nystagmus, strabismus and photophobia. Six genes are known to be involved in nonsyndromic oculocutaneous albinism (OCA). In this study, we aimed to find the disease causing mutations in albinism patients using homozygosity mapping. Twenty three unrelated patients with nonsyndromic OCA or autosomal recessive ocular albinism were recruited in this study. All of the patients' parents had consanguineous marriage and all were screened for TYR mutations previously. At first, we performed homozygosity mapping using fluorescently labeled primers to amplify a novel panel of 13 STR markers inside the OCA genes and then the screened loci in each family were studied using PCR and cycle sequencing methods. We found five mutations including three mutations in OCA2, one mutation in SLC45A2 and one mutation in C10ORF11 genes, all of which were novel. In cases where the disease causing mutations are identical by descent due to a common ancestor, these STR markers can enable us to screen for the responsible genes.

Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivocal conditions: a Norrie disease case study.

PubMed

Chini, Vasiliki; Stambouli, Danai; Nedelea, Florina Mihaela; Filipescu, George Alexandru; Mina, Diana; Kambouris, Marios; El-Shantil, Hatem

2014-06-01

Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members. Mapping of the X chromosome and candidate gene mutation screening identified a c.C267A[p.F89L] mutation in NPD previously described as possibly causing Norrie disease. The detection of the c.C267A[p.F89L] variant in another unrelated family confirms the pathogenic nature of the mutation for the Norrie disease phenotype. Gene mapping, haplotype analysis, and candidate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information. The clinical diagnosis and mutation identification were critical for providing proper genetic counseling and prenatal diagnosis for this family.

Spatiotemporal Bayesian analysis of Lyme disease in New York state, 1990-2000.

PubMed

Chen, Haiyan; Stratton, Howard H; Caraco, Thomas B; White, Dennis J

2006-07-01

Mapping ordinarily increases our understanding of nontrivial spatial and temporal heterogeneities in disease rates. However, the large number of parameters required by the corresponding statistical models often complicates detailed analysis. This study investigates the feasibility of a fully Bayesian hierarchical regression approach to the problem and identifies how it outperforms two more popular methods: crude rate estimates (CRE) and empirical Bayes standardization (EBS). In particular, we apply a fully Bayesian approach to the spatiotemporal analysis of Lyme disease incidence in New York state for the period 1990-2000. These results are compared with those obtained by CRE and EBS in Chen et al. (2005). We show that the fully Bayesian regression model not only gives more reliable estimates of disease rates than the other two approaches but also allows for tractable models that can accommodate more numerous sources of variation and unknown parameters.

AlignerBoost: A Generalized Software Toolkit for Boosting Next-Gen Sequencing Mapping Accuracy Using a Bayesian-Based Mapping Quality Framework

PubMed Central

Zheng, Qi; Grice, Elizabeth A.

2016-01-01

Accurate mapping of next-generation sequencing (NGS) reads to reference genomes is crucial for almost all NGS applications and downstream analyses. Various repetitive elements in human and other higher eukaryotic genomes contribute in large part to ambiguously (non-uniquely) mapped reads. Most available NGS aligners attempt to address this by either removing all non-uniquely mapping reads, or reporting one random or "best" hit based on simple heuristics. Accurate estimation of the mapping quality of NGS reads is therefore critical albeit completely lacking at present. Here we developed a generalized software toolkit "AlignerBoost", which utilizes a Bayesian-based framework to accurately estimate mapping quality of ambiguously mapped NGS reads. We tested AlignerBoost with both simulated and real DNA-seq and RNA-seq datasets at various thresholds. In most cases, but especially for reads falling within repetitive regions, AlignerBoost dramatically increases the mapping precision of modern NGS aligners without significantly compromising the sensitivity even without mapping quality filters. When using higher mapping quality cutoffs, AlignerBoost achieves a much lower false mapping rate while exhibiting comparable or higher sensitivity compared to the aligner default modes, therefore significantly boosting the detection power of NGS aligners even using extreme thresholds. AlignerBoost is also SNP-aware, and higher quality alignments can be achieved if provided with known SNPs. AlignerBoost’s algorithm is computationally efficient, and can process one million alignments within 30 seconds on a typical desktop computer. AlignerBoost is implemented as a uniform Java application and is freely available at https://github.com/Grice-Lab/AlignerBoost. PMID:27706155

Occurrence of Mycobacterium avium subspecies paratuberculosis and Neospora caninum in Alberta cow-calf operations.

PubMed

Pruvot, M; Kutz, S; Barkema, H W; De Buck, J; Orsel, K

2014-11-01

Mycobacterium avium subsp. paratuberculosis (MAP) and Neospora caninum (NC) are two pathogens causing important production limiting diseases in the cattle industry. Significant impacts of MAP and NC have been reported on dairy cattle herds, but little is known about the importance, risk factors and transmission patterns in western Canadian cow-calf herds. In this cross-sectional study, the prevalence of MAP and NC infection in southwest Alberta cow-calf herds was estimated, risk factors for NC were identified, and the reproductive impacts of the two pathogens were assessed. Blood and fecal samples were collected from 840 cows on 28 cow-calf operations. Individual cow and herd management information was collected by self-administered questionnaires and one-on-one interviews. Bayesian estimates of the true prevalence of MAP and NC were computed, and bivariable and multivariable statistical analysis were done to assess the association between the NC serological status and ranch management risk factors, and the clinical effects of the two pathogens. Bayesian estimates of true prevalence indicated that 20% (95% probability interval: 8-38%) of herds had at least one MAP-positive cow, with a within-herd prevalence in positive herds of 22% (8-45%). From the Bayesian posterior distributions of NC prevalence, the median herd-level prevalence was 66% (33-95%) with 10% (4-21%) cow-level prevalence in positive herds. Multivariable analysis indicated that introducing purchased animals in the herd might increase the risk of NC. The negative association of NC with proper carcass disposal and presence of horses on ranch (possibly in relation to herd monitoring and guarding activities), may suggest the importance of wild carnivores in the dynamics of this pathogen in the study area. We also observed an association between MAP and NC serological status and the number of abortions. Additional studies should be done to further examine specific risk factors for MAP and NC, assess the consequences on the reproductive performances in cow-calf herds, and evaluate the overall impact of these pathogens on cow-calf operations. Copyright © 2014 Elsevier B.V. All rights reserved.

SOMBI: Bayesian identification of parameter relations in unstructured cosmological data

NASA Astrophysics Data System (ADS)

Frank, Philipp; Jasche, Jens; Enßlin, Torsten A.

2016-11-01

This work describes the implementation and application of a correlation determination method based on self organizing maps and Bayesian inference (SOMBI). SOMBI aims to automatically identify relations between different observed parameters in unstructured cosmological or astrophysical surveys by automatically identifying data clusters in high-dimensional datasets via the self organizing map neural network algorithm. Parameter relations are then revealed by means of a Bayesian inference within respective identified data clusters. Specifically such relations are assumed to be parametrized as a polynomial of unknown order. The Bayesian approach results in a posterior probability distribution function for respective polynomial coefficients. To decide which polynomial order suffices to describe correlation structures in data, we include a method for model selection, the Bayesian information criterion, to the analysis. The performance of the SOMBI algorithm is tested with mock data. As illustration we also provide applications of our method to cosmological data. In particular, we present results of a correlation analysis between galaxy and active galactic nucleus (AGN) properties provided by the SDSS catalog with the cosmic large-scale-structure (LSS). The results indicate that the combined galaxy and LSS dataset indeed is clustered into several sub-samples of data with different average properties (for example different stellar masses or web-type classifications). The majority of data clusters appear to have a similar correlation structure between galaxy properties and the LSS. In particular we revealed a positive and linear dependency between the stellar mass, the absolute magnitude and the color of a galaxy with the corresponding cosmic density field. A remaining subset of data shows inverted correlations, which might be an artifact of non-linear redshift distortions.

Measles virus genetic evolution throughout an imported epidemic outbreak in a highly vaccinated population.

PubMed

Muñoz-Alía, Miguel Ángel; Fernández-Muñoz, Rafael; Casasnovas, José María; Porras-Mansilla, Rebeca; Serrano-Pardo, Ángela; Pagán, Israel; Ordobás, María; Ramírez, Rosa; Celma, María Luisa

2015-01-22

Measles virus circulates endemically in African and Asian large urban populations, causing outbreaks worldwide in populations with up-to-95% immune protection. We studied the natural genetic variability of genotype B3.1 in a population with 95% vaccine coverage throughout an imported six month measles outbreak. From first pass viral isolates of 47 patients we performed direct sequencing of genomic cDNA. Whilst no variation from index case sequence occurred in the Nucleocapsid gene hyper-variable carboxy end, in the Hemagglutinin gene, main target for neutralizing antibodies, we observed gradual nucleotide divergence from index case along the outbreak (0% to 0.380%, average 0.138%) with the emergence of transient and persistent non-synonymous and synonymous mutations. Little or no variation was observed between the index and last outbreak cases in Phosphoprotein, Nucleocapsid, Matrix and Fusion genes. Most of the H non-synonymous mutations were mapped on the protein surface near antigenic and receptors binding sites. We estimated a MV-Hemagglutinin nucleotide substitution rate of 7.28 × 10-6 substitutions/site/day by a Bayesian phylogenetic analysis. The dN/dS analysis did not suggest significant immune or other selective pressures on the H gene during the outbreak. These results emphasize the usefulness of MV-H sequence analysis in measles epidemiological surveillance and elimination programs, and in detection of potentially emergence of measles virus neutralization-resistant mutants. Copyright © 2014 Elsevier B.V. All rights reserved.

Mapping local and global variability in plant trait distributions

DOE PAGES

Butler, Ethan E.; Datta, Abhirup; Flores-Moreno, Habacuc; ...

2017-12-01

Accurate trait-environment relationships and global maps of plant trait distributions represent a needed stepping stone in global biogeography and are critical constraints of key parameters for land models. Here, we use a global data set of plant traits to map trait distributions closely coupled to photosynthesis and foliar respiration: specific leaf area (SLA), and dry mass-based concentrations of leaf nitrogen (Nm) and phosphorus (Pm); We propose two models to extrapolate geographically sparse point data to continuous spatial surfaces. The first is a categorical model using species mean trait values, categorized into plant functional types (PFTs) and extrapolating to PFT occurrencemore » ranges identified by remote sensing. The second is a Bayesian spatial model that incorporates information about PFT, location and environmental covariates to estimate trait distributions. Both models are further stratified by varying the number of PFTs; The performance of the models was evaluated based on their explanatory and predictive ability. The Bayesian spatial model leveraging the largest number of PFTs produced the best maps; The interpolation of full trait distributions enables a wider diversity of vegetation to be represented across the land surface. These maps may be used as input to Earth System Models and to evaluate other estimates of functional diversity.« less

Mapping local and global variability in plant trait distributions

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

Butler, Ethan E.; Datta, Abhirup; Flores-Moreno, Habacuc

Accurate trait-environment relationships and global maps of plant trait distributions represent a needed stepping stone in global biogeography and are critical constraints of key parameters for land models. Here, we use a global data set of plant traits to map trait distributions closely coupled to photosynthesis and foliar respiration: specific leaf area (SLA), and dry mass-based concentrations of leaf nitrogen (Nm) and phosphorus (Pm); We propose two models to extrapolate geographically sparse point data to continuous spatial surfaces. The first is a categorical model using species mean trait values, categorized into plant functional types (PFTs) and extrapolating to PFT occurrencemore » ranges identified by remote sensing. The second is a Bayesian spatial model that incorporates information about PFT, location and environmental covariates to estimate trait distributions. Both models are further stratified by varying the number of PFTs; The performance of the models was evaluated based on their explanatory and predictive ability. The Bayesian spatial model leveraging the largest number of PFTs produced the best maps; The interpolation of full trait distributions enables a wider diversity of vegetation to be represented across the land surface. These maps may be used as input to Earth System Models and to evaluate other estimates of functional diversity.« less

Dissecting enzyme function with microfluidic-based deep mutational scanning.

PubMed

Romero, Philip A; Tran, Tuan M; Abate, Adam R

2015-06-09

Natural enzymes are incredibly proficient catalysts, but engineering them to have new or improved functions is challenging due to the complexity of how an enzyme's sequence relates to its biochemical properties. Here, we present an ultrahigh-throughput method for mapping enzyme sequence-function relationships that combines droplet microfluidic screening with next-generation DNA sequencing. We apply our method to map the activity of millions of glycosidase sequence variants. Microfluidic-based deep mutational scanning provides a comprehensive and unbiased view of the enzyme function landscape. The mapping displays expected patterns of mutational tolerance and a strong correspondence to sequence variation within the enzyme family, but also reveals previously unreported sites that are crucial for glycosidase function. We modified the screening protocol to include a high-temperature incubation step, and the resulting thermotolerance landscape allowed the discovery of mutations that enhance enzyme thermostability. Droplet microfluidics provides a general platform for enzyme screening that, when combined with DNA-sequencing technologies, enables high-throughput mapping of enzyme sequence space.

MUTYH-associated colorectal cancer and adenomatous polyposis.

PubMed

Yamaguchi, Satoru; Ogata, Hideo; Katsumata, Daisuke; Nakajima, Masanobu; Fujii, Takaaki; Tsutsumi, Soichi; Asao, Takayuki; Sasaki, Kinro; Kuwano, Hiroyuki; Kato, Hiroyuki

2014-04-01

MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10-100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis.

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

DOE PAGES

Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore; ...

2017-04-13

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here in this paper, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strongmore » sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. In conclusion, the occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.« less

A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

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

Viel, Alessandra; Bruselles, Alessandro; Meccia, Ettore

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here in this paper, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strongmore » sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. In conclusion, the occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.« less

Using Object Oriented Bayesian Networks to Model Linkage, Linkage Disequilibrium and Mutations between STR Markers

PubMed Central

Kling, Daniel; Egeland, Thore; Mostad, Petter

2012-01-01

In a number of applications there is a need to determine the most likely pedigree for a group of persons based on genetic markers. Adequate models are needed to reach this goal. The markers used to perform the statistical calculations can be linked and there may also be linkage disequilibrium (LD) in the population. The purpose of this paper is to present a graphical Bayesian Network framework to deal with such data. Potential LD is normally ignored and it is important to verify that the resulting calculations are not biased. Even if linkage does not influence results for regular paternity cases, it may have substantial impact on likelihood ratios involving other, more extended pedigrees. Models for LD influence likelihoods for all pedigrees to some degree and an initial estimate of the impact of ignoring LD and/or linkage is desirable, going beyond mere rules of thumb based on marker distance. Furthermore, we show how one can readily include a mutation model in the Bayesian Network; extending other programs or formulas to include such models may require considerable amounts of work and will in many case not be practical. As an example, we consider the two STR markers vWa and D12S391. We estimate probabilities for population haplotypes to account for LD using a method based on data from trios, while an estimate for the degree of linkage is taken from the literature. The results show that accounting for haplotype frequencies is unnecessary in most cases for this specific pair of markers. When doing calculations on regular paternity cases, the markers can be considered statistically independent. In more complex cases of disputed relatedness, for instance cases involving siblings or so-called deficient cases, or when small differences in the LR matter, independence should not be assumed. (The networks are freely available at http://arken.umb.no/~dakl/BayesianNetworks.) PMID:22984448

Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer

ClinicalTrials.gov

2018-05-31

ATM Gene Mutation; ATR Gene Mutation; BARD1 Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; BRIP1 Gene Mutation; CHEK1 Gene Mutation; CHEK2 Gene Mutation; FANCA Gene Mutation; FANCC Gene Mutation; FANCD2 Gene Mutation; FANCF Gene Mutation; FANCM Gene Mutation; NBN Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; RAD51B Gene Mutation; RAD54L Gene Mutation; Recurrent Squamous Cell Lung Carcinoma; RPA1 Gene Mutation; Stage IV Squamous Cell Lung Carcinoma AJCC v7

A note on the efficiencies of sampling strategies in two-stage Bayesian regional fine mapping of a quantitative trait.

PubMed

Chen, Zhijian; Craiu, Radu V; Bull, Shelley B

2014-11-01

In focused studies designed to follow up associations detected in a genome-wide association study (GWAS), investigators can proceed to fine-map a genomic region by targeted sequencing or dense genotyping of all variants in the region, aiming to identify a functional sequence variant. For the analysis of a quantitative trait, we consider a Bayesian approach to fine-mapping study design that incorporates stratification according to a promising GWAS tag SNP in the same region. Improved cost-efficiency can be achieved when the fine-mapping phase incorporates a two-stage design, with identification of a smaller set of more promising variants in a subsample taken in stage 1, followed by their evaluation in an independent stage 2 subsample. To avoid the potential negative impact of genetic model misspecification on inference we incorporate genetic model selection based on posterior probabilities for each competing model. Our simulation study shows that, compared to simple random sampling that ignores genetic information from GWAS, tag-SNP-based stratified sample allocation methods reduce the number of variants continuing to stage 2 and are more likely to promote the functional sequence variant into confirmation studies. © 2014 WILEY PERIODICALS, INC.

Genetic Characterization of the SufJ Frameshift Suppressor in SALMONELLA TYPHIMURIUM

PubMed Central

Bossi, Lionello; Kohno, Tadahiko; Roth, John R.

1983-01-01

A new suppressor of +1 frameshift mutations has been isolated in Salmonella typhimurium. This suppressor, sufJ, maps at minute 89 on the Salmonella genetic map between the argH and rpo(rif) loci, closely linked to the gene for the ochre suppressor tyrU(supM). The suppressor mutation is dominant to its wild-type allele, consistent with the suppressor phenotype being caused by an altered tRNA species. The sufJ map position coincides with that of a threonine tRNA(ACC/U) gene; the suppressor has been shown to read the related fourbase codons ACCU, ACCC, ACCA.—The ability of sufJ to correct one particular mutation depends on the presence of a hisT mutation which causes a defect in tRNA modification. This requirement is allele specific, since other frameshift mutations can be corrected by sufJ regardless of the state of the hisT locus.—Strains carrying both a sufJ and a hisT mutation are acutely sensitive to growth inhibition by uracil; the inhibition is reversed by arginine. This behavior is characteristic of strains with mutations affecting the arginine-uracil biosynthetic enzyme carbamyl phosphate synthetase. The combination of two mutations affecting tRNA structure may reduce expression of the structural gene for this enzyme (pyrA). PMID:6188650

Extensively Parameterized Mutation-Selection Models Reliably Capture Site-Specific Selective Constraint.

PubMed

Spielman, Stephanie J; Wilke, Claus O

2016-11-01

The mutation-selection model of coding sequence evolution has received renewed attention for its use in estimating site-specific amino acid propensities and selection coefficient distributions. Two computationally tractable mutation-selection inference frameworks have been introduced: One framework employs a fixed-effects, highly parameterized maximum likelihood approach, whereas the other employs a random-effects Bayesian Dirichlet Process approach. While both implementations follow the same model, they appear to make distinct predictions about the distribution of selection coefficients. The fixed-effects framework estimates a large proportion of highly deleterious substitutions, whereas the random-effects framework estimates that all substitutions are either nearly neutral or weakly deleterious. It remains unknown, however, how accurately each method infers evolutionary constraints at individual sites. Indeed, selection coefficient distributions pool all site-specific inferences, thereby obscuring a precise assessment of site-specific estimates. Therefore, in this study, we use a simulation-based strategy to determine how accurately each approach recapitulates the selective constraint at individual sites. We find that the fixed-effects approach, despite its extensive parameterization, consistently and accurately estimates site-specific evolutionary constraint. By contrast, the random-effects Bayesian approach systematically underestimates the strength of natural selection, particularly for slowly evolving sites. We also find that, despite the strong differences between their inferred selection coefficient distributions, the fixed- and random-effects approaches yield surprisingly similar inferences of site-specific selective constraint. We conclude that the fixed-effects mutation-selection framework provides the more reliable software platform for model application and future development. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells.

PubMed

Eid, Mohammed Mansour Abbas; Shimoda, Mayuko; Singh, Shailendra Kumar; Almofty, Sarah Ameen; Pham, Phuong; Goodman, Myron F; Maeda, Kazuhiko; Sakaguchi, Nobuo

2017-05-01

Immunoglobulin affinity maturation depends on somatic hypermutation (SHM) in immunoglobulin variable (IgV) regions initiated by activation-induced cytidine deaminase (AID). AID induces transition mutations by C→U deamination on both strands, causing C:G→T:A. Error-prone repairs of U by base excision and mismatch repairs (MMRs) create transversion mutations at C/G and mutations at A/T sites. In Neuberger's model, it remained to be clarified how transition/transversion repair is regulated. We investigate the role of AID-interacting GANP (germinal center-associated nuclear protein) in the IgV SHM profile. GANP enhances transition mutation of the non-transcribed strand G and reduces mutation at A, restricted to GYW of the AID hotspot motif. It reduces DNA polymerase η hotspot mutations associated with MMRs followed by uracil-DNA glycosylase. Mutation comparison between IgV complementary and framework regions (FWRs) by Bayesian statistical estimation demonstrates that GANP supports the preservation of IgV FWR genomic sequences. GANP works to maintain antibody structure by reducing drastic changes in the IgV FWR in affinity maturation. © The Author 2017. Published by Oxford University Press on behalf of The Japanese Society for Immunology.

REMOVING BIASES IN RESOLVED STELLAR MASS MAPS OF GALAXY DISKS THROUGH SUCCESSIVE BAYESIAN MARGINALIZATION

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

Martínez-García, Eric E.; González-Lópezlira, Rosa A.; Bruzual A, Gustavo

2017-01-20

Stellar masses of galaxies are frequently obtained by fitting stellar population synthesis models to galaxy photometry or spectra. The state of the art method resolves spatial structures within a galaxy to assess the total stellar mass content. In comparison to unresolved studies, resolved methods yield, on average, higher fractions of stellar mass for galaxies. In this work we improve the current method in order to mitigate a bias related to the resolved spatial distribution derived for the mass. The bias consists in an apparent filamentary mass distribution and a spatial coincidence between mass structures and dust lanes near spiral arms.more » The improved method is based on iterative Bayesian marginalization, through a new algorithm we have named Bayesian Successive Priors (BSP). We have applied BSP to M51 and to a pilot sample of 90 spiral galaxies from the Ohio State University Bright Spiral Galaxy Survey. By quantitatively comparing both methods, we find that the average fraction of stellar mass missed by unresolved studies is only half what previously thought. In contrast with the previous method, the output BSP mass maps bear a better resemblance to near-infrared images.« less

Genetic Correlations Greatly Increase Mutational Robustness and Can Both Reduce and Enhance Evolvability

PubMed Central

Greenbury, Sam F.; Schaper, Steffen; Ahnert, Sebastian E.; Louis, Ard A.

2016-01-01

Mutational neighbourhoods in genotype-phenotype (GP) maps are widely believed to be more likely to share characteristics than expected from random chance. Such genetic correlations should strongly influence evolutionary dynamics. We explore and quantify these intuitions by comparing three GP maps—a model for RNA secondary structure, the HP model for protein tertiary structure, and the Polyomino model for protein quaternary structure—to a simple random null model that maintains the number of genotypes mapping to each phenotype, but assigns genotypes randomly. The mutational neighbourhood of a genotype in these GP maps is much more likely to contain genotypes mapping to the same phenotype than in the random null model. Such neutral correlations can be quantified by the robustness to mutations, which can be many orders of magnitude larger than that of the null model, and crucially, above the critical threshold for the formation of large neutral networks of mutationally connected genotypes which enhance the capacity for the exploration of phenotypic novelty. Thus neutral correlations increase evolvability. We also study non-neutral correlations: Compared to the null model, i) If a particular (non-neutral) phenotype is found once in the 1-mutation neighbourhood of a genotype, then the chance of finding that phenotype multiple times in this neighbourhood is larger than expected; ii) If two genotypes are connected by a single neutral mutation, then their respective non-neutral 1-mutation neighbourhoods are more likely to be similar; iii) If a genotype maps to a folding or self-assembling phenotype, then its non-neutral neighbours are less likely to be a potentially deleterious non-folding or non-assembling phenotype. Non-neutral correlations of type i) and ii) reduce the rate at which new phenotypes can be found by neutral exploration, and so may diminish evolvability, while non-neutral correlations of type iii) may instead facilitate evolutionary exploration and so increase evolvability. PMID:26937652

Proposal of Classification Method of Time Series Data in International Emissions Trading Market Using Agent-based Simulation

NASA Astrophysics Data System (ADS)

Nakada, Tomohiro; Takadama, Keiki; Watanabe, Shigeyoshi

This paper proposes the classification method using Bayesian analytical method to classify the time series data in the international emissions trading market depend on the agent-based simulation and compares the case with Discrete Fourier transform analytical method. The purpose demonstrates the analytical methods mapping time series data such as market price. These analytical methods have revealed the following results: (1) the classification methods indicate the distance of mapping from the time series data, it is easier the understanding and inference than time series data; (2) these methods can analyze the uncertain time series data using the distance via agent-based simulation including stationary process and non-stationary process; and (3) Bayesian analytical method can show the 1% difference description of the emission reduction targets of agent.

The landscape of cancer genes and mutational processes in breast cancer

PubMed Central

Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; Loo, Peter Van; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; OSBREAC; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van ’t Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S.; Aparicio, Samuel A. J. R.; Salomon, Anne Vincent; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.

2012-01-01

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. PMID:22722201

Large-scale identification of chemically induced mutations in Drosophila melanogaster

PubMed Central

Haelterman, Nele A.; Jiang, Lichun; Li, Yumei; Bayat, Vafa; Sandoval, Hector; Ugur, Berrak; Tan, Kai Li; Zhang, Ke; Bei, Danqing; Xiong, Bo; Charng, Wu-Lin; Busby, Theodore; Jawaid, Adeel; David, Gabriela; Jaiswal, Manish; Venken, Koen J.T.; Yamamoto, Shinya

2014-01-01

Forward genetic screens using chemical mutagens have been successful in defining the function of thousands of genes in eukaryotic model organisms. The main drawback of this strategy is the time-consuming identification of the molecular lesions causative of the phenotypes of interest. With whole-genome sequencing (WGS), it is now possible to sequence hundreds of strains, but determining which mutations are causative among thousands of polymorphisms remains challenging. We have sequenced 394 mutant strains, generated in a chemical mutagenesis screen, for essential genes on the Drosophila X chromosome and describe strategies to reduce the number of candidate mutations from an average of ∼3500 to 35 single-nucleotide variants per chromosome. By combining WGS with a rough mapping method based on large duplications, we were able to map 274 (∼70%) mutations. We show that these mutations are causative, using small 80-kb duplications that rescue lethality. Hence, our findings demonstrate that combining rough mapping with WGS dramatically expands the toolkit necessary for assigning function to genes. PMID:25258387

Sparse Bayesian Information Filters for Localization and Mapping

DTIC Science & Technology

2008-02-01

a set of smaller, more manageable maps [76, 51, 139, 77, 12]. These appropriately-named submap algorithms greatly reduce the effects of map size on...An intuitive way of dealing with this limitation is to divide the world into numerous sub-environments, each comprised of a more manageable number of...p (xt, M I z t , u t) = p (M I xt, zt) • p (xt zt, ut) (2.16) 6 This assumes knowledge of the mean, which is necessary for observations that are

Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.

PubMed

Hudson, Andrew M; Stephenson, Natalie L; Li, Cynthia; Trotter, Eleanor; Fletcher, Adam J; Katona, Gitta; Bieniasz-Krzywiec, Patrycja; Howell, Matthew; Wirth, Chris; Furney, Simon; Miller, Crispin J; Brognard, John

2018-04-17

A major challenge in cancer genomics is identifying "driver" mutations from the many neutral "passenger" mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations

PubMed Central

Schafernak, Kristian T.; Geyer, Julia T.; Kovach, Alexandra E.; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G.; Paxton, Christian N.; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A.; Neuberg, Donna S.; South, Sarah T.; Harris, Marian H.; Hasserjian, Robert P.; Hochberg, Ephraim P.; Garraway, Levi A.; Harris, Nancy Lee; Weinstock, David M.

2016-01-01

Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. PMID:27325104

Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.

PubMed

Louissaint, Abner; Schafernak, Kristian T; Geyer, Julia T; Kovach, Alexandra E; Ghandi, Mahmoud; Gratzinger, Dita; Roth, Christine G; Paxton, Christian N; Kim, Sunhee; Namgyal, Chungdak; Morin, Ryan; Morgan, Elizabeth A; Neuberg, Donna S; South, Sarah T; Harris, Marian H; Hasserjian, Robert P; Hochberg, Ephraim P; Garraway, Levi A; Harris, Nancy Lee; Weinstock, David M

2016-08-25

Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers. © 2016 by The American Society of Hematology.

Cassava haplotype map highlights fixation of deleterious mutations during clonal propagation

USDA-ARS?s Scientific Manuscript database

Cassava (Manihot esculenta Crantz) is an important staple food crop in Africa and South America whose fitness may be severely reduced by ubiquitous deleterious variation. To evaluate these deleterious mutations in cassava genome, we constructed a cassava haplotype map by deep sequencing of 241 diver...

Predicting human immunodeficiency virus inhibitors using multi-dimensional Bayesian network classifiers.

PubMed

Borchani, Hanen; Bielza, Concha; Toro, Carlos; Larrañaga, Pedro

2013-03-01

Our aim is to use multi-dimensional Bayesian network classifiers in order to predict the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease inhibitors given an input set of respective resistance mutations that an HIV patient carries. Multi-dimensional Bayesian network classifiers (MBCs) are probabilistic graphical models especially designed to solve multi-dimensional classification problems, where each input instance in the data set has to be assigned simultaneously to multiple output class variables that are not necessarily binary. In this paper, we introduce a new method, named MB-MBC, for learning MBCs from data by determining the Markov blanket around each class variable using the HITON algorithm. Our method is applied to both reverse transcriptase and protease data sets obtained from the Stanford HIV-1 database. Regarding the prediction of antiretroviral combination therapies, the experimental study shows promising results in terms of classification accuracy compared with state-of-the-art MBC learning algorithms. For reverse transcriptase inhibitors, we get 71% and 11% in mean and global accuracy, respectively; while for protease inhibitors, we get more than 84% and 31% in mean and global accuracy, respectively. In addition, the analysis of MBC graphical structures lets us gain insight into both known and novel interactions between reverse transcriptase and protease inhibitors and their respective resistance mutations. MB-MBC algorithm is a valuable tool to analyze the HIV-1 reverse transcriptase and protease inhibitors prediction problem and to discover interactions within and between these two classes of inhibitors. Copyright © 2012 Elsevier B.V. All rights reserved.

Bayesian population receptive field modelling.

PubMed

Zeidman, Peter; Silson, Edward Harry; Schwarzkopf, Dietrich Samuel; Baker, Chris Ian; Penny, Will

2017-09-08

We introduce a probabilistic (Bayesian) framework and associated software toolbox for mapping population receptive fields (pRFs) based on fMRI data. This generic approach is intended to work with stimuli of any dimension and is demonstrated and validated in the context of 2D retinotopic mapping. The framework enables the experimenter to specify generative (encoding) models of fMRI timeseries, in which experimental stimuli enter a pRF model of neural activity, which in turns drives a nonlinear model of neurovascular coupling and Blood Oxygenation Level Dependent (BOLD) response. The neuronal and haemodynamic parameters are estimated together on a voxel-by-voxel or region-of-interest basis using a Bayesian estimation algorithm (variational Laplace). This offers several novel contributions to receptive field modelling. The variance/covariance of parameters are estimated, enabling receptive fields to be plotted while properly representing uncertainty about pRF size and location. Variability in the haemodynamic response across the brain is accounted for. Furthermore, the framework introduces formal hypothesis testing to pRF analysis, enabling competing models to be evaluated based on their log model evidence (approximated by the variational free energy), which represents the optimal tradeoff between accuracy and complexity. Using simulations and empirical data, we found that parameters typically used to represent pRF size and neuronal scaling are strongly correlated, which is taken into account by the Bayesian methods we describe when making inferences. We used the framework to compare the evidence for six variants of pRF model using 7 T functional MRI data and we found a circular Difference of Gaussians (DoG) model to be the best explanation for our data overall. We hope this framework will prove useful for mapping stimulus spaces with any number of dimensions onto the anatomy of the brain. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5.

PubMed Central

Nagle, D L; Martin-DeLeon, P; Hough, R B; Bućan, M

1994-01-01

We are studying the chromosomal structure of three developmental mutations, dominant spotting (W), patch (Ph), and rump white (Rw) on mouse chromosome 5. These mutations are clustered in a region containing three genes encoding tyrosine kinase receptors (Kit, Pdgfra, and Flk1). Using probes for these genes and for a closely linked locus, D5Mn125, we established a high-resolution physical map covering approximately 2.8 Mb. The entire chromosomal segment mapped in this study is deleted in the W19H mutation. The map indicates the position of the Ph deletion, which encompasses not more than 400 kb around and including the Pdgfra gene. The map also places the distal breakpoint of the Rw inversion to a limited chromosomal segment between Kit and Pdgfra. In light of the structure of the Ph-W-Rw region, we interpret the previously published complementation analyses as indicating that the pigmentation defect in Rw/+ heterozygotes could be due to the disruption of Kit and/or Pdgfra regulatory sequences, whereas the gene(s) responsible for the recessive lethality of Rw/Rw embryos is not closely linked to the Ph and W loci and maps proximally to the W19H deletion. The structural analysis of chromosomal rearrangements associated with W19H, Ph, and Rw combined with the high-resolution physical mapping points the way toward the definition of these mutations in molecular terms and isolation of homologous genes on human chromosome 4. Images PMID:8041773

Efficient fuzzy Bayesian inference algorithms for incorporating expert knowledge in parameter estimation

NASA Astrophysics Data System (ADS)

Rajabi, Mohammad Mahdi; Ataie-Ashtiani, Behzad

2016-05-01

Bayesian inference has traditionally been conceived as the proper framework for the formal incorporation of expert knowledge in parameter estimation of groundwater models. However, conventional Bayesian inference is incapable of taking into account the imprecision essentially embedded in expert provided information. In order to solve this problem, a number of extensions to conventional Bayesian inference have been introduced in recent years. One of these extensions is 'fuzzy Bayesian inference' which is the result of integrating fuzzy techniques into Bayesian statistics. Fuzzy Bayesian inference has a number of desirable features which makes it an attractive approach for incorporating expert knowledge in the parameter estimation process of groundwater models: (1) it is well adapted to the nature of expert provided information, (2) it allows to distinguishably model both uncertainty and imprecision, and (3) it presents a framework for fusing expert provided information regarding the various inputs of the Bayesian inference algorithm. However an important obstacle in employing fuzzy Bayesian inference in groundwater numerical modeling applications is the computational burden, as the required number of numerical model simulations often becomes extremely exhaustive and often computationally infeasible. In this paper, a novel approach of accelerating the fuzzy Bayesian inference algorithm is proposed which is based on using approximate posterior distributions derived from surrogate modeling, as a screening tool in the computations. The proposed approach is first applied to a synthetic test case of seawater intrusion (SWI) in a coastal aquifer. It is shown that for this synthetic test case, the proposed approach decreases the number of required numerical simulations by an order of magnitude. Then the proposed approach is applied to a real-world test case involving three-dimensional numerical modeling of SWI in Kish Island, located in the Persian Gulf. An expert elicitation methodology is developed and applied to the real-world test case in order to provide a road map for the use of fuzzy Bayesian inference in groundwater modeling applications.

Sparse Bayesian Learning for Identifying Imaging Biomarkers in AD Prediction

PubMed Central

Shen, Li; Qi, Yuan; Kim, Sungeun; Nho, Kwangsik; Wan, Jing; Risacher, Shannon L.; Saykin, Andrew J.

2010-01-01

We apply sparse Bayesian learning methods, automatic relevance determination (ARD) and predictive ARD (PARD), to Alzheimer’s disease (AD) classification to make accurate prediction and identify critical imaging markers relevant to AD at the same time. ARD is one of the most successful Bayesian feature selection methods. PARD is a powerful Bayesian feature selection method, and provides sparse models that is easy to interpret. PARD selects the model with the best estimate of the predictive performance instead of choosing the one with the largest marginal model likelihood. Comparative study with support vector machine (SVM) shows that ARD/PARD in general outperform SVM in terms of prediction accuracy. Additional comparison with surface-based general linear model (GLM) analysis shows that regions with strongest signals are identified by both GLM and ARD/PARD. While GLM P-map returns significant regions all over the cortex, ARD/PARD provide a small number of relevant and meaningful imaging markers with predictive power, including both cortical and subcortical measures. PMID:20879451

A Bayesian nonparametric approach to dynamical noise reduction

NASA Astrophysics Data System (ADS)

Kaloudis, Konstantinos; Hatjispyros, Spyridon J.

2018-06-01

We propose a Bayesian nonparametric approach for the noise reduction of a given chaotic time series contaminated by dynamical noise, based on Markov Chain Monte Carlo methods. The underlying unknown noise process (possibly) exhibits heavy tailed behavior. We introduce the Dynamic Noise Reduction Replicator model with which we reconstruct the unknown dynamic equations and in parallel we replicate the dynamics under reduced noise level dynamical perturbations. The dynamic noise reduction procedure is demonstrated specifically in the case of polynomial maps. Simulations based on synthetic time series are presented.

Source Detection with Bayesian Inference on ROSAT All-Sky Survey Data Sample

NASA Astrophysics Data System (ADS)

Guglielmetti, F.; Voges, W.; Fischer, R.; Boese, G.; Dose, V.

2004-07-01

We employ Bayesian inference for the joint estimation of sources and background on ROSAT All-Sky Survey (RASS) data. The probabilistic method allows for detection improvement of faint extended celestial sources compared to the Standard Analysis Software System (SASS). Background maps were estimated in a single step together with the detection of sources without pixel censoring. Consistent uncertainties of background and sources are provided. The source probability is evaluated for single pixels as well as for pixel domains to enhance source detection of weak and extended sources.

A Bayesian network model for predicting pregnancy after in vitro fertilization.

PubMed

Corani, G; Magli, C; Giusti, A; Gianaroli, L; Gambardella, L M

2013-11-01

We present a Bayesian network model for predicting the outcome of in vitro fertilization (IVF). The problem is characterized by a particular missingness process; we propose a simple but effective averaging approach which improves parameter estimates compared to the traditional MAP estimation. We present results with generated data and the analysis of a real data set. Moreover, we assess by means of a simulation study the effectiveness of the model in supporting the selection of the embryos to be transferred. © 2013 Elsevier Ltd. All rights reserved.

Homozygosity Mapping in Patients with Cone–Rod Dystrophy: Novel Mutations and Clinical Characterizations

PubMed Central

Littink, Karin W.; Koenekoop, Robert K.; van den Born, L. Ingeborgh; Collin, Rob W. J.; Moruz, Luminita; Veltman, Joris A.; Roosing, Susanne; Zonneveld, Marijke N.; Omar, Amer; Darvish, Mahshad; Lopez, Irma; Kroes, Hester Y.; van Genderen, Maria M.; Hoyng, Carel B.; Rohrschneider, Klaus; van Schooneveld, Mary J.; Cremers, Frans P. M.

2010-01-01

Purpose. To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone–rod dystrophy (CRD) patients. Methods. One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination. Results. Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging. Conclusions. Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2. PMID:20554613

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.

PubMed

Lee, M H; Hazard, S; Carpten, J D; Yi, S; Cohen, J; Gerhardt, G T; Salen, G; Patel, S B

2001-02-01

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.

Mapping a Mutation in "Caenorhabditis elegans" Using a Polymerase Chain Reaction-Based Approach

ERIC Educational Resources Information Center

Myers, Edith M.

2014-01-01

Many single nucleotide polymorphisms (SNPs) have been identified within the "Caenorhabditis elegans" genome. SNPs present in the genomes of two isogenic "C. elegans" strains have been routinely used as a tool in forward genetics to map a mutation to a particular chromosome. This article describes a laboratory exercise in which…

Somatic activating mutations in MAP2K1 cause melorheostosis.

PubMed

Kang, Heeseog; Jha, Smita; Deng, Zuoming; Fratzl-Zelman, Nadja; Cabral, Wayne A; Ivovic, Aleksandra; Meylan, Françoise; Hanson, Eric P; Lange, Eileen; Katz, James; Roschger, Paul; Klaushofer, Klaus; Cowen, Edward W; Siegel, Richard M; Marini, Joan C; Bhattacharyya, Timothy

2018-04-11

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.

A single predator multiple prey model with prey mutation

NASA Astrophysics Data System (ADS)

Mullan, Rory; Abernethy, Gavin M.; Glass, David H.; McCartney, Mark

2016-11-01

A multiple species predator-prey model is expanded with the introduction of a coupled map lattice for the prey, allowing the prey to mutate discretely into other prey species. The model is examined in its single predator, multiple mutating prey form. Two unimodal maps are used for the underlying dynamics of the prey species, with different predation strategies being used. Conclusions are drawn on how varying the control parameters of the model governs the overall behaviour and survival of the species. It is observed that in such a complex system, with multiple mutating prey, a large range of non-linear dynamics is possible.

Development of a database system for mapping insertional mutations onto the mouse genome with large-scale experimental data

PubMed Central

2009-01-01

Background Insertional mutagenesis is an effective method for functional genomic studies in various organisms. It can rapidly generate easily tractable mutations. A large-scale insertional mutagenesis with the piggyBac (PB) transposon is currently performed in mice at the Institute of Developmental Biology and Molecular Medicine (IDM), Fudan University in Shanghai, China. This project is carried out via collaborations among multiple groups overseeing interconnected experimental steps and generates a large volume of experimental data continuously. Therefore, the project calls for an efficient database system for recording, management, statistical analysis, and information exchange. Results This paper presents a database application called MP-PBmice (insertional mutation mapping system of PB Mutagenesis Information Center), which is developed to serve the on-going large-scale PB insertional mutagenesis project. A lightweight enterprise-level development framework Struts-Spring-Hibernate is used here to ensure constructive and flexible support to the application. The MP-PBmice database system has three major features: strict access-control, efficient workflow control, and good expandability. It supports the collaboration among different groups that enter data and exchange information on daily basis, and is capable of providing real time progress reports for the whole project. MP-PBmice can be easily adapted for other large-scale insertional mutation mapping projects and the source code of this software is freely available at http://www.idmshanghai.cn/PBmice. Conclusion MP-PBmice is a web-based application for large-scale insertional mutation mapping onto the mouse genome, implemented with the widely used framework Struts-Spring-Hibernate. This system is already in use by the on-going genome-wide PB insertional mutation mapping project at IDM, Fudan University. PMID:19958505

Bayesian Scalar-on-Image Regression with Application to Association Between Intracranial DTI and Cognitive Outcomes

PubMed Central

Huang, Lei; Goldsmith, Jeff; Reiss, Philip T.; Reich, Daniel S.; Crainiceanu, Ciprian M.

2013-01-01

Diffusion tensor imaging (DTI) measures water diffusion within white matter, allowing for in vivo quantification of brain pathways. These pathways often subserve specific functions, and impairment of those functions is often associated with imaging abnormalities. As a method for predicting clinical disability from DTI images, we propose a hierarchical Bayesian “scalar-on-image” regression procedure. Our procedure introduces a latent binary map that estimates the locations of predictive voxels and penalizes the magnitude of effect sizes in these voxels, thereby resolving the ill-posed nature of the problem. By inducing a spatial prior structure, the procedure yields a sparse association map that also maintains spatial continuity of predictive regions. The method is demonstrated on a simulation study and on a study of association between fractional anisotropy and cognitive disability in a cross-sectional sample of 135 multiple sclerosis patients. PMID:23792220

Semi-blind Bayesian inference of CMB map and power spectrum

NASA Astrophysics Data System (ADS)

Vansyngel, Flavien; Wandelt, Benjamin D.; Cardoso, Jean-François; Benabed, Karim

2016-04-01

We present a new blind formulation of the cosmic microwave background (CMB) inference problem. The approach relies on a phenomenological model of the multifrequency microwave sky without the need for physical models of the individual components. For all-sky and high resolution data, it unifies parts of the analysis that had previously been treated separately such as component separation and power spectrum inference. We describe an efficient sampling scheme that fully explores the component separation uncertainties on the inferred CMB products such as maps and/or power spectra. External information about individual components can be incorporated as a prior giving a flexible way to progressively and continuously introduce physical component separation from a maximally blind approach. We connect our Bayesian formalism to existing approaches such as Commander, spectral mismatch independent component analysis (SMICA), and internal linear combination (ILC), and discuss possible future extensions.

Diagnosis support system based on clinical guidelines: comparison between case-based fuzzy cognitive maps and Bayesian networks.

PubMed

Douali, Nassim; Csaba, Huszka; De Roo, Jos; Papageorgiou, Elpiniki I; Jaulent, Marie-Christine

2014-01-01

Several studies have described the prevalence and severity of diagnostic errors. Diagnostic errors can arise from cognitive, training, educational and other issues. Examples of cognitive issues include flawed reasoning, incomplete knowledge, faulty information gathering or interpretation, and inappropriate use of decision-making heuristics. We describe a new approach, case-based fuzzy cognitive maps, for medical diagnosis and evaluate it by comparison with Bayesian belief networks. We created a semantic web framework that supports the two reasoning methods. We used database of 174 anonymous patients from several European hospitals: 80 of the patients were female and 94 male with an average age 45±16 (average±stdev). Thirty of the 80 female patients were pregnant. For each patient, signs/symptoms/observables/age/sex were taken into account by the system. We used a statistical approach to compare the two methods. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Tmax Determined Using a Bayesian Estimation Deconvolution Algorithm Applied to Bolus Tracking Perfusion Imaging: A Digital Phantom Validation Study.

PubMed

Uwano, Ikuko; Sasaki, Makoto; Kudo, Kohsuke; Boutelier, Timothé; Kameda, Hiroyuki; Mori, Futoshi; Yamashita, Fumio

2017-01-10

The Bayesian estimation algorithm improves the precision of bolus tracking perfusion imaging. However, this algorithm cannot directly calculate Tmax, the time scale widely used to identify ischemic penumbra, because Tmax is a non-physiological, artificial index that reflects the tracer arrival delay (TD) and other parameters. We calculated Tmax from the TD and mean transit time (MTT) obtained by the Bayesian algorithm and determined its accuracy in comparison with Tmax obtained by singular value decomposition (SVD) algorithms. The TD and MTT maps were generated by the Bayesian algorithm applied to digital phantoms with time-concentration curves that reflected a range of values for various perfusion metrics using a global arterial input function. Tmax was calculated from the TD and MTT using constants obtained by a linear least-squares fit to Tmax obtained from the two SVD algorithms that showed the best benchmarks in a previous study. Correlations between the Tmax values obtained by the Bayesian and SVD methods were examined. The Bayesian algorithm yielded accurate TD and MTT values relative to the true values of the digital phantom. Tmax calculated from the TD and MTT values with the least-squares fit constants showed excellent correlation (Pearson's correlation coefficient = 0.99) and agreement (intraclass correlation coefficient = 0.99) with Tmax obtained from SVD algorithms. Quantitative analyses of Tmax values calculated from Bayesian-estimation algorithm-derived TD and MTT from a digital phantom correlated and agreed well with Tmax values determined using SVD algorithms.

A hybrid expectation maximisation and MCMC sampling algorithm to implement Bayesian mixture model based genomic prediction and QTL mapping.

PubMed

Wang, Tingting; Chen, Yi-Ping Phoebe; Bowman, Phil J; Goddard, Michael E; Hayes, Ben J

2016-09-21

Bayesian mixture models in which the effects of SNP are assumed to come from normal distributions with different variances are attractive for simultaneous genomic prediction and QTL mapping. These models are usually implemented with Monte Carlo Markov Chain (MCMC) sampling, which requires long compute times with large genomic data sets. Here, we present an efficient approach (termed HyB_BR), which is a hybrid of an Expectation-Maximisation algorithm, followed by a limited number of MCMC without the requirement for burn-in. To test prediction accuracy from HyB_BR, dairy cattle and human disease trait data were used. In the dairy cattle data, there were four quantitative traits (milk volume, protein kg, fat% in milk and fertility) measured in 16,214 cattle from two breeds genotyped for 632,002 SNPs. Validation of genomic predictions was in a subset of cattle either from the reference set or in animals from a third breeds that were not in the reference set. In all cases, HyB_BR gave almost identical accuracies to Bayesian mixture models implemented with full MCMC, however computational time was reduced by up to 1/17 of that required by full MCMC. The SNPs with high posterior probability of a non-zero effect were also very similar between full MCMC and HyB_BR, with several known genes affecting milk production in this category, as well as some novel genes. HyB_BR was also applied to seven human diseases with 4890 individuals genotyped for around 300 K SNPs in a case/control design, from the Welcome Trust Case Control Consortium (WTCCC). In this data set, the results demonstrated again that HyB_BR performed as well as Bayesian mixture models with full MCMC for genomic predictions and genetic architecture inference while reducing the computational time from 45 h with full MCMC to 3 h with HyB_BR. The results for quantitative traits in cattle and disease in humans demonstrate that HyB_BR can perform equally well as Bayesian mixture models implemented with full MCMC in terms of prediction accuracy, but with up to 17 times faster than the full MCMC implementations. The HyB_BR algorithm makes simultaneous genomic prediction, QTL mapping and inference of genetic architecture feasible in large genomic data sets.

Automated Bayesian model development for frequency detection in biological time series.

PubMed

Granqvist, Emma; Oldroyd, Giles E D; Morris, Richard J

2011-06-24

A first step in building a mathematical model of a biological system is often the analysis of the temporal behaviour of key quantities. Mathematical relationships between the time and frequency domain, such as Fourier Transforms and wavelets, are commonly used to extract information about the underlying signal from a given time series. This one-to-one mapping from time points to frequencies inherently assumes that both domains contain the complete knowledge of the system. However, for truncated, noisy time series with background trends this unique mapping breaks down and the question reduces to an inference problem of identifying the most probable frequencies. In this paper we build on the method of Bayesian Spectrum Analysis and demonstrate its advantages over conventional methods by applying it to a number of test cases, including two types of biological time series. Firstly, oscillations of calcium in plant root cells in response to microbial symbionts are non-stationary and noisy, posing challenges to data analysis. Secondly, circadian rhythms in gene expression measured over only two cycles highlights the problem of time series with limited length. The results show that the Bayesian frequency detection approach can provide useful results in specific areas where Fourier analysis can be uninformative or misleading. We demonstrate further benefits of the Bayesian approach for time series analysis, such as direct comparison of different hypotheses, inherent estimation of noise levels and parameter precision, and a flexible framework for modelling the data without pre-processing. Modelling in systems biology often builds on the study of time-dependent phenomena. Fourier Transforms are a convenient tool for analysing the frequency domain of time series. However, there are well-known limitations of this method, such as the introduction of spurious frequencies when handling short and noisy time series, and the requirement for uniformly sampled data. Biological time series often deviate significantly from the requirements of optimality for Fourier transformation. In this paper we present an alternative approach based on Bayesian inference. We show the value of placing spectral analysis in the framework of Bayesian inference and demonstrate how model comparison can automate this procedure.

Automated Bayesian model development for frequency detection in biological time series

PubMed Central

2011-01-01

Background A first step in building a mathematical model of a biological system is often the analysis of the temporal behaviour of key quantities. Mathematical relationships between the time and frequency domain, such as Fourier Transforms and wavelets, are commonly used to extract information about the underlying signal from a given time series. This one-to-one mapping from time points to frequencies inherently assumes that both domains contain the complete knowledge of the system. However, for truncated, noisy time series with background trends this unique mapping breaks down and the question reduces to an inference problem of identifying the most probable frequencies. Results In this paper we build on the method of Bayesian Spectrum Analysis and demonstrate its advantages over conventional methods by applying it to a number of test cases, including two types of biological time series. Firstly, oscillations of calcium in plant root cells in response to microbial symbionts are non-stationary and noisy, posing challenges to data analysis. Secondly, circadian rhythms in gene expression measured over only two cycles highlights the problem of time series with limited length. The results show that the Bayesian frequency detection approach can provide useful results in specific areas where Fourier analysis can be uninformative or misleading. We demonstrate further benefits of the Bayesian approach for time series analysis, such as direct comparison of different hypotheses, inherent estimation of noise levels and parameter precision, and a flexible framework for modelling the data without pre-processing. Conclusions Modelling in systems biology often builds on the study of time-dependent phenomena. Fourier Transforms are a convenient tool for analysing the frequency domain of time series. However, there are well-known limitations of this method, such as the introduction of spurious frequencies when handling short and noisy time series, and the requirement for uniformly sampled data. Biological time series often deviate significantly from the requirements of optimality for Fourier transformation. In this paper we present an alternative approach based on Bayesian inference. We show the value of placing spectral analysis in the framework of Bayesian inference and demonstrate how model comparison can automate this procedure. PMID:21702910

Clinical high-resolution mapping of the proteoglycan-bound water fraction in articular cartilage of the human knee joint.

PubMed

Bouhrara, Mustapha; Reiter, David A; Sexton, Kyle W; Bergeron, Christopher M; Zukley, Linda M; Spencer, Richard G

2017-11-01

We applied our recently introduced Bayesian analytic method to achieve clinically-feasible in-vivo mapping of the proteoglycan water fraction (PgWF) of human knee cartilage with improved spatial resolution and stability as compared to existing methods. Multicomponent driven equilibrium single-pulse observation of T 1 and T 2 (mcDESPOT) datasets were acquired from the knees of two healthy young subjects and one older subject with previous knee injury. Each dataset was processed using Bayesian Monte Carlo (BMC) analysis incorporating a two-component tissue model. We assessed the performance and reproducibility of BMC and of the conventional analysis of stochastic region contraction (SRC) in the estimation of PgWF. Stability of the BMC analysis of PgWF was tested by comparing independent high-resolution (HR) datasets from each of the two young subjects. Unlike SRC, the BMC-derived maps from the two HR datasets were essentially identical. Furthermore, SRC maps showed substantial random variation in estimated PgWF, and mean values that differed from those obtained using BMC. In addition, PgWF maps derived from conventional low-resolution (LR) datasets exhibited partial volume and magnetic susceptibility effects. These artifacts were absent in HR PgWF images. Finally, our analysis showed regional variation in PgWF estimates, and substantially higher values in the younger subjects as compared to the older subject. BMC-mcDESPOT permits HR in-vivo mapping of PgWF in human knee cartilage in a clinically-feasible acquisition time. HR mapping reduces the impact of partial volume and magnetic susceptibility artifacts compared to LR mapping. Finally, BMC-mcDESPOT demonstrated excellent reproducibility in the determination of PgWF. Published by Elsevier Inc.

Experiments in Error Propagation within Hierarchal Combat Models

DTIC Science & Technology

2015-09-01

Bayesian Information Criterion CNO Chief of Naval Operations DOE Design of Experiments DOD Department of Defense MANA Map Aware Non-uniform Automata ...ground up” approach. First, it develops a mission-level model for one on one submarine combat in Map Aware Non-uniform Automata (MANA) simulation, an... Automata (MANA), an agent based simulation that can model the different postures of submarines. It feeds the results from MANA into stochastic

Spatiotemporal analysis and mapping of oral cancer risk in changhua county (taiwan): an application of generalized bayesian maximum entropy method.

PubMed

Yu, Hwa-Lung; Chiang, Chi-Ting; Lin, Shu-De; Chang, Tsun-Kuo

2010-02-01

Incidence rate of oral cancer in Changhua County is the highest among the 23 counties of Taiwan during 2001. However, in health data analysis, crude or adjusted incidence rates of a rare event (e.g., cancer) for small populations often exhibit high variances and are, thus, less reliable. We proposed a generalized Bayesian Maximum Entropy (GBME) analysis of spatiotemporal disease mapping under conditions of considerable data uncertainty. GBME was used to study the oral cancer population incidence in Changhua County (Taiwan). Methodologically, GBME is based on an epistematics principles framework and generates spatiotemporal estimates of oral cancer incidence rates. In a way, it accounts for the multi-sourced uncertainty of rates, including small population effects, and the composite space-time dependence of rare events in terms of an extended Poisson-based semivariogram. The results showed that GBME analysis alleviates the noises of oral cancer data from population size effect. Comparing to the raw incidence data, the maps of GBME-estimated results can identify high risk oral cancer regions in Changhua County, where the prevalence of betel quid chewing and cigarette smoking is relatively higher than the rest of the areas. GBME method is a valuable tool for spatiotemporal disease mapping under conditions of uncertainty. 2010 Elsevier Inc. All rights reserved.

Bayesian Maximum Entropy space/time estimation of surface water chloride in Maryland using river distances.

PubMed

Jat, Prahlad; Serre, Marc L

2016-12-01

Widespread contamination of surface water chloride is an emerging environmental concern. Consequently accurate and cost-effective methods are needed to estimate chloride along all river miles of potentially contaminated watersheds. Here we introduce a Bayesian Maximum Entropy (BME) space/time geostatistical estimation framework that uses river distances, and we compare it with Euclidean BME to estimate surface water chloride from 2005 to 2014 in the Gunpowder-Patapsco, Severn, and Patuxent subbasins in Maryland. River BME improves the cross-validation R 2 by 23.67% over Euclidean BME, and river BME maps are significantly different than Euclidean BME maps, indicating that it is important to use river BME maps to assess water quality impairment. The river BME maps of chloride concentration show wide contamination throughout Baltimore and Columbia-Ellicott cities, the disappearance of a clean buffer separating these two large urban areas, and the emergence of multiple localized pockets of contamination in surrounding areas. The number of impaired river miles increased by 0.55% per year in 2005-2009 and by 1.23% per year in 2011-2014, corresponding to a marked acceleration of the rate of impairment. Our results support the need for control measures and increased monitoring of unassessed river miles. Copyright © 2016. Published by Elsevier Ltd.

Evaluating Spatial Variability in Sediment and Phosphorus Concentration-Discharge Relationships Using Bayesian Inference and Self-Organizing Maps

NASA Astrophysics Data System (ADS)

Underwood, Kristen L.; Rizzo, Donna M.; Schroth, Andrew W.; Dewoolkar, Mandar M.

2017-12-01

Given the variable biogeochemical, physical, and hydrological processes driving fluvial sediment and nutrient export, the water science and management communities need data-driven methods to identify regions prone to production and transport under variable hydrometeorological conditions. We use Bayesian analysis to segment concentration-discharge linear regression models for total suspended solids (TSS) and particulate and dissolved phosphorus (PP, DP) using 22 years of monitoring data from 18 Lake Champlain watersheds. Bayesian inference was leveraged to estimate segmented regression model parameters and identify threshold position. The identified threshold positions demonstrated a considerable range below and above the median discharge—which has been used previously as the default breakpoint in segmented regression models to discern differences between pre and post-threshold export regimes. We then applied a Self-Organizing Map (SOM), which partitioned the watersheds into clusters of TSS, PP, and DP export regimes using watershed characteristics, as well as Bayesian regression intercepts and slopes. A SOM defined two clusters of high-flux basins, one where PP flux was predominantly episodic and hydrologically driven; and another in which the sediment and nutrient sourcing and mobilization were more bimodal, resulting from both hydrologic processes at post-threshold discharges and reactive processes (e.g., nutrient cycling or lateral/vertical exchanges of fine sediment) at prethreshold discharges. A separate DP SOM defined two high-flux clusters exhibiting a bimodal concentration-discharge response, but driven by differing land use. Our novel framework shows promise as a tool with broad management application that provides insights into landscape drivers of riverine solute and sediment export.

BAYESIAN SEMI-BLIND COMPONENT SEPARATION FOR FOREGROUND REMOVAL IN INTERFEROMETRIC 21 cm OBSERVATIONS

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

Zhang, Le; Timbie, Peter T.; Bunn, Emory F.

In this paper, we present a new Bayesian semi-blind approach for foreground removal in observations of the 21 cm signal measured by interferometers. The technique, which we call H i Expectation–Maximization Independent Component Analysis (HIEMICA), is an extension of the Independent Component Analysis technique developed for two-dimensional (2D) cosmic microwave background maps to three-dimensional (3D) 21 cm cosmological signals measured by interferometers. This technique provides a fully Bayesian inference of power spectra and maps and separates the foregrounds from the signal based on the diversity of their power spectra. Relying only on the statistical independence of the components, this approachmore » can jointly estimate the 3D power spectrum of the 21 cm signal, as well as the 2D angular power spectrum and the frequency dependence of each foreground component, without any prior assumptions about the foregrounds. This approach has been tested extensively by applying it to mock data from interferometric 21 cm intensity mapping observations under idealized assumptions of instrumental effects. We also discuss the impact when the noise properties are not known completely. As a first step toward solving the 21 cm power spectrum analysis problem, we compare the semi-blind HIEMICA technique to the commonly used Principal Component Analysis. Under the same idealized circumstances, the proposed technique provides significantly improved recovery of the power spectrum. This technique can be applied in a straightforward manner to all 21 cm interferometric observations, including epoch of reionization measurements, and can be extended to single-dish observations as well.« less

PyClone: statistical inference of clonal population structure in cancer.

PubMed

Roth, Andrew; Khattra, Jaswinder; Yap, Damian; Wan, Adrian; Laks, Emma; Biele, Justina; Ha, Gavin; Aparicio, Samuel; Bouchard-Côté, Alexandre; Shah, Sohrab P

2014-04-01

We introduce PyClone, a statistical model for inference of clonal population structures in cancers. PyClone is a Bayesian clustering method for grouping sets of deeply sequenced somatic mutations into putative clonal clusters while estimating their cellular prevalences and accounting for allelic imbalances introduced by segmental copy-number changes and normal-cell contamination. Single-cell sequencing validation demonstrates PyClone's accuracy.

RATES OF FITNESS DECLINE AND REBOUND SUGGEST PERVASIVE EPISTASIS

PubMed Central

Perfeito, L; Sousa, A; Bataillon, T; Gordo, I

2014-01-01

Unraveling the factors that determine the rate of adaptation is a major question in evolutionary biology. One key parameter is the effect of a new mutation on fitness, which invariably depends on the environment and genetic background. The fate of a mutation also depends on population size, which determines the amount of drift it will experience. Here, we manipulate both population size and genotype composition and follow adaptation of 23 distinct Escherichia coli genotypes. These have previously accumulated mutations under intense genetic drift and encompass a substantial fitness variation. A simple rule is uncovered: the net fitness change is negatively correlated with the fitness of the genotype in which new mutations appear—a signature of epistasis. We find that Fisher's geometrical model can account for the observed patterns of fitness change and infer the parameters of this model that best fit the data, using Approximate Bayesian Computation. We estimate a genomic mutation rate of 0.01 per generation for fitness altering mutations, albeit with a large confidence interval, a mean fitness effect of mutations of −0.01, and an effective number of traits nine in mutS− E. coli. This framework can be extended to confront a broader range of models with data and test different classes of fitness landscape models. PMID:24372601

Fine structure of OXI1, the mitochondrial gene coding for subunit II of yeast cytochrome c oxidase.

PubMed

Weiss-Brummer, B; Guba, R; Haid, A; Schweyen, R J

1979-12-01

Genetic and biochemical studies have been performed with 110 mutants which are defective in cytochrome a·a3 and map in the regions on mit DNA previously designated OXI1 and OXI2. With 88 mutations allocated to OXI1 fine structure mapping was achieved by the analysis of rho (-) deletions. The order of six groups of mutational sites (A 1, A2, B 1, B2, C 1, C2) thus determined was confirmed by oxi i x oxi j recombination analysis.Analysis of mitochondrially translated polypeptides of oxil mutants by SDS-polyacrylamide electrophoresis reveals three classes of mutant patterns: i) similar to wild-tpye (19 mutants); ii) lacking SU II of cytochrome c oxidase (53 mutants); iii) lacking this subunit and exhibiting a single new polypeptide of lower Mr (16 mutants). Mutations of each of these classes are scattered over the OXI1 region without any detectable clustering; this is consistent with the assumption that all oxil mutations studied are within the same gene.New polypeptides observed in oxil mutants of class iii) vary in Mr in the range from 10,500 to 33,000. Those of Mr 17,000 to 33,000 are shown to be antigenically related to subunit II of cytochrome c oxidase. Colinearity is established between the series of new polypeptides of Mr values increasing from 10,500 to 31,500 and the order of the respective mutational sites on the map, e.g. mutations mapping in A 1 generate the smallest and mutations mapping in C2 the largest mutant fragments.From these data we conclude that i) all mutations allocated to the OXI1 region are in the same gene; ii) this gene codes for subunit II of cytochrome c oxidase; iii) the direction of translation is from CAP to 0X12. Out of 19 mutants allocated to OXI2 three exhibit a new polypeptide; these and all the other oxi2 mutants lack subunit III of cytochrome oxidase. This result provides preliminary evidence that the OXI2 region harbours the structural gene for this subunit III.

The mutY gene: a mutator locus in Escherichia coli that generates G.C----T.A transversions.

PubMed Central

Nghiem, Y; Cabrera, M; Cupples, C G; Miller, J H

1988-01-01

We have used a strain with an altered lacZ gene, which reverts to wild type via only certain transversions, to detect transversion-specific mutators in Escherichia coli. Detection relied on a papillation technique that uses a combination of beta-galactosides to reveal blue Lac+ papillae. One class of mutators is specific for the G.C----T.A transversion as determined by the reversion pattern of a set of lacZ mutations and by the distribution of forward nonsense mutations in the lacI gene. The locus responsible for the mutator phenotype is designated mutY and maps near 64 min on the genetic map of E. coli. The mutY locus may act in a similar but reciprocal fashion to the previously characterized mutT locus, which results in A.T----C.G transversions. Images PMID:3128795

a Novel Discrete Optimal Transport Method for Bayesian Inverse Problems

NASA Astrophysics Data System (ADS)

Bui-Thanh, T.; Myers, A.; Wang, K.; Thiery, A.

2017-12-01

We present the Augmented Ensemble Transform (AET) method for generating approximate samples from a high-dimensional posterior distribution as a solution to Bayesian inverse problems. Solving large-scale inverse problems is critical for some of the most relevant and impactful scientific endeavors of our time. Therefore, constructing novel methods for solving the Bayesian inverse problem in more computationally efficient ways can have a profound impact on the science community. This research derives the novel AET method for exploring a posterior by solving a sequence of linear programming problems, resulting in a series of transport maps which map prior samples to posterior samples, allowing for the computation of moments of the posterior. We show both theoretical and numerical results, indicating this method can offer superior computational efficiency when compared to other SMC methods. Most of this efficiency is derived from matrix scaling methods to solve the linear programming problem and derivative-free optimization for particle movement. We use this method to determine inter-well connectivity in a reservoir and the associated uncertainty related to certain parameters. The attached file shows the difference between the true parameter and the AET parameter in an example 3D reservoir problem. The error is within the Morozov discrepancy allowance with lower computational cost than other particle methods.

Profile-Based LC-MS Data Alignment—A Bayesian Approach

PubMed Central

Tsai, Tsung-Heng; Tadesse, Mahlet G.; Wang, Yue; Ressom, Habtom W.

2014-01-01

A Bayesian alignment model (BAM) is proposed for alignment of liquid chromatography-mass spectrometry (LC-MS) data. BAM belongs to the category of profile-based approaches, which are composed of two major components: a prototype function and a set of mapping functions. Appropriate estimation of these functions is crucial for good alignment results. BAM uses Markov chain Monte Carlo (MCMC) methods to draw inference on the model parameters and improves on existing MCMC-based alignment methods through 1) the implementation of an efficient MCMC sampler and 2) an adaptive selection of knots. A block Metropolis-Hastings algorithm that mitigates the problem of the MCMC sampler getting stuck at local modes of the posterior distribution is used for the update of the mapping function coefficients. In addition, a stochastic search variable selection (SSVS) methodology is used to determine the number and positions of knots. We applied BAM to a simulated data set, an LC-MS proteomic data set, and two LC-MS metabolomic data sets, and compared its performance with the Bayesian hierarchical curve registration (BHCR) model, the dynamic time-warping (DTW) model, and the continuous profile model (CPM). The advantage of applying appropriate profile-based retention time correction prior to performing a feature-based approach is also demonstrated through the metabolomic data sets. PMID:23929872

Exploring the Specifications of Spatial Adjacencies and Weights in Bayesian Spatial Modeling with Intrinsic Conditional Autoregressive Priors in a Small-area Study of Fall Injuries

PubMed Central

Law, Jane

2016-01-01

Intrinsic conditional autoregressive modeling in a Bayeisan hierarchical framework has been increasingly applied in small-area ecological studies. This study explores the specifications of spatial structure in this Bayesian framework in two aspects: adjacency, i.e., the set of neighbor(s) for each area; and (spatial) weight for each pair of neighbors. Our analysis was based on a small-area study of falling injuries among people age 65 and older in Ontario, Canada, that was aimed to estimate risks and identify risk factors of such falls. In the case study, we observed incorrect adjacencies information caused by deficiencies in the digital map itself. Further, when equal weights was replaced by weights based on a variable of expected count, the range of estimated risks increased, the number of areas with probability of estimated risk greater than one at different probability thresholds increased, and model fit improved. More importantly, significance of a risk factor diminished. Further research to thoroughly investigate different methods of variable weights; quantify the influence of specifications of spatial weights; and develop strategies for better defining spatial structure of a map in small-area analysis in Bayesian hierarchical spatial modeling is recommended. PMID:29546147

[Bayesian geostatistical prediction of soil organic carbon contents of solonchak soils in nor-thern Tarim Basin, Xinjiang, China.

PubMed

Wu, Wei Mo; Wang, Jia Qiang; Cao, Qi; Wu, Jia Ping

2017-02-01

Accurate prediction of soil organic carbon (SOC) distribution is crucial for soil resources utilization and conservation, climate change adaptation, and ecosystem health. In this study, we selected a 1300 m×1700 m solonchak sampling area in northern Tarim Basin, Xinjiang, China, and collected a total of 144 soil samples (5-10 cm). The objectives of this study were to build a Baye-sian geostatistical model to predict SOC content, and to assess the performance of the Bayesian model for the prediction of SOC content by comparing with other three geostatistical approaches [ordinary kriging (OK), sequential Gaussian simulation (SGS), and inverse distance weighting (IDW)]. In the study area, soil organic carbon contents ranged from 1.59 to 9.30 g·kg -1 with a mean of 4.36 g·kg -1 and a standard deviation of 1.62 g·kg -1 . Sample semivariogram was best fitted by an exponential model with the ratio of nugget to sill being 0.57. By using the Bayesian geostatistical approach, we generated the SOC content map, and obtained the prediction variance, upper 95% and lower 95% of SOC contents, which were then used to evaluate the prediction uncertainty. Bayesian geostatistical approach performed better than that of the OK, SGS and IDW, demonstrating the advantages of Bayesian approach in SOC prediction.

Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations

PubMed Central

Marzouka, Nour al Dain; Hebrard, Maxime; Manes, Gaël; Sénéchal, Audrey; Meunier, Isabelle; Hamel, Christian P.

2013-01-01

Purpose Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. Methods arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. Results We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. Conclusions Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families. PMID:24339724

GNAq mutations are not identified in papillary thyroid carcinomas and hyperfunctioning thyroid nodules.

PubMed

Cassol, Clarissa A; Guo, Miao; Ezzat, Shereen; Asa, Sylvia L

2010-12-01

Activating mutations of GNAq protein in a hotspot at codon 209 have been recently described in uveal melanomas. Since these neoplasms share with thyroid carcinomas a high frequency of MAP kinase pathway-activating mutations, we hypothesized whether GNAq mutations could also play a role in the development of thyroid carcinomas. Additionally, activating mutations of another subtype of G protein (GNAS1) are frequently found in hyperfunctioning thyroid adenomas, making it plausible that GNAq-activating mutations could also be found in some of these nodules. To investigate thyroid papillary carcinomas and thyroid hyperfunctioning nodules for GNAq mutations in exon 5, codon 209, a total of 32 RET/PTC, BRAF, and RAS negative thyroid papillary carcinomas and 13 hyperfunctioning thyroid nodules were evaluated. No mutations were identified. Although plausible, GNAq mutations seem not to play an important role in the development of thyroid follicular neoplasms, either benign hyperfunctioning nodules or malignant papillary carcinomas. Our results are in accordance with the literature, in which no GNAq hotspot mutations were found in thyroid papillary carcinomas, as well as in an extensive panel of other tumors. The molecular basis for MAP-kinase pathway activation in RET-PTC/BRAF/RAS negative thyroid carcinomas remains to be determined.

The role of MAP4K3 in lifespan regulation of Caenorhabditiselegans

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

Khan, Maruf H.; Hart, Matthew J., E-mail: HartMJ@uthscsa.edu; Rea, Shane L., E-mail: reas3@uthscsa.edu

2012-08-24

Highlights: Black-Right-Pointing-Pointer Inhibition of MAP4K3 by RNAi leads to increased mean lifespan in Caenorhabditis elegans. Black-Right-Pointing-Pointer Mutation in the citron homology domain of MAP4K3 leads to increased mean lifespan. Black-Right-Pointing-Pointer Mutation in the kinase domain of MAP4K3 has no significant effect on mean lifespan. -- Abstract: The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation - when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that hasmore » recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditiselegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan.« less

Lunar Terrain and Albedo Reconstruction from Apollo Imagery

NASA Technical Reports Server (NTRS)

Nefian, Ara V.; Kim, Taemin; Broxton, Michael; Moratto, Zach

2010-01-01

Generating accurate three dimensional planetary models and albedo maps is becoming increasingly more important as NASA plans more robotics missions to the Moon in the coming years. This paper describes a novel approach for separation of topography and albedo maps from orbital Lunar images. Our method uses an optimal Bayesian correlator to refine the stereo disparity map and generate a set of accurate digital elevation models (DEM). The albedo maps are obtained using a multi-image formation model that relies on the derived DEMs and the Lunar- Lambert reflectance model. The method is demonstrated on a set of high resolution scanned images from the Apollo era missions.

A novel candidate gene for mouse and human preaxial polydactyly with altered expression in limbs of Hemimelic extra-toes mutant mice.

PubMed

Clark, R M; Marker, P C; Kingsley, D M

2000-07-01

Polydactyly is a common malformation of vertebrate limbs. In humans a major locus for nonsyndromic pre-axial polydactyly (PPD) has been mapped previously to 7q36. The mouse Hemimelic extra-toes (Hx) mutation maps to a homologous chromosome segment and has been proposed to affect a homologous gene. To understand the molecular changes underlying PPD, we used a positional cloning approach to identify the gene or genes disrupted by the Hx mutation and a closely linked limb mutation, Hammertoe (Hm). High resolution genetic mapping identified a small candidate interval for the mouse mutations located 1.2 cM distal to the Shh locus. The nonrecombinant interval was completely cloned in bacterial artificial chromosomes and searched for genes using a combination of exon trapping, sample sequencing, and mapping of known genes. Two novel genes, Lmbr1 and Lmbr2, are entirely within the candidate interval we defined genetically. The open reading frame of both genes is intact in mutant mice, but the expression of the Lmbr1 gene is dramatically altered in developing limbs of Hx mutant mice. The correspondence between the spatial and temporal changes in Lmbr1 expression and the embryonic onset of the Hx mutant phenotype suggests that the mouse Hx mutation may be a regulatory allele of Lmbr1. The human ortholog of Lmbr1 maps within the recently described interval for human PPD, strengthening the possibility that both mouse and human limb abnormalities are due to defects in the same highly conserved gene.

New mutations in BBS genes in small consanguineous families with Bardet-Biedl syndrome: Detection of candidate regions by homozygosity mapping

PubMed Central

Pereiro, Ines; Piñeiro-Gallego, Teresa; Baiget, Montserrat; Borrego, Salud; Ayuso, Carmen; Searby, Charles; Nishimura, Darryl

2010-01-01

Purpose Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare multi-organ disorder in which BBS patients manifest a variable phenotype that includes retinal dystrophy, polydactyly, mental delay, obesity, and also reproductive tract and renal abnormalities. Mutations in 14 genes (BBS1–BBS14) are found in 70% of the patients, indicating that additional mutations in known and new BBS genes remain to be identified. Therefore, the molecular diagnosis of this complex disorder is a challenging task. Methods In this study we show the use of the genome-wide homozygosity mapping strategy in the mutation detection of nine Caucasian BBS families, eight of them consanguineous and one from the same geographic area with no proven consanguinity. Results We identified the disease-causing mutation in six of the families studied, five of which had novel sequence variants in BBS3, BBS6, and BBS12. This is the first null mutation reported in BBS3. Furthermore, this approach defined homozygous candidate regions that could harbor potential candidate genes for BBS in three of the families. Conclusions These findings further underline the importance of homozygosity mapping as a useful technology for diagnosis in small consanguineous families with a complex disease like BBS. PMID:20142850

Long term economic relationships from cointegration maps

NASA Astrophysics Data System (ADS)

Vicente, Renato; Pereira, Carlos de B.; Leite, Vitor B. P.; Caticha, Nestor

2007-07-01

We employ the Bayesian framework to define a cointegration measure aimed to represent long term relationships between time series. For visualization of these relationships we introduce a dissimilarity matrix and a map based on the sorting points into neighborhoods (SPIN) technique, which has been previously used to analyze large data sets from DNA arrays. We exemplify the technique in three data sets: US interest rates (USIR), monthly inflation rates and gross domestic product (GDP) growth rates.

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15.

PubMed

Doucette, Lance; Merner, Nancy D; Cooke, Sandra; Ives, Elizabeth; Galutira, Dante; Walsh, Vanessa; Walsh, Tom; MacLaren, Linda; Cater, Tracey; Fernandez, Bridget; Green, Jane S; Wilcox, Edward R; Shotland, Lawrence I; Shotland, Larry; Li, Xiaoyan Cindy; Li, X C; Lee, Ming; King, Mary-Claire; Young, Terry-Lynn

2009-05-01

We studied a consanguineous family (Family A) from the island of Newfoundland with an autosomal recessive form of prelingual, profound, nonsyndromic sensorineural hearing loss. A genome-wide scan mapped the deafness trait to 10q21-22 (max LOD score of 4.0; D10S196) and fine mapping revealed a 16 Mb ancestral haplotype in deaf relatives. The PCDH15 gene was mapped within the critical region and was an interesting candidate because truncating mutations cause Usher syndrome type IF (USH1F) and two missense mutations have been previously associated with isolated deafness (DFNB23). Sequencing of the PCDH15 gene revealed 33 sequencing variants. Three of these variants were homozygous exclusively in deaf siblings but only one of them was not seen in ethnically matched controls. This novel c.1583 T>A transversion predicts an amino-acid substitution of a valine with an aspartic acid at codon 528 (V528D). Like the two DFNB23 mutations, the V528D mutation in Family A occurs in a highly conserved extracellular cadherin (EC) domain of PCDH15 and is predicted to be more deleterious than the previously identified DFNB23 missense mutations (R134G and G262D). Physical assessment, vestibular and visual function testing in deaf adults ruled out syndromic deafness because of Usher syndrome. This study validates the DFNB23 designation and supports the hypothesis that missense mutations in conserved motifs of PCDH15 cause nonsyndromic hearing loss. This emerging genotype-phenotype correlation in USH1F is similar to that in several other USH1 genes and cautions against a prognosis of a dual sensory loss in deaf children found to be homozygous for hypomorphic mutations at the USH1F locus.

Co-endemicity of Pulmonary Tuberculosis and Intestinal Helminth Infection in the People’s Republic of China

PubMed Central

Li, Xin-Xu; Ren, Zhou-Peng; Wang, Li-Xia; Zhang, Hui; Jiang, Shi-Wen; Chen, Jia-Xu; Wang, Jin-Feng; Zhou, Xiao-Nong

2016-01-01

Both pulmonary tuberculosis (PTB) and intestinal helminth infection (IHI) affect millions of individuals every year in China. However, the national-scale estimation of prevalence predictors and prevalence maps for these diseases, as well as co-endemic relative risk (RR) maps of both diseases’ prevalence are not well developed. There are co-endemic, high prevalence areas of both diseases, whose delimitation is essential for devising effective control strategies. Bayesian geostatistical logistic regression models including socio-economic, climatic, geographical and environmental predictors were fitted separately for active PTB and IHI based on data from the national surveys for PTB and major human parasitic diseases that were completed in 2010 and 2004, respectively. Prevalence maps and co-endemic RR maps were constructed for both diseases by means of Bayesian Kriging model and Bayesian shared component model capable of appraising the fraction of variance of spatial RRs shared by both diseases, and those specific for each one, under an assumption that there are unobserved covariates common to both diseases. Our results indicate that gross domestic product (GDP) per capita had a negative association, while rural regions, the arid and polar zones and elevation had positive association with active PTB prevalence; for the IHI prevalence, GDP per capita and distance to water bodies had a negative association, the equatorial and warm zones and the normalized difference vegetation index had a positive association. Moderate to high prevalence of active PTB and low prevalence of IHI were predicted in western regions, low to moderate prevalence of active PTB and low prevalence of IHI were predicted in north-central regions and the southeast coastal regions, and moderate to high prevalence of active PTB and high prevalence of IHI were predicted in the south-western regions. Thus, co-endemic areas of active PTB and IHI were located in the south-western regions of China, which might be determined by socio-economic factors, such as GDP per capita. PMID:27088504

Next-Generation Sequencing-Based Approaches for Mutation Mapping and Identification in Caenorhabditis elegans

PubMed Central

Doitsidou, Maria; Jarriault, Sophie; Poole, Richard J.

2016-01-01

The use of next-generation sequencing (NGS) has revolutionized the way phenotypic traits are assigned to genes. In this review, we describe NGS-based methods for mapping a mutation and identifying its molecular identity, with an emphasis on applications in Caenorhabditis elegans. In addition to an overview of the general principles and concepts, we discuss the main methods, provide practical and conceptual pointers, and guide the reader in the types of bioinformatics analyses that are required. Owing to the speed and the plummeting costs of NGS-based methods, mapping and cloning a mutation of interest has become straightforward, quick, and relatively easy. Removing this bottleneck previously associated with forward genetic screens has significantly advanced the use of genetics to probe fundamental biological processes in an unbiased manner. PMID:27729495

Spatial analysis and risk mapping of soil-transmitted helminth infections in Brazil, using Bayesian geostatistical models.

PubMed

Scholte, Ronaldo G C; Schur, Nadine; Bavia, Maria E; Carvalho, Edgar M; Chammartin, Frédérique; Utzinger, Jürg; Vounatsou, Penelope

2013-11-01

Soil-transmitted helminths (Ascaris lumbricoides, Trichuris trichiura and hookworm) negatively impact the health and wellbeing of hundreds of millions of people, particularly in tropical and subtropical countries, including Brazil. Reliable maps of the spatial distribution and estimates of the number of infected people are required for the control and eventual elimination of soil-transmitted helminthiasis. We used advanced Bayesian geostatistical modelling, coupled with geographical information systems and remote sensing to visualize the distribution of the three soil-transmitted helminth species in Brazil. Remotely sensed climatic and environmental data, along with socioeconomic variables from readily available databases were employed as predictors. Our models provided mean prevalence estimates for A. lumbricoides, T. trichiura and hookworm of 15.6%, 10.1% and 2.5%, respectively. By considering infection risk and population numbers at the unit of the municipality, we estimate that 29.7 million Brazilians are infected with A. lumbricoides, 19.2 million with T. trichiura and 4.7 million with hookworm. Our model-based maps identified important risk factors related to the transmission of soiltransmitted helminths and confirm that environmental variables are closely associated with indices of poverty. Our smoothed risk maps, including uncertainty, highlight areas where soil-transmitted helminthiasis control interventions are most urgently required, namely in the North and along most of the coastal areas of Brazil. We believe that our predictive risk maps are useful for disease control managers for prioritising control interventions and for providing a tool for more efficient surveillance-response mechanisms.

Mapping local and global variability in plant trait distributions

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

Butler, Ethan E.; Datta, Abhirup; Flores-Moreno, Habacuc

2017-12-01

Our ability to understand and predict the response of ecosystems to a changing environment depends on quantifying vegetation functional diversity. However, representing this diversity at the global scale is challenging. Typically, in Earth system models, characterization of plant diversity has been limited to grouping related species into plant functional types (PFTs), with all trait variation in a PFT collapsed into a single mean value that is applied globally. Using the largest global plant trait database and state of the art Bayesian modeling, we created fine-grained global maps of plant trait distributions that can be applied to Earth system models. Focusingmore » on a set of plant traits closely coupled to photosynthesis and foliar respiration—specific leaf area (SLA) and dry mass-based concentrations of leaf nitrogen (N m) and phosphorus (P m), we characterize how traits vary within and among over 50,000 ~50×50-km cells across the entire vegetated land surface. We do this in several ways—without defining the PFT of each grid cell and using 4 or 14 PFTs; each model’s predictions are evaluated against out-of-sample data. This endeavor advances prior trait mapping by generating global maps that preserve variability across scales by using modern Bayesian spatial statistical modeling in combination with a database over three times larger than that in previous analyses. Our maps further reveal that the most diverse grid cells possess trait variability close to the range of global PFT means.« less

Mapping local and global variability in plant trait distributions.

PubMed

Butler, Ethan E; Datta, Abhirup; Flores-Moreno, Habacuc; Chen, Ming; Wythers, Kirk R; Fazayeli, Farideh; Banerjee, Arindam; Atkin, Owen K; Kattge, Jens; Amiaud, Bernard; Blonder, Benjamin; Boenisch, Gerhard; Bond-Lamberty, Ben; Brown, Kerry A; Byun, Chaeho; Campetella, Giandiego; Cerabolini, Bruno E L; Cornelissen, Johannes H C; Craine, Joseph M; Craven, Dylan; de Vries, Franciska T; Díaz, Sandra; Domingues, Tomas F; Forey, Estelle; González-Melo, Andrés; Gross, Nicolas; Han, Wenxuan; Hattingh, Wesley N; Hickler, Thomas; Jansen, Steven; Kramer, Koen; Kraft, Nathan J B; Kurokawa, Hiroko; Laughlin, Daniel C; Meir, Patrick; Minden, Vanessa; Niinemets, Ülo; Onoda, Yusuke; Peñuelas, Josep; Read, Quentin; Sack, Lawren; Schamp, Brandon; Soudzilovskaia, Nadejda A; Spasojevic, Marko J; Sosinski, Enio; Thornton, Peter E; Valladares, Fernando; van Bodegom, Peter M; Williams, Mathew; Wirth, Christian; Reich, Peter B

2017-12-19

Our ability to understand and predict the response of ecosystems to a changing environment depends on quantifying vegetation functional diversity. However, representing this diversity at the global scale is challenging. Typically, in Earth system models, characterization of plant diversity has been limited to grouping related species into plant functional types (PFTs), with all trait variation in a PFT collapsed into a single mean value that is applied globally. Using the largest global plant trait database and state of the art Bayesian modeling, we created fine-grained global maps of plant trait distributions that can be applied to Earth system models. Focusing on a set of plant traits closely coupled to photosynthesis and foliar respiration-specific leaf area (SLA) and dry mass-based concentrations of leaf nitrogen ([Formula: see text]) and phosphorus ([Formula: see text]), we characterize how traits vary within and among over 50,000 [Formula: see text]-km cells across the entire vegetated land surface. We do this in several ways-without defining the PFT of each grid cell and using 4 or 14 PFTs; each model's predictions are evaluated against out-of-sample data. This endeavor advances prior trait mapping by generating global maps that preserve variability across scales by using modern Bayesian spatial statistical modeling in combination with a database over three times larger than that in previous analyses. Our maps reveal that the most diverse grid cells possess trait variability close to the range of global PFT means.

Geographical mapping and Bayesian spatial modeling of malaria incidence in Sistan and Baluchistan province, Iran.

PubMed

Zayeri, Farid; Salehi, Masoud; Pirhosseini, Hasan

2011-12-01

To present the geographical map of malaria and identify some of the important environmental factors of this disease in Sistan and Baluchistan province, Iran. We used the registered malaria data to compute the standard incidence rates (SIRs) of malaria in different areas of Sistan and Baluchistan province for a nine-year period (from 2001 to 2009). Statistical analyses consisted of two different parts: geographical mapping of malaria incidence rates, and modeling the environmental factors. The empirical Bayesian estimates of malaria SIRs were utilized for geographical mapping of malaria and a Poisson random effects model was used for assessing the effect of environmental factors on malaria SIRs. In general, 64,926 new cases of malaria were registered in Sistan and Baluchistan Province from 2001 to 2009. Among them, 42,695 patients (65.8%) were male and 22,231 patients (34.2%) were female. Modeling the environmental factors showed that malaria incidence rates had positive relationship with humidity, elevation, average minimum temperature and average maximum temperature, while rainfall had negative effect on malaria SIRs in this province. The results of the present study reveals that malaria is still a serious health problem in Sistan and Baluchistan province, Iran. Geographical map and related environmental factors of malaria can help the health policy makers to intervene in high risk areas more efficiently and allocate the resources in a proper manner. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Bayesian Lagrangian Data Assimilation and Drifter Deployment Strategies

NASA Astrophysics Data System (ADS)

Dutt, A.; Lermusiaux, P. F. J.

2017-12-01

Ocean currents transport a variety of natural (e.g. water masses, phytoplankton, zooplankton, sediments, etc.) and man-made materials and other objects (e.g. pollutants, floating debris, search and rescue, etc.). Lagrangian Coherent Structures (LCSs) or the most influential/persistent material lines in a flow, provide a robust approach to characterize such Lagrangian transports and organize classic trajectories. Using the flow-map stochastic advection and a dynamically-orthogonal decomposition, we develop uncertainty prediction schemes for both Eulerian and Lagrangian variables. We then extend our Bayesian Gaussian Mixture Model (GMM)-DO filter to a joint Eulerian-Lagrangian Bayesian data assimilation scheme. The resulting nonlinear filter allows the simultaneous non-Gaussian estimation of Eulerian variables (e.g. velocity, temperature, salinity, etc.) and Lagrangian variables (e.g. drifter/float positions, trajectories, LCSs, etc.). Its results are showcased using a double-gyre flow with a random frequency, a stochastic flow past a cylinder, and realistic ocean examples. We further show how our Bayesian mutual information and adaptive sampling equations provide a rigorous efficient methodology to plan optimal drifter deployment strategies and predict the optimal times, locations, and types of measurements to be collected.

Inference on the Genetic Basis of Eye and Skin Color in an Admixed Population via Bayesian Linear Mixed Models.

PubMed

Lloyd-Jones, Luke R; Robinson, Matthew R; Moser, Gerhard; Zeng, Jian; Beleza, Sandra; Barsh, Gregory S; Tang, Hua; Visscher, Peter M

2017-06-01

Genetic association studies in admixed populations are underrepresented in the genomics literature, with a key concern for researchers being the adequate control of spurious associations due to population structure. Linear mixed models (LMMs) are well suited for genome-wide association studies (GWAS) because they account for both population stratification and cryptic relatedness and achieve increased statistical power by jointly modeling all genotyped markers. Additionally, Bayesian LMMs allow for more flexible assumptions about the underlying distribution of genetic effects, and can concurrently estimate the proportion of phenotypic variance explained by genetic markers. Using three recently published Bayesian LMMs, Bayes R, BSLMM, and BOLT-LMM, we investigate an existing data set on eye ( n = 625) and skin ( n = 684) color from Cape Verde, an island nation off West Africa that is home to individuals with a broad range of phenotypic values for eye and skin color due to the mix of West African and European ancestry. We use simulations to demonstrate the utility of Bayesian LMMs for mapping loci and studying the genetic architecture of quantitative traits in admixed populations. The Bayesian LMMs provide evidence for two new pigmentation loci: one for eye color ( AHRR ) and one for skin color ( DDB1 ). Copyright © 2017 by the Genetics Society of America.

Mutation spectrum in BBS genes guided by homozygosity mapping in an Indian cohort.

PubMed

Sathya Priya, C; Sen, P; Umashankar, V; Gupta, N; Kabra, M; Kumaramanickavel, G; Stoetzel, C; Dollfus, H; Sripriya, S

2015-02-01

Bardet-Biedl syndrome (BBS), a ciliopathy disorder with pleiotropic effect manifests primarily as retinal degeneration along with renal insufficiency, polydactyly and obesity. In this study, we have performed homozygosity mapping using NspI 250K affymetrix gene chip followed by mutation screening of the candidate genes located in the homozygous blocks. These regions are prioritized based on the block length and candidature of the genes in BBS and other ciliopathies. Gene alterations in known BBS (22) and other ciliopathy genes such as ALMS1 (2) were seen in 24 of 30 families (80%). Mutations in BBS3 gene, inclusive of a novel recurrent mutation (p.I91T) accounted for 18% of the identified variations. Disease associated polymorphisms p.S70N (BBS2), rs1545 and rs1547 (BBS6) were also observed. This is the first study in Indian BBS patients and homozygosity mapping has proved to be an effective tool in prioritizing the candidate genes in consanguineous pedigrees. The study reveals a different mutation profile in the ciliopathy genes in Indian population and implication of novel loci/genes in 20% of the study group. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mapping Second Chromosome Mutations to Defined Genomic Regions in Drosophila melanogaster

PubMed Central

Kahsai, Lily; Cook, Kevin R.

2017-01-01

Hundreds of Drosophila melanogaster stocks are currently maintained at the Bloomington Drosophila Stock Center with mutations that have not been associated with sequence-defined genes. They have been preserved because they have interesting loss-of-function phenotypes. The experimental value of these mutations would be increased by tying them to specific genomic intervals so that geneticists can more easily associate them with annotated genes. Here, we report the mapping of 85 second chromosome complementation groups in the Bloomington collection to specific, small clusters of contiguous genes or individual genes in the sequenced genome. This information should prove valuable to Drosophila geneticists interested in processes associated with particular phenotypes and those searching for mutations affecting specific sequence-defined genes. PMID:29066472

Recent Transmission Clustering of HIV-1 C and CRF17_BF Strains Characterized by NNRTI-Related Mutations among Newly Diagnosed Men in Central Italy

PubMed Central

Orchi, Nicoletta; Gori, Caterina; Bertoli, Ada; Forbici, Federica; Montella, Francesco; Pennica, Alfredo; De Carli, Gabriella; Giuliani, Massimo; Continenza, Fabio; Pinnetti, Carmela; Nicastri, Emanuele; Ceccherini-Silberstein, Francesca; Mastroianni, Claudio Maria; Girardi, Enrico; Andreoni, Massimo; Antinori, Andrea; Santoro, Maria Mercedes; Perno, Carlo Federico

2015-01-01

Background Increased evidence of relevant HIV-1 epidemic transmission in European countries is being reported, with an increased circulation of non-B-subtypes. Here, we present two recent HIV-1 non-B transmission clusters characterized by NNRTI-related amino-acidic mutations among newly diagnosed HIV-1 infected men, living in Rome (Central-Italy). Methods Pol and V3 sequences were available at the time of diagnosis for all individuals. Maximum-Likelihood and Bayesian phylogenetic-trees with bootstrap and Bayesian-probability supports defined transmission-clusters. HIV-1 drug-resistance and V3-tropism were also evaluated. Results Among 534 new HIV-1 non-B cases, diagnosed from 2011 to 2014, in Central-Italy, 35 carried virus gathering in two distinct clusters, including 27 HIV-1 C and 8 CRF17_BF subtypes, respectively. Both clusters were centralized in Rome, and their origin was estimated to have been after 2007. All individuals within both clusters were males and 37.1% of them had been recently-infected. While C-cluster was entirely composed by Italian men-who-have-sex-with-men, with a median-age of 34 years (IQR:30–39), individuals in CRF17_BF-cluster were older, with a median-age of 51 years (IQR:48–59) and almost all reported sexual-contacts with men and women. All carried R5-tropic viruses, with evidence of atypical or resistance amino-acidic mutations related to NNRTI-drugs (K103Q in C-cluster, and K101E+E138K in CRF17_BF-cluster). Conclusions These two epidemiological clusters provided evidence of a strong and recent circulation of C and CRF17_BF strains in central Italy, characterized by NNRTI-related mutations among men engaging in high-risk behaviours. These findings underline the role of molecular epidemiology in identifying groups at increased risk of HIV-1 transmission, and in enhancing additional prevention efforts. PMID:26270824

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

PubMed

Lucotte, Gérard; Dieterlen, Florent

2003-01-01

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

PyBetVH: A Python tool for probabilistic volcanic hazard assessment and for generation of Bayesian hazard curves and maps

NASA Astrophysics Data System (ADS)

Tonini, Roberto; Sandri, Laura; Anne Thompson, Mary

2015-06-01

PyBetVH is a completely new, free, open-source and cross-platform software implementation of the Bayesian Event Tree for Volcanic Hazard (BET_VH), a tool for estimating the probability of any magmatic hazardous phenomenon occurring in a selected time frame, accounting for all the uncertainties. New capabilities of this implementation include the ability to calculate hazard curves which describe the distribution of the exceedance probability as a function of intensity (e.g., tephra load) on a grid of points covering the target area. The computed hazard curves are (i) absolute (accounting for the probability of eruption in a given time frame, and for all the possible vent locations and eruptive sizes) and (ii) Bayesian (computed at different percentiles, in order to quantify the epistemic uncertainty). Such curves allow representation of the full information contained in the probabilistic volcanic hazard assessment (PVHA) and are well suited to become a main input to quantitative risk analyses. PyBetVH allows for interactive visualization of both the computed hazard curves, and the corresponding Bayesian hazard/probability maps. PyBetVH is designed to minimize the efforts of end users, making PVHA results accessible to people who may be less experienced in probabilistic methodologies, e.g. decision makers. The broad compatibility of Python language has also allowed PyBetVH to be installed on the VHub cyber-infrastructure, where it can be run online or downloaded at no cost. PyBetVH can be used to assess any type of magmatic hazard from any volcano. Here we illustrate how to perform a PVHA through PyBetVH using the example of analyzing tephra fallout from the Okataina Volcanic Centre (OVC), New Zealand, and highlight the range of outputs that the tool can generate.

A Bayesian Hierarchical Modeling Scheme for Estimating Erosion Rates Under Current Climate Conditions

NASA Astrophysics Data System (ADS)

Lowman, L.; Barros, A. P.

2014-12-01

Computational modeling of surface erosion processes is inherently difficult because of the four-dimensional nature of the problem and the multiple temporal and spatial scales that govern individual mechanisms. Landscapes are modified via surface and fluvial erosion and exhumation, each of which takes place over a range of time scales. Traditional field measurements of erosion/exhumation rates are scale dependent, often valid for a single point-wise location or averaging over large aerial extents and periods with intense and mild erosion. We present a method of remotely estimating erosion rates using a Bayesian hierarchical model based upon the stream power erosion law (SPEL). A Bayesian approach allows for estimating erosion rates using the deterministic relationship given by the SPEL and data on channel slopes and precipitation at the basin and sub-basin scale. The spatial scale associated with this framework is the elevation class, where each class is characterized by distinct morphologic behavior observed through different modes in the distribution of basin outlet elevations. Interestingly, the distributions of first-order outlets are similar in shape and extent to the distribution of precipitation events (i.e. individual storms) over a 14-year period between 1998-2011. We demonstrate an application of the Bayesian hierarchical modeling framework for five basins and one intermontane basin located in the central Andes between 5S and 20S. Using remotely sensed data of current annual precipitation rates from the Tropical Rainfall Measuring Mission (TRMM) and topography from a high resolution (3 arc-seconds) digital elevation map (DEM), our erosion rate estimates are consistent with decadal-scale estimates based on landslide mapping and sediment flux observations and 1-2 orders of magnitude larger than most millennial and million year timescale estimates from thermochronology and cosmogenic nuclides.

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

PubMed Central

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N.; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier. PMID:26147992

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

PubMed

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

Toward Universal Forward Genetics: Using a Draft Genome Sequence of the Nematode Oscheius tipulae To Identify Mutations Affecting Vulva Development

PubMed Central

Besnard, Fabrice; Koutsovoulos, Georgios; Dieudonné, Sana; Blaxter, Mark; Félix, Marie-Anne

2017-01-01

Mapping-by-sequencing has become a standard method to map and identify phenotype-causing mutations in model species. Here, we show that a fragmented draft assembly is sufficient to perform mapping-by-sequencing in nonmodel species. We generated a draft assembly and annotation of the genome of the free-living nematode Oscheius tipulae, a distant relative of the model Caenorhabditis elegans. We used this draft to identify the likely causative mutations at the O. tipulae cov-3 locus, which affect vulval development. The cov-3 locus encodes the O. tipulae ortholog of C. elegans mig-13, and we further show that Cel-mig-13 mutants also have an unsuspected vulval-development phenotype. In a virtuous circle, we were able to use the linkage information collected during mutant mapping to improve the genome assembly. These results showcase the promise of genome-enabled forward genetics in nonmodel species. PMID:28630114

High-throughput gene mapping in Caenorhabditis elegans.

PubMed

Swan, Kathryn A; Curtis, Damian E; McKusick, Kathleen B; Voinov, Alexander V; Mapa, Felipa A; Cancilla, Michael R

2002-07-01

Positional cloning of mutations in model genetic systems is a powerful method for the identification of targets of medical and agricultural importance. To facilitate the high-throughput mapping of mutations in Caenorhabditis elegans, we have identified a further 9602 putative new single nucleotide polymorphisms (SNPs) between two C. elegans strains, Bristol N2 and the Hawaiian mapping strain CB4856, by sequencing inserts from a CB4856 genomic DNA library and using an informatics pipeline to compare sequences with the canonical N2 genomic sequence. When combined with data from other laboratories, our marker set of 17,189 SNPs provides even coverage of the complete worm genome. To date, we have confirmed >1099 evenly spaced SNPs (one every 91 +/- 56 kb) across the six chromosomes and validated the utility of our SNP marker set and new fluorescence polarization-based genotyping methods for systematic and high-throughput identification of genes in C. elegans by cloning several proprietary genes. We illustrate our approach by recombination mapping and confirmation of the mutation in the cloned gene, dpy-18.

Toward Universal Forward Genetics: Using a Draft Genome Sequence of the Nematode Oscheius tipulae To Identify Mutations Affecting Vulva Development.

PubMed

Besnard, Fabrice; Koutsovoulos, Georgios; Dieudonné, Sana; Blaxter, Mark; Félix, Marie-Anne

2017-08-01

Mapping-by-sequencing has become a standard method to map and identify phenotype-causing mutations in model species. Here, we show that a fragmented draft assembly is sufficient to perform mapping-by-sequencing in nonmodel species. We generated a draft assembly and annotation of the genome of the free-living nematode Oscheius tipulae , a distant relative of the model Caenorhabditis elegans We used this draft to identify the likely causative mutations at the O. tipulae cov -3 locus, which affect vulval development. The cov-3 locus encodes the O. tipulae ortholog of C. elegans mig-13 , and we further show that Cel-mig-13 mutants also have an unsuspected vulval-development phenotype. In a virtuous circle, we were able to use the linkage information collected during mutant mapping to improve the genome assembly. These results showcase the promise of genome-enabled forward genetics in nonmodel species. Copyright © 2017 by the Genetics Society of America.

In Darwinian evolution, feedback from natural selection leads to biased mutations.

PubMed

Caporale, Lynn Helena; Doyle, John

2013-12-01

Natural selection provides feedback through which information about the environment and its recurring challenges is captured, inherited, and accumulated within genomes in the form of variations that contribute to survival. The variation upon which natural selection acts is generally described as "random." Yet evidence has been mounting for decades, from such phenomena as mutation hotspots, horizontal gene transfer, and highly mutable repetitive sequences, that variation is far from the simplifying idealization of random processes as white (uniform in space and time and independent of the environment or context).  This paper focuses on what is known about the generation and control of mutational variation, emphasizing that it is not uniform across the genome or in time, not unstructured with respect to survival, and is neither memoryless nor independent of the (also far from white) environment. We suggest that, as opposed to frequentist methods, Bayesian analysis could capture the evolution of nonuniform probabilities of distinct classes of mutation, and argue not only that the locations, styles, and timing of real mutations are not correctly modeled as generated by a white noise random process, but that such a process would be inconsistent with evolutionary theory. © 2013 New York Academy of Sciences.

Modular analysis of the probabilistic genetic interaction network.

PubMed

Hou, Lin; Wang, Lin; Qian, Minping; Li, Dong; Tang, Chao; Zhu, Yunping; Deng, Minghua; Li, Fangting

2011-03-15

Epistatic Miniarray Profiles (EMAP) has enabled the mapping of large-scale genetic interaction networks; however, the quantitative information gained from EMAP cannot be fully exploited since the data are usually interpreted as a discrete network based on an arbitrary hard threshold. To address such limitations, we adopted a mixture modeling procedure to construct a probabilistic genetic interaction network and then implemented a Bayesian approach to identify densely interacting modules in the probabilistic network. Mixture modeling has been demonstrated as an effective soft-threshold technique of EMAP measures. The Bayesian approach was applied to an EMAP dataset studying the early secretory pathway in Saccharomyces cerevisiae. Twenty-seven modules were identified, and 14 of those were enriched by gold standard functional gene sets. We also conducted a detailed comparison with state-of-the-art algorithms, hierarchical cluster and Markov clustering. The experimental results show that the Bayesian approach outperforms others in efficiently recovering biologically significant modules.

Epistasis and Pleiotropy Affect the Modularity of the Genotype-Phenotype Map of Cross-Resistance in HIV-1.

PubMed

Polster, Robert; Petropoulos, Christos J; Bonhoeffer, Sebastian; Guillaume, Frédéric

2016-12-01

The genotype-phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

A Novel MAPT Mutation, G55R, in a Frontotemporal Dementia Patient Leads to Altered Tau Function

PubMed Central

Guzman, Elmer; Barczak, Anna; Chodakowska-Żebrowska, Małgorzata; Barcikowska, Maria; Feinstein, Stuart

2013-01-01

Over two dozen mutations in the gene encoding the microtubule associated protein tau cause a variety of neurodegenerative dementias known as tauopathies, including frontotemporal dementia (FTD), PSP, CBD and Pick's disease. The vast majority of these mutations map to the C-terminal region of tau possessing microtubule assembly and microtubule dynamics regulatory activities as well as the ability to promote pathological tau aggregation. Here, we describe a novel and non-conservative tau mutation (G55R) mapping to an alternatively spliced exon encoding part of the N-terminal region of the protein in a patient with the behavioral variant of FTD. Although less well understood than the C-terminal region of tau, the N-terminal region can influence both MT mediated effects as well as tau aggregation. The mutation changes an uncharged glycine to a basic arginine in the midst of a highly conserved and very acidic region. In vitro, 4-repeat G55R tau nucleates microtubule assembly more effectively than wild-type 4-repeat tau; surprisingly, this effect is tau isoform specific and is not observed in a 3-repeat G55R tau versus 3-repeat wild-type tau comparison. In contrast, the G55R mutation has no effect upon the abilities of tau to regulate MT growing and shortening dynamics or to aggregate. Additionally, the mutation has no effect upon kinesin translocation in a microtubule gliding assay. Together, (i) we have identified a novel tau mutation mapping to a mutation deficient region of the protein in a bvFTD patient, and (ii) the G55R mutation affects the ability of tau to nucleate microtubule assembly in vitro in a 4-repeat tau isoform specific manner. This altered capability could markedly affect in vivo microtubule function and neuronal cell biology. We consider G55R to be a candidate mutation for bvFTD since additional criteria required to establish causality are not yet available for assessment. PMID:24086739

A mutation in a new gene bglJ, activates the bgl operon in Escherichia coli K-12

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

Giel, M.; Desnoyer, M.; Lopilato, J.

1996-06-01

A new mutation , bglJ4, has been characterized that results in the expression of the silent bgl operon. The bgl operon encodes proteins necessary for the transport and utilization of the aromatic {beta}-glucosides arbutin and salicin. A variety of mutations activate the operon and result in a Bgl{sup +} phenotype. Activating mutations are located upstream of the bgl promoter and in genes located elsewhere on the chromosome. Mutations outside of the bgl operon occur in the genes encoding DNA gyrase and in the gene encoding the nucleoid associated protein H-NS. The mutation described here, bglJ4, has been mapped to amore » new locus at min 99 on the Escherichia coli K-12 genetic map. The putative protein encoded by the bglJ gene has homology to a family of transcriptional activators. Evidence is presented that increased expression of the bglJ product is needed for activation of the bgl operon. 56 refs., 3 figs., 3 tabs.« less

Use of space-time models to investigate the stability of patterns of disease.

PubMed

Abellan, Juan Jose; Richardson, Sylvia; Best, Nicky

2008-08-01

The use of Bayesian hierarchical spatial models has become widespread in disease mapping and ecologic studies of health-environment associations. In this type of study, the data are typically aggregated over an extensive time period, thus neglecting the time dimension. The output of purely spatial disease mapping studies is therefore the average spatial pattern of risk over the period analyzed, but the results do not inform about, for example, whether a high average risk was sustained over time or changed over time. We investigated how including the time dimension in disease-mapping models strengthens the epidemiologic interpretation of the overall pattern of risk. We discuss a class of Bayesian hierarchical models that simultaneously characterize and estimate the stable spatial and temporal patterns as well as departures from these stable components. We show how useful rules for classifying areas as stable can be constructed based on the posterior distribution of the space-time interactions. We carry out a simulation study to investigate the sensitivity and specificity of the decision rules we propose, and we illustrate our approach in a case study of congenital anomalies in England. Our results confirm that extending hierarchical disease-mapping models to models that simultaneously consider space and time leads to a number of benefits in terms of interpretation and potential for detection of localized excesses.

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “de novo” SCN1A Mutations in Children with Dravet Syndrome

PubMed Central

Xu, Xiaojing; Yang, Xiaoxu; Wu, Qixi; Liu, Aijie; Yang, Xiaoling; Ye, Adam Yongxin; Huang, August Yue; Li, Jiarui; Wang, Meng; Yu, Zhe; Wang, Sheng; Zhang, Zhichao; Wu, Xiru

2015-01-01

ABSTRACT The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low‐level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling. PMID:26096185

Bayesian Deconvolution for Angular Super-Resolution in Forward-Looking Scanning Radar

PubMed Central

Zha, Yuebo; Huang, Yulin; Sun, Zhichao; Wang, Yue; Yang, Jianyu

2015-01-01

Scanning radar is of notable importance for ground surveillance, terrain mapping and disaster rescue. However, the angular resolution of a scanning radar image is poor compared to the achievable range resolution. This paper presents a deconvolution algorithm for angular super-resolution in scanning radar based on Bayesian theory, which states that the angular super-resolution can be realized by solving the corresponding deconvolution problem with the maximum a posteriori (MAP) criterion. The algorithm considers that the noise is composed of two mutually independent parts, i.e., a Gaussian signal-independent component and a Poisson signal-dependent component. In addition, the Laplace distribution is used to represent the prior information about the targets under the assumption that the radar image of interest can be represented by the dominant scatters in the scene. Experimental results demonstrate that the proposed deconvolution algorithm has higher precision for angular super-resolution compared with the conventional algorithms, such as the Tikhonov regularization algorithm, the Wiener filter and the Richardson–Lucy algorithm. PMID:25806871

The morbid anatomy of the human genome: chromosomal location of mutations causing disease.

PubMed Central

McKusick, V A; Amberger, J S

1993-01-01

Information is given in tabular form derived from a synopsis of the human gene map which has been updated continuously since 1973 as part of Mendelian Inheritance in Man (Johns Hopkins University Press, 10th ed, 1992) and of OMIM (Online Mendelian Inheritance in Man, available generally since 1987). The part of the synopsis reproduced here consists of chromosome by chromosome gene lists of loci for which there are associated disorders (table 1), a pictorial representation of this information (fig 1a-d), and an index of disorders for which the causative mutations have been mapped (table 2). In table 1, information on genes that have been located to specific chromosomal positions and are also the site of disease producing mutations is arranged by chromosome, starting with chromosome 1 and with the end of the short arm of the chromosome in each case. In table 2 an alphabetized list of these disorders and the chromosomal location of the mutation in each case are provided. Both in the 'Disorder' field of table 1 and in table 2, the numbers 1, 2, or 3 in parentheses after the name of the disorder indicate that its chromosomal location was determined by mapping of the wildtype gene (1), by mapping of the clinical phenotype (2), or by both strategies (3). PMID:8423603

Characterization of Nucleoside Reverse Transcriptase Inhibitor-Associated Mutations in the RNase H Region of HIV-1 Subtype C Infected Individuals.

PubMed

Ngcapu, Sinaye; Theys, Kristof; Libin, Pieter; Marconi, Vincent C; Sunpath, Henry; Ndung'u, Thumbi; Gordon, Michelle L

2017-11-08

The South African national treatment programme includes nucleoside reverse transcriptase inhibitors (NRTIs) in both first and second line highly active antiretroviral therapy regimens. Mutations in the RNase H domain have been associated with resistance to NRTIs but primarily in HIV-1 subtype B studies. Here, we investigated the prevalence and association of RNase H mutations with NRTI resistance in sequences from HIV-1 subtype C infected individuals. RNase H sequences from 112 NRTI treated but virologically failing individuals and 28 antiretroviral therapy (ART)-naive individuals were generated and analysed. In addition, sequences from 359 subtype C ART-naive sequences were downloaded from Los Alamos database to give a total of 387 sequences from ART-naive individuals for the analysis. Fisher's exact test was used to identify mutations and Bayesian network learning was applied to identify novel NRTI resistance mutation pathways in RNase H domain. The mutations A435L, S468A, T470S, L484I, A508S, Q509L, L517I, Q524E and E529D were more prevalent in sequences from treatment-experienced compared to antiretroviral treatment naive individuals, however, only the E529D mutation remained significant after correction for multiple comparison. Our findings suggest a potential interaction between E529D and NRTI-treatment; however, site-directed mutagenesis is needed to understand the impact of this RNase H mutation.

A high-resolution genetic, physical, and comparative gene map of the doublefoot (Dbf) region of mouse chromosome 1 and the region of conserved synteny on human chromosome 2q35.

PubMed

Hayes, C; Rump, A; Cadman, M R; Harrison, M; Evans, E P; Lyon, M F; Morriss-Kay, G M; Rosenthal, A; Brown, S D

2001-12-01

The mouse doublefoot (Dbf) mutant exhibits preaxial polydactyly in association with craniofacial defects. This mutation has previously been mapped to mouse chromosome 1. We have used a positional cloning strategy, coupled with a comparative sequencing approach using available human draft sequence, to identify putative candidates for the Dbf gene in the mouse and in homologous human region. We have constructed a high-resolution genetic map of the region, localizing the mutation to a 0.4-cM (+/-0.0061) interval on mouse chromosome 1. Furthermore, we have constructed contiguous BAC/PAC clone maps across the mouse and human Dbf region. Using existing markers and additional sequence tagged sites, which we have generated, we have anchored the physical map to the genetic map. Through the comparative sequencing of these clones we have identified 35 genes within this interval, indicating that the region is gene-rich. From this we have identified several genes that are known to be differentially expressed in the developing mid-gestation mouse embryo, some in the developing embryonic limb buds. These genes include those encoding known developmental signaling molecules such as WNT proteins and IHH, and we provide evidence that these genes are candidates for the Dbf mutation.

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

PubMed

Stephen, Joshi; Nampoothiri, Sheela; Vinayan, K P; Yesodharan, Dhanya; Remesh, Preetha; Gahl, William A; Malicdan, May Christine V

2018-05-16

Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

Lung-MAP: AZD4547 as Second-Line Therapy in Treating FGFR Positive Patients With Recurrent Stage IV Squamous Cell Lung Cancer

ClinicalTrials.gov

2017-12-13

FGFR1 Gene Amplification; FGFR1 Gene Mutation; FGFR2 Gene Amplification; FGFR2 Gene Mutation; FGFR3 Gene Amplification; FGFR3 Gene Mutation; Recurrent Squamous Cell Lung Carcinoma; Stage IV Squamous Cell Lung Carcinoma AJCC v7

SUVI Thematic Maps: A new tool for space weather forecasting

NASA Astrophysics Data System (ADS)

Hughes, J. M.; Seaton, D. B.; Darnel, J.

2017-12-01

The new Solar Ultraviolet Imager (SUVI) instruments aboard NOAA's GOES-R series satellites collect continuous, high-quality imagery of the Sun in six wavelengths. SUVI imagers produce at least one image every 10 seconds, or 8,640 images per day, considerably more data than observers can digest in real time. Over the projected 20-year lifetime of the four GOES-R series spacecraft, SUVI will provide critical imagery for space weather forecasters and produce an extensive but unwieldy archive. In order to condense the database into a dynamic and searchable form we have developed solar thematic maps, maps of the Sun with key features, such as coronal holes, flares, bright regions, quiet corona, and filaments, identified. Thematic maps will be used in NOAA's Space Weather Prediction Center to improve forecaster response time to solar events and generate several derivative products. Likewise, scientists use thematic maps to find observations of interest more easily. Using an expert-trained, naive Bayesian classifier to label each pixel, we create thematic maps in real-time. We created software to collect expert classifications of solar features based on SUVI images. Using this software, we compiled a database of expert classifications, from which we could characterize the distribution of pixels associated with each theme. Given new images, the classifier assigns each pixel the most appropriate label according to the trained distribution. Here we describe the software to collect expert training and the successes and limitations of the classifier. The algorithm excellently identifies coronal holes but fails to consistently detect filaments and prominences. We compare the Bayesian classifier to an artificial neural network, one of our attempts to overcome the aforementioned limitations. These results are very promising and encourage future research into an ensemble classification approach.

Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation

PubMed Central

Olson, Timothy M.; Michels, Virginia V.; Ballew, Jeffrey D.; Reyna, Sandra P.; Karst, Margaret L.; Herron, Kathleen J.; Horton, Steven C.; Rodeheffer, Richard J.; Anderson, Jeffrey L.

2007-01-01

Context Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. Objectives To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Design, Setting, and Participants Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated pro-bands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Main Outcome Measure Correlation of identified mutations with cardiac phenotype. Results Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). Conclusions Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both. PMID:15671429

Inferring the global phylodynamics of influenza A/H3N2 viruses in Taiwan.

PubMed

Gong, Yu-Nong; Tsao, Kuo-Chien; Chen, Guang-Wu

2018-02-20

Influenza A/H3N2 viruses are characterized by highly mutated RNA genomes. In this study, we focused on tracing the phylodynamics of Taiwanese strains over the past four decades. All Taiwanese H3N2 HA1 sequences and references were downloaded from public database. A Bayesian skyline plot (BSP) and phylogenetic tree were used to analyze the evolutionary history, and Bayesian phylogeographic analysis was applied to predict the spatiotemporal migrations of influenza outbreaks. Genetic diversity was found to have peaked near the summer of 2009 in BSP, in addition to the two earlier reported ones in summer of 2005 and 2007. We predicted their spatiotemporal migrations and found the summer epidemic of 2005 from Korea, and 2007 and 2009 from the Western United States. BSP also predicted an elevated genetic diversity in 2015-2017. Quasispecies were found over approximately 20% of the strains included in this time span. In addition, a first-time seen N31S mutation was noted in Taiwan in 2016-2017. We comprehensively investigated the evolutionary history of Taiwanese strains in 1979-2017. An epidemic caution could thus be raised if genetic diversity was found to have peaked. An example showed a newly-discovered cluster in 2016-2017 strains featuring a mutation N31S together with HA-160 quasispecies. Phylogeographic analysis, moreover, provided useful insights in tracing the possible source and migrations of these epidemics around the world. We demonstrated that Asian destinations including Taiwan were the immediate followers, while U.S. continent was predicted the origin of two summer epidemics in 2007 and 2009. Copyright © 2018. Published by Elsevier B.V.

The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer

PubMed Central

Krogan, Nevan J.; Lippman, Scott; Agard, David A.; Ashworth, Alan; Ideker, Trey

2017-01-01

Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, called The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these Cancer Cell Maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. PMID:26000852

The cancer cell map initiative: defining the hallmark networks of cancer.

PubMed

Krogan, Nevan J; Lippman, Scott; Agard, David A; Ashworth, Alan; Ideker, Trey

2015-05-21

Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. Here we announce the creation of a new effort, The Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. We discuss recent progress that enables creation of these cancer cell maps across a range of tumor types and how they can be used to target networks disrupted in individual patients, significantly accelerating the development of precision medicine. Copyright © 2015 Elsevier Inc. All rights reserved.

Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross.

PubMed

Buckwalter, M S; Katz, R W; Camper, S A

1991-07-01

Ames dwarf (df) is an autosomal recessive mutation characterized by severe dwarfism and infertility. This mutation provides a mouse model for panhypopituitarism. The dwarf phenotype results from failure in the differentiation of the cells which produce growth hormone, prolactin, and thyroid stimulating hormone. Using the backcross (DF/B-df/df X CASA/Rk) X DF/B-df/df, we confirmed the assignment of df to mouse chromosome 11 and demonstrated recombination between df and the growth hormone gene. This backcross is an invaluable resource for screening candidate genes for the df mutation. The df locus maps to less than 1 cM distal to Pad-1 (0.85 +/- 0.85 cM). Two new genes localized on mouse chromosome 11, Rpo2-1, and Edp-1, map to a region of conserved synteny with human chromosome 17. The localization of the alpha 1 adrenergic receptor, Adra-1, extends a known region of synteny conservation between mouse chromosome 11 and human chromosome 5, and suggests that a human counterpart to df would map to human chromosome 5.

MTHFR Gene Polymorphism-Mutations and Air Pollution as Risk Factors for Breast Cancer

PubMed Central

Gonzales, Mildred C.; Yu, Pojui; Shiao, S. Pamela K.

2017-01-01

Background The methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways. Objectives The objectives of this metaprediction study were to examine the polymorphism-mutation risk subtypes of MTHFR and air pollution as contributing factors for breast cancer. Methods For triangulation purposes in metapredictive analyses, we used a recursive partition tree, nonlinear association curve fit, and heat maps for data visualization, in addition to the conventional comparison procedure and pooled analyses. Results We included 36,683 breast cancer cases and 40,689 controls across 82 studies for MTHFR 677 and 23,252 cases and 27,094 controls across 50 studies for MTHFR 1298. MTHFR 677 TT was a risk genotype for breast cancer (p = .0004) and in the East Asian subgroup (p = .005). On global maps, the most polymorphism-mutations on MTHFR 677 TT were found in the Middle East, Europe, Asia, and the Americas, whereas the most mutations on MTHFR 1298 CC were located in Europe and the Middle East for the control group. The geographic information system maps further revealed that MTHFR 677 TT mutations yielded a higher risk of breast cancer for Australia, East Asia, the Middle East, South Europe, Morocco, and the Americas and that MTHFR 1298 CC mutations yielded a higher risk in Asia, the Middle East, South Europe, and South America. Metapredictive analysis revealed that air pollution level was significantly associated with MTHFR 677 TT polymorphism-mutation genotype. Discussion We present the most comprehensive analyses to date of MTHFR polymorphism-mutations and breast cancer risk. Future nursing studies are needed to investigate the health impact on breast cancer of epigenetics and air pollution across populations. PMID:28114181

MTHFR Gene Polymorphism-Mutations and Air Pollution as Risk Factors for Breast Cancer: A Metaprediction Study.

PubMed

Gonzales, Mildred C; Yu, Pojui; Shiao, S Pamela K

The methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways. The objectives of this metaprediction study were to examine the polymorphism-mutation risk subtypes of MTHFR and air pollution as contributing factors for breast cancer. For triangulation purposes in metapredictive analyses, we used a recursive partition tree, nonlinear association curve fit, and heat maps for data visualization, in addition to the conventional comparison procedure and pooled analyses. We included 36,683 breast cancer cases and 40,689 controls across 82 studies for MTHFR 677 and 23,252 cases and 27,094 controls across 50 studies for MTHFR 1298. MTHFR 677 TT was a risk genotype for breast cancer (p = .0004) and in the East Asian subgroup (p = .005). On global maps, the most polymorphism-mutations on MTHFR 677 TT were found in the Middle East, Europe, Asia, and the Americas, whereas the most mutations on MTHFR 1298 CC were located in Europe and the Middle East for the control group. The geographic information system maps further revealed that MTHFR 677 TT mutations yielded a higher risk of breast cancer for Australia, East Asia, the Middle East, South Europe, Morocco, and the Americas and that MTHFR 1298 CC mutations yielded a higher risk in Asia, the Middle East, South Europe, and South America. Metapredictive analysis revealed that air pollution level was significantly associated with MTHFR 677 TT polymorphism-mutation genotype. We present the most comprehensive analyses to date of MTHFR polymorphism-mutations and breast cancer risk. Future nursing studies are needed to investigate the health impact on breast cancer of epigenetics and air pollution across populations.

Predictive model of outcome of targeted nodal assessment in colorectal cancer.

PubMed

Nissan, Aviram; Protic, Mladjan; Bilchik, Anton; Eberhardt, John; Peoples, George E; Stojadinovic, Alexander

2010-02-01

Improvement in staging accuracy is the principal aim of targeted nodal assessment in colorectal carcinoma. Technical factors independently predictive of false negative (FN) sentinel lymph node (SLN) mapping should be identified to facilitate operative decision making. To define independent predictors of FN SLN mapping and to develop a predictive model that could support surgical decisions. Data was analyzed from 2 completed prospective clinical trials involving 278 patients with colorectal carcinoma undergoing SLN mapping. Clinical outcome of interest was FN SLN(s), defined as one(s) with no apparent tumor cells in the presence of non-SLN metastases. To assess the independent predictive effect of a covariate for a nominal response (FN SLN), a logistic regression model was constructed and parameters estimated using maximum likelihood. A probabilistic Bayesian model was also trained and cross validated using 10-fold train-and-test sets to predict FN SLN mapping. Area under the curve (AUC) from receiver operating characteristics curves of these predictions was calculated to determine the predictive value of the model. Number of SLNs (<3; P = 0.03) and tumor-replaced nodes (P < 0.01) independently predicted FN SLN. Cross validation of the model created with Bayesian Network Analysis effectively predicted FN SLN (area under the curve = 0.84-0.86). The positive and negative predictive values of the model are 83% and 97%, respectively. This study supports a minimum threshold of 3 nodes for targeted nodal assessment in colorectal cancer, and establishes sufficient basis to conclude that SLN mapping and biopsy cannot be justified in the presence of clinically apparent tumor-replaced nodes.

Identification and analysis of mutational hotspots in oncogenes and tumour suppressors.

PubMed

Baeissa, Hanadi; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

2017-03-28

The key to interpreting the contribution of a disease-associated mutation in the development and progression of cancer is an understanding of the consequences of that mutation both on the function of the affected protein and on the pathways in which that protein is involved. Protein domains encapsulate function and position-specific domain based analysis of mutations have been shown to help elucidate their phenotypes. In this paper we examine the domain biases in oncogenes and tumour suppressors, and find that their domain compositions substantially differ. Using data from over 30 different cancers from whole-exome sequencing cancer genomic projects we mapped over one million mutations to their respective Pfam domains to identify which domains are enriched in any of three different classes of mutation; missense, indels or truncations. Next, we identified the mutational hotspots within domain families by mapping small mutations to equivalent positions in multiple sequence alignments of protein domainsWe find that gain of function mutations from oncogenes and loss of function mutations from tumour suppressors are normally found in different domain families and when observed in the same domain families, hotspot mutations are located at different positions within the multiple sequence alignment of the domain. By considering hotspots in tumour suppressors and oncogenes independently, we find that there are different specific positions within domain families that are particularly suited to accommodate either a loss or a gain of function mutation. The position is also dependent on the class of mutation.We find rare mutations co-located with well-known functional mutation hotspots, in members of homologous domain superfamilies, and we detect novel mutation hotspots in domain families previously unconnected with cancer. The results of this analysis can be accessed through the MOKCa database (http://strubiol.icr.ac.uk/extra/MOKCa).

Mycobacterium avium subsp. paratuberculosis PPE Protein MAP1152 and Conserved Protein MAP1156 are Antigenic in Experimentally and Naturally Infected Cattle

USDA-ARS?s Scientific Manuscript database

Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne’s Disease (JD) in ruminants resulting in significant production losses. An insertion mutation upstream from the MAP1152-MAP1156 region causes a change in colony morphotype and results in an attenuated phenotype in bovine monocyte derive...

The Genetics of a Small Chromosome Region of DROSOPHILA MELANOGASTER Containing the Structural Gene for Alcohol Dehydrogenase. IV: Scutoid, an Antimorphic Mutation

PubMed Central

Ashburner, M.; Tsubota, S.; Woodruff, R. C.

1982-01-01

Exchange mapping locates the dominant mutation Scutoid to the right of Adh on chromosome arm 2L of D. melanogaster. However, deletion mapping indicates that Sco is to the left of Adh. The phenotype of Sco is sensitive to mutation, or deletion, of noc+ and of three genes, el, l(2)br22, and l(2)br29 mapping immediately distal to noc. The four contiguous loci, el, l(2)br22, l(2)br29 and noc, although separable by deletion end points, interact, because certain (or all) alleles of these four loci show partial failure of complementation, or even negative complementation. The simplest hypothesis is that Sco is a small reciprocal transposition, the genes noc, osp, and Adh exchanging places with three genes normally mapping proximal to them: l(2)br34, l(2)br35 and rd. The Sco phenotype is thought to result from a position effect at the newly created noc/l(2)br28 junction. PMID:6816673

The center for causal discovery of biomedical knowledge from big data

PubMed Central

Bahar, Ivet; Becich, Michael J; Benos, Panayiotis V; Berg, Jeremy; Espino, Jeremy U; Glymour, Clark; Jacobson, Rebecca Crowley; Kienholz, Michelle; Lee, Adrian V; Lu, Xinghua; Scheines, Richard

2015-01-01

The Big Data to Knowledge (BD2K) Center for Causal Discovery is developing and disseminating an integrated set of open source tools that support causal modeling and discovery of biomedical knowledge from large and complex biomedical datasets. The Center integrates teams of biomedical and data scientists focused on the refinement of existing and the development of new constraint-based and Bayesian algorithms based on causal Bayesian networks, the optimization of software for efficient operation in a supercomputing environment, and the testing of algorithms and software developed using real data from 3 representative driving biomedical projects: cancer driver mutations, lung disease, and the functional connectome of the human brain. Associated training activities provide both biomedical and data scientists with the knowledge and skills needed to apply and extend these tools. Collaborative activities with the BD2K Consortium further advance causal discovery tools and integrate tools and resources developed by other centers. PMID:26138794

PIMMS (Pragmatic Insertional Mutation Mapping System) Laboratory Methodology a Readily Accessible Tool for Identification of Essential Genes in Streptococcus

PubMed Central

Blanchard, Adam M.; Egan, Sharon A.; Emes, Richard D.; Warry, Andrew; Leigh, James A.

2016-01-01

The Pragmatic Insertional Mutation Mapping (PIMMS) laboratory protocol was developed alongside various bioinformatics packages (Blanchard et al., 2015) to enable detection of essential and conditionally essential genes in Streptococcus and related bacteria. This extended the methodology commonly used to locate insertional mutations in individual mutants to the analysis of mutations in populations of bacteria. In Streptococcus uberis, a pyogenic Streptococcus associated with intramammary infection and mastitis in ruminants, the mutagen pGhost9:ISS1 was shown to integrate across the entire genome. Analysis of >80,000 mutations revealed 196 coding sequences, which were not be mutated and a further 67 where mutation only occurred beyond the 90th percentile of the coding sequence. These sequences showed good concordance with sequences within the database of essential genes and typically matched sequences known to be associated with basic cellular functions. Due to the broad utility of this mutagen and the simplicity of the methodology it is anticipated that PIMMS will be of value to a wide range of laboratories in functional genomic analysis of a wide range of Gram positive bacteria (Streptococcus, Enterococcus, and Lactococcus) of medical, veterinary, and industrial significance. PMID:27826289

Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia.

PubMed

Enokizono, Mikako; Aida, Noriko; Niwa, Tetsu; Osaka, Hitoshi; Naruto, Takuya; Kurosawa, Kenji; Ohba, Chihiro; Suzuki, Toshifumi; Saitsu, Hirotomo; Goto, Tomohide; Matsumoto, Naomichi

2017-05-15

Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations. Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations). In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP). The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS. Copyright © 2017 Elsevier B.V. All rights reserved.

Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans

PubMed Central

Zheng, Chaogu; Diaz-Cuadros, Margarete; Nguyen, Ken C. Q.; Hall, David H.; Chalfie, Martin

2017-01-01

Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an α-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization. PMID:28835377

Frameshift Suppression in SACCHAROMYCES CEREVISIAE. III. Isolation and Genetic Properties of Group III Suppressors

PubMed Central

Cummins, Claudia M.; Gaber, Richard F.; Culbertson, Michael R.; Mann, Richard; Fink, Gerald R.

1980-01-01

Suppressors of ICR-induced mutations that exhibit behavior similar to bacterial frameshift suppressors have been identified in the yeast Saccharomyces cerevisiae. The yeast suppressors have been divided into two groups. Previous evidence indicated that suppressors of one group (Group II: SUF1, SUF3, SUF4, SUF5 and SUF6) represent mutations in the structural genes for glycyl-tRNA's. Suppressors of the other group (Group III: SUF2 and SUF7) were less well characterized. Although they suppressed some ICR-revertible mutations, they failed to suppress Group II frameshift mutations. This communication provides a more thorough characterization of the Group III suppressors and describes the isolation and properties of four new suppressors in that group (SUF8, SUF9, SUF10 and suf11).——In our original study, Group III suppressors were isolated as revertants of the Group III mutations his4–712 and his4–713. All suppressors obtained as ICR-induced revertants of these mutations mapped at the SUF2 locus near the centromere of chromosome III. Suppressors mapping at other loci were obtained in this study by analyzing spontaneous and UV-induced revertants of the Group III mutations. SUF2 and SUF10 suppress both Group III his4 mutations, whereas SUF7, SUF8, SUF9 and suf11 suppress his4–713, but not his4–712. All of the suppressors except suf11 are dominant in diploids homozygous for his4-713. The suppressors fail to suppress representative UAA, UAG and UGA nonsense mutations.——SUF9 is linked to the centromere of chromosome VI, and SUF10 is linked to the centromere of chromosome XIV. A triploid mapping procedure was used to determine the chromosome locations of SUF7 and SUF8. Subsequent standard crosses revealed linkage of SUF7 to cdc5 on chromosome XIII and linkage of SUF8 to cdc12 and pet3 on chromosome VIII. PMID:7009319

Incorporating Functional Annotations for Fine-Mapping Causal Variants in a Bayesian Framework Using Summary Statistics.

PubMed

Chen, Wenan; McDonnell, Shannon K; Thibodeau, Stephen N; Tillmans, Lori S; Schaid, Daniel J

2016-11-01

Functional annotations have been shown to improve both the discovery power and fine-mapping accuracy in genome-wide association studies. However, the optimal strategy to incorporate the large number of existing annotations is still not clear. In this study, we propose a Bayesian framework to incorporate functional annotations in a systematic manner. We compute the maximum a posteriori solution and use cross validation to find the optimal penalty parameters. By extending our previous fine-mapping method CAVIARBF into this framework, we require only summary statistics as input. We also derived an exact calculation of Bayes factors using summary statistics for quantitative traits, which is necessary when a large proportion of trait variance is explained by the variants of interest, such as in fine mapping expression quantitative trait loci (eQTL). We compared the proposed method with PAINTOR using different strategies to combine annotations. Simulation results show that the proposed method achieves the best accuracy in identifying causal variants among the different strategies and methods compared. We also find that for annotations with moderate effects from a large annotation pool, screening annotations individually and then combining the top annotations can produce overly optimistic results. We applied these methods on two real data sets: a meta-analysis result of lipid traits and a cis-eQTL study of normal prostate tissues. For the eQTL data, incorporating annotations significantly increased the number of potential causal variants with high probabilities. Copyright © 2016 by the Genetics Society of America.

QTL fine mapping with Bayes C(π): a simulation study.

PubMed

van den Berg, Irene; Fritz, Sébastien; Boichard, Didier

2013-06-19

Accurate QTL mapping is a prerequisite in the search for causative mutations. Bayesian genomic selection models that analyse many markers simultaneously should provide more accurate QTL detection results than single-marker models. Our objectives were to (a) evaluate by simulation the influence of heritability, number of QTL and number of records on the accuracy of QTL mapping with Bayes Cπ and Bayes C; (b) estimate the QTL status (homozygous vs. heterozygous) of the individuals analysed. This study focussed on the ten largest detected QTL, assuming they are candidates for further characterization. Our simulations were based on a true dairy cattle population genotyped for 38,277 phased markers. Some of these markers were considered biallelic QTL and used to generate corresponding phenotypes. Different numbers of records (4387 and 1500), heritability values (0.1, 0.4 and 0.7) and numbers of QTL (10, 100 and 1000) were studied. QTL detection was based on the posterior inclusion probability for individual markers, or on the sum of the posterior inclusion probabilities for consecutive markers, estimated using Bayes C or Bayes Cπ. The QTL status of the individuals was derived from the contrast between the sums of the SNP allelic effects of their chromosomal segments. The proportion of markers with null effect (π) frequently did not reach convergence, leading to poor results for Bayes Cπ in QTL detection. Fixing π led to better results. Detection of the largest QTL was most accurate for medium to high heritability, for low to moderate numbers of QTL, and with a large number of records. The QTL status was accurately inferred when the distribution of the contrast between chromosomal segment effects was bimodal. QTL detection is feasible with Bayes C. For QTL detection, it is recommended to use a large dataset and to focus on highly heritable traits and on the largest QTL. QTL statuses were inferred based on the distribution of the contrast between chromosomal segment effects.

CDMBE: A Case Description Model Based on Evidence

PubMed Central

Zhu, Jianlin; Yang, Xiaoping; Zhou, Jing

2015-01-01

By combining the advantages of argument map and Bayesian network, a case description model based on evidence (CDMBE), which is suitable to continental law system, is proposed to describe the criminal cases. The logic of the model adopts the credibility logical reason and gets evidence-based reasoning quantitatively based on evidences. In order to consist with practical inference rules, five types of relationship and a set of rules are defined to calculate the credibility of assumptions based on the credibility and supportability of the related evidences. Experiments show that the model can get users' ideas into a figure and the results calculated from CDMBE are in line with those from Bayesian model. PMID:26421006

Correlation between Relatives given Complete Genotypes: from Identity by Descent to Identity by Function

PubMed Central

Sverdlov, Serge; Thompson, Elizabeth A.

2013-01-01

In classical quantitative genetics, the correlation between the phenotypes of individuals with unknown genotypes and a known pedigree relationship is expressed in terms of probabilities of IBD states. In existing approaches to the inverse problem where genotypes are observed but pedigree relationships are not, dependence between phenotypes is either modeled as Bayesian uncertainty or mapped to an IBD model via inferred relatedness parameters. Neither approach yields a relationship between genotypic similarity and phenotypic similarity with a probabilistic interpretation corresponding to a generative model. We introduce a generative model for diploid allele effect based on the classic infinite allele mutation process. This approach motivates the concept of IBF (Identity by Function). The phenotypic covariance between two individuals given their diploid genotypes is expressed in terms of functional identity states. The IBF parameters define a genetic architecture for a trait without reference to specific alleles or population. Given full genome sequences, we treat a gene-scale functional region, rather than a SNP, as a QTL, modeling patterns of dominance for multiple alleles. Applications demonstrated by simulation include phenotype and effect prediction and association, and estimation of heritability and classical variance components. A simulation case study of the Missing Heritability problem illustrates a decomposition of heritability under the IBF framework into Explained and Unexplained components. PMID:23851163

Bayesian spatio-temporal discard model in a demersal trawl fishery

NASA Astrophysics Data System (ADS)

Grazia Pennino, M.; Muñoz, Facundo; Conesa, David; López-Quílez, Antonio; Bellido, José M.

2014-07-01

Spatial management of discards has recently been proposed as a useful tool for the protection of juveniles, by reducing discard rates and can be used as a buffer against management errors and recruitment failure. In this study Bayesian hierarchical spatial models have been used to analyze about 440 trawl fishing operations of two different metiers, sampled between 2009 and 2012, in order to improve our understanding of factors that influence the quantity of discards and to identify their spatio-temporal distribution in the study area. Our analysis showed that the relative importance of each variable was different for each metier, with a few similarities. In particular, the random vessel effect and seasonal variability were identified as main driving variables for both metiers. Predictive maps of the abundance of discards and maps of the posterior mean of the spatial component show several hot spots with high discard concentration for each metier. We argue how the seasonal/spatial effects, and the knowledge about the factors influential to discarding, could potentially be exploited as potential mitigation measures for future fisheries management strategies. However, misidentification of hotspots and uncertain predictions can culminate in inappropriate mitigation practices which can sometimes be irreversible. The proposed Bayesian spatial method overcomes these issues, since it offers a unified approach which allows the incorporation of spatial random-effect terms, spatial correlation of the variables and the uncertainty of the parameters in the modeling process, resulting in a better quantification of the uncertainty and accurate predictions.

Pixel-based skin segmentation in psoriasis images.

PubMed

George, Y; Aldeen, M; Garnavi, R

2016-08-01

In this paper, we present a detailed comparison study of skin segmentation methods for psoriasis images. Different techniques are modified and then applied to a set of psoriasis images acquired from the Royal Melbourne Hospital, Melbourne, Australia, with aim of finding the best technique suited for application to psoriasis images. We investigate the effect of different colour transformations on skin detection performance. In this respect, explicit skin thresholding is evaluated with three different decision boundaries (CbCr, HS and rgHSV). Histogram-based Bayesian classifier is applied to extract skin probability maps (SPMs) for different colour channels. This is then followed by using different approaches to find a binary skin map (SM) image from the SPMs. The approaches used include binary decision tree (DT) and Otsu's thresholding. Finally, a set of morphological operations are implemented to refine the resulted SM image. The paper provides detailed analysis and comparison of the performance of the Bayesian classifier in five different colour spaces (YCbCr, HSV, RGB, XYZ and CIELab). The results show that histogram-based Bayesian classifier is more effective than explicit thresholding, when applied to psoriasis images. It is also found that decision boundary CbCr outperforms HS and rgHSV. Another finding is that the SPMs of Cb, Cr, H and B-CIELab colour bands yield the best SMs for psoriasis images. In this study, we used a set of 100 psoriasis images for training and testing the presented methods. True Positive (TP) and True Negative (TN) are used as statistical evaluation measures.

Bayesian decoding using unsorted spikes in the rat hippocampus

PubMed Central

Layton, Stuart P.; Chen, Zhe; Wilson, Matthew A.

2013-01-01

A fundamental task in neuroscience is to understand how neural ensembles represent information. Population decoding is a useful tool to extract information from neuronal populations based on the ensemble spiking activity. We propose a novel Bayesian decoding paradigm to decode unsorted spikes in the rat hippocampus. Our approach uses a direct mapping between spike waveform features and covariates of interest and avoids accumulation of spike sorting errors. Our decoding paradigm is nonparametric, encoding model-free for representing stimuli, and extracts information from all available spikes and their waveform features. We apply the proposed Bayesian decoding algorithm to a position reconstruction task for freely behaving rats based on tetrode recordings of rat hippocampal neuronal activity. Our detailed decoding analyses demonstrate that our approach is efficient and better utilizes the available information in the nonsortable hash than the standard sorting-based decoding algorithm. Our approach can be adapted to an online encoding/decoding framework for applications that require real-time decoding, such as brain-machine interfaces. PMID:24089403

Deletion Mapping of zwf, the Gene for a Constitutive Enzyme, Glucose 6-Phosphate Dehydrogenase in ESCHERICHIA COLI

PubMed Central

Fraenkel, D. G.; Banerjee, Santimoy

1972-01-01

Genes for three enzymes of intermediary sugar metabolism in E. coli, zwf (glucose 6-phosphate dehydrogenase, constitutive), edd (gluconate 6-phosphate dehydrase, inducible), and eda (2-keto-3-deoxygluconate 6-phosphate aldolase, differently inducible) are closely linked on the E. coli genetic map, the overall gene order being man... old... eda. edd. zwf... cheB... uvrC... his. One class of apparent revertants of an eda mutant strain contains a secondary mutation in edd, and some of these mutations are deletions extending into zwf. We have used a series of spontaneous edd-zwf deletions to map a series of point mutants in zwf and thus report the first fine structure map of a gene for a constitutive enzyme (zwf). PMID:4560065

Mapping Interaction Sites on Human Chemokine Receptors by Deep Mutational Scanning.

PubMed

Heredia, Jeremiah D; Park, Jihye; Brubaker, Riley J; Szymanski, Steven K; Gill, Kevin S; Procko, Erik

2018-06-01

Chemokine receptors CXCR4 and CCR5 regulate WBC trafficking and are engaged by the HIV-1 envelope glycoprotein gp120 during infection. We combine a selection of human CXCR4 and CCR5 libraries comprising nearly all of ∼7000 single amino acid substitutions with deep sequencing to define sequence-activity landscapes for surface expression and ligand interactions. After consideration of sequence constraints for surface expression, known interaction sites with HIV-1-blocking Abs were appropriately identified as conserved residues following library sorting for Ab binding, validating the use of deep mutational scanning to map functional interaction sites in G protein-coupled receptors. Chemokine CXCL12 was found to interact with residues extending asymmetrically into the CXCR4 ligand-binding cavity, similar to the binding surface of CXCR4 recognized by an antagonistic viral chemokine previously observed crystallographically. CXCR4 mutations distal from the chemokine binding site were identified that enhance chemokine recognition. This included disruptive mutations in the G protein-coupling site that diminished calcium mobilization, as well as conservative mutations to a membrane-exposed site (CXCR4 residues H79 2.45 and W161 4.50 ) that increased ligand binding without loss of signaling. Compared with CXCR4-CXCL12 interactions, CCR5 residues conserved for gp120 (HIV-1 BaL strain) interactions map to a more expansive surface, mimicking how the cognate chemokine CCL5 makes contacts across the entire CCR5 binding cavity. Acidic substitutions in the CCR5 N terminus and extracellular loops enhanced gp120 binding. This study demonstrates how comprehensive mutational scanning can define functional interaction sites on receptors, and novel mutations that enhance receptor activities can be found simultaneously. Copyright © 2018 by The American Association of Immunologists, Inc.

Mutations affecting transport of the hexitols D-mannitol, D-glucitol, and galactitol in Escherichia coli K-12: isolation and mapping.

PubMed Central

Lengeler, J

1975-01-01

Mutants of Escherichia coli K-12 unable to grow on any of the three naturally occurring hexitols D-manitol, D-glucitol, and galactitol and, among these specifically, mutants with altered transport and phosphorylating activity have been isolated. Different isolation procedures have been utilized, including suicide by D-[3H]mannitol, chemotaxis, and resistance to the toxic hexitol analogue 2-deoxy-arabino-hexitol. Mutations thus obtained have been mapped in four distinct operons. (i) Mutations affecting an enzyme II-complexmt1 activity of the phosphoenolpyruvate-dependent phosphotransferase system all map in gene mtlA. This gene has previously been shown (Solomon and Lin, 1972) to be part of an operon, mtl, located at 71 min on the E. coli linkage map containing, in addition to mtlA, the cis-dominant regulatory gene mtlC and mtlD, the structural gene for the enzyme D-mannitol-1-phosphate dehydrogenase. The gene order in this operon, induced by D-mannitol, is mtlC A D. (ii) Mutations in gene gutA affecting a second enzyme II-complexgut of the phosphotransferase system map at 51 min, clustered in operon gutC A D together with the cis-dominant regulatory gene gutC and the structural gene gutD for the enzyme D-glucitol-6-phosphate dehydrogenase. The gut operon, previously called sbl or srl, is induced by D-glucitol. (iii) Mutations affecting the transport and catabolism of galactitol are clustered in a third operon, gatC A D, located at 40.5 min. This operon again contains a cis-dominant regulatory gene, gatC, the structural gene gatD for galactitol-1-phosphate dehydrogenase, and gene gatA coding for a thrid hexitol-specific enzyme II-complexgat. Other genes coding for two additional enzymes involved in galactitol catabolism apparently are not linked to gatC A D. (iv) A fourth class of mutants pleiotropically negative for hexitol growth and transport maps in the pts operon. Triple-negative mutants (mtlA gutA gatA) do not have further transport or phosphorylating activity for any of the three hexitols. PMID:1100602

p53 regulates ERK1/2/CREB cascade via a novel SASH1/MAP2K2 crosstalk to induce hyperpigmentation.

PubMed

Zhou, Ding'an; Kuang, Zhongshu; Zeng, Xing; Wang, Ke; Ma, Jiangshu; Luo, Huangchao; Chen, Mei; Li, Yan; Zeng, Jiawei; Li, Shu; Luan, Fujun; He, Yong; Dai, Hongying; Liu, Beizhong; Li, Hui; He, Lin; Xing, Qinghe

2017-10-01

We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH1 binds with MAP2K2 and is induced by p53-POMC-MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis-specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53-POMC-MC1R cascade to cause hyperpigmentation phenotype of DUH. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Linkage disequilibrium between STRPs and SNPs across the human genome.

PubMed

Payseur, Bret A; Place, Michael; Weber, James L

2008-05-01

Patterns of linkage disequilibrium (LD) reveal the action of evolutionary processes and provide crucial information for association mapping of disease genes. Although recent studies have described the landscape of LD among single nucleotide polymorphisms (SNPs) from across the human genome, associations involving other classes of molecular variation remain poorly understood. In addition to recombination and population history, mutation rate and process are expected to shape LD. To test this idea, we measured associations between short-tandem-repeat polymorphisms (STRPs), which can mutate rapidly and recurrently, and SNPs in 721 regions across the human genome. We directly compared STRP-SNP LD with SNP-SNP LD from the same genomic regions in the human HapMap populations. The intensity of STRP-SNP LD, measured by the average of D', was reduced, consistent with the action of recurrent mutation. Nevertheless, a higher fraction of STRP-SNP pairs than SNP-SNP pairs showed significant LD, on both short (up to 50 kb) and long (cM) scales. These results reveal the substantial effects of mutational processes on LD at STRPs and provide important measures of the potential of STRPs for association mapping of disease genes.

Single-cell paired-end genome sequencing reveals structural variation per cell cycle

PubMed Central

Voet, Thierry; Kumar, Parveen; Van Loo, Peter; Cooke, Susanna L.; Marshall, John; Lin, Meng-Lay; Zamani Esteki, Masoud; Van der Aa, Niels; Mateiu, Ligia; McBride, David J.; Bignell, Graham R.; McLaren, Stuart; Teague, Jon; Butler, Adam; Raine, Keiran; Stebbings, Lucy A.; Quail, Michael A.; D’Hooghe, Thomas; Moreau, Yves; Futreal, P. Andrew; Stratton, Michael R.; Vermeesch, Joris R.; Campbell, Peter J.

2013-01-01

The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis. PMID:23630320

Intragenic Mapping of Chemically Induced ad-7 Mutants of Schizosaccharomyces pombe

PubMed Central

Loprieno, Nicola

1967-01-01

Thirty adenine-requiring ad-7 mutants of Schizosaccharomyces pombe, induced by ethylmethanesulfonate, methyl-methanesulfonate, and hydroxylamine and exhibiting low spontaneous reversion frequencies, were located by intragenic recombination analysis. Their identification as ad-7 mutants was assessed in relation to two previously mapped ad-7 mutants. Each mutant was found to occupy a distinct mutational site; the smallest recombination fraction observed between the two closest mutational sites was of the order of 0.5 × 10−6. PMID:6051345

Identification and Characterization of Genes Required for Early Myxococcus xanthus Developmental Gene Expression

PubMed Central

Guo, Dongchuan; Wu, Yun; Kaplan, Heidi B.

2000-01-01

Starvation and cell density regulate the developmental expression of Myxococcus xanthus gene 4521. Three classes of mutants allow expression of this developmental gene during growth on nutrient agar, such that colonies of strains containing a Tn5 lac Ω4521 fusion are Lac+. One class of these mutants inactivates SasN, a negative regulator of 4521 expression; another class activates SasS, a sensor kinase-positive regulator of 4521 expression; and a third class blocks lipopolysaccharide (LPS) O-antigen biosynthesis. To identify additional positive regulators of 4521 expression, 11 Lac− TnV.AS transposon insertion mutants were isolated from a screen of 18,000 Lac+ LPS O-antigen mutants containing Tn5 lac Ω4521 (Tcr). Ten mutations identified genes that could encode positive regulators of 4521 developmental expression based on their ability to abolish 4521 expression during development in the absence of LPS O antigen and in an otherwise wild-type background. Eight of these mutations mapped to the sasB locus, which encodes the known 4521 regulators SasS and SasN. One mapped to sasS, whereas seven identified new genes. Three mutations mapped to a gene encoding an NtrC-like response regulator homologue, designated sasR, and four others mapped to a gene designated sasP. One mutation, designated ssp10, specifically suppressed the LPS O-antigen defect; the ssp10 mutation had no effect on 4521 expression in an otherwise wild-type background but reduced 4521 developmental expression in the absence of LPS O antigen to a level close to that of the parent strain. All of the mutations except those in sasP conferred defects during growth and development. These data indicate that a number of elements are required for 4521 developmental expression and that most of these are necessary for normal growth and fruiting body development. PMID:10913090

VizieR Online Data Catalog: X-ray sources in the AKARI NEP deep field (Krumpe+, 2015)

NASA Astrophysics Data System (ADS)

Krumpe, M.; Miyaji, T.; Brunner, H.; Hanami, H.; Ishigaki, T.; Takagi, T.; Markowitz, A. G.; Goto, T.; Malkan, M. A.; Matsuhara, H.; Pearson, C.; Ueda, Y.; Wada, T.

2015-06-01

The fits images labelled SeMap* are the sensitivity maps in which we give the minimum flux that would have caused a detection at each position. This flux depends on the maximum likelihood threshold chosen in the source detection run, the point spread function, and the background level at the chosen position. We create sensitivity maps in different energy bands (0.5-2, 0.5-7, 2-4, 2-7, and 4-7keV) by searching for the flux to reject the null-hypothesis that the flux at a given position is only caused by a background fluctuation. In a chosen energy band, we determine for each position in the survey the flux required to obtain a certain Poisson probability above the background counts. Since ML=-ln(P), we know from our ML=12 threshold the probability we are aiming for. In practice, we search for a value of -ln P_total that falls within Delta ML=+/-0.2 of our targeted ML threshold. This tolerance range corresponds to having one spurious source more or less in the whole survey. Note, that outside the deep Subaru/Suprime-Cam imaging the sensitivity maps should be used with caution since we assume for their generation a ML=12 over the whole area covered by Chandra. More details on the procedure of producing the sensitivity maps, including the PSF-summed background map and PSF-weighted averaged exposure maps are given in the paper, section 5.3. The fits images labelled u90* are the upper limit maps, where the upper 90 per cent confidence flux limit is given at each position. We take a Bayesian approach following Kraft, Burrows & Nousek, 1991ApJ...374..344K. Consequently, we obtain the upper 90~per cent confidence flux limit by searching for the flux such that given the observed counts the Bayesian probability of having this flux or larger is 10~per cent. More details on the procedure of producing the upper 90 per cent flux limit maps are given in the paper, section 5.4. (6 data files).

Inference of pain stimulus level from stereotypical behavioral response of C.elegans allows quantification of effects of anesthesia and mutation

NASA Astrophysics Data System (ADS)

Leung, Kawai; Mohammadi, Aylia; Ryu, William; Nemenman, Ilya

In animals, we must infer the pain level from experimental characterization of behavior. This is not trivial since behaviors are very complex and multidimensional. To establish C.elegans as a model for pain research, we propose for the first time a quantitative model that allows inference of a thermal nociceptive stimulus level from the behavior of an individual worm. We apply controlled levels of pain by locally heating worms with an infrared laser and capturing the subsequent behavior. We discover that the behavioral response is a product of stereotypical behavior and a nonlinear function of the strength of stimulus. The same stereotypical behavior is observed in normal, anesthetized and mutated worms. From this result we build a Bayesian model to infer the strength of laser stimulus from the behavior. This model allows us to measure the efficacy of anaesthetization and mutation by comparing the inferred strength of stimulus. Based on the measured nociceptive escape of over 200 worms, our model is able to significantly differentiate normal, anaesthetized and mutated worms with 40 worm samples. This work was partially supported by NSF Grant No. IOS/1208126 and HFSP Grant No. RGY0084/.

Speech Enhancement, Gain, and Noise Spectrum Adaptation Using Approximate Bayesian Estimation

PubMed Central

Hao, Jiucang; Attias, Hagai; Nagarajan, Srikantan; Lee, Te-Won; Sejnowski, Terrence J.

2010-01-01

This paper presents a new approximate Bayesian estimator for enhancing a noisy speech signal. The speech model is assumed to be a Gaussian mixture model (GMM) in the log-spectral domain. This is in contrast to most current models in frequency domain. Exact signal estimation is a computationally intractable problem. We derive three approximations to enhance the efficiency of signal estimation. The Gaussian approximation transforms the log-spectral domain GMM into the frequency domain using minimal Kullback–Leiber (KL)-divergency criterion. The frequency domain Laplace method computes the maximum a posteriori (MAP) estimator for the spectral amplitude. Correspondingly, the log-spectral domain Laplace method computes the MAP estimator for the log-spectral amplitude. Further, the gain and noise spectrum adaptation are implemented using the expectation–maximization (EM) algorithm within the GMM under Gaussian approximation. The proposed algorithms are evaluated by applying them to enhance the speeches corrupted by the speech-shaped noise (SSN). The experimental results demonstrate that the proposed algorithms offer improved signal-to-noise ratio, lower word recognition error rate, and less spectral distortion. PMID:20428253

Truncating mutation in the NHS gene: phenotypic heterogeneity of Nance-Horan syndrome in an asian Indian family.

PubMed

Ramprasad, Vedam Lakshmi; Thool, Alka; Murugan, Sakthivel; Nancarrow, Derek; Vyas, Prateep; Rao, Srinivas Kamalakar; Vidhya, Authiappan; Ravishankar, Krishnamoorthy; Kumaramanickavel, Govindasamy

2005-01-01

A four-generation family containing eight affected males who inherited X-linked developmental lens opacity and microcornea was studied. Some members in the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. The purpose of the study was to map genetically the gene in the large 57-live-member Asian-Indian pedigree. PCR-based genotyping was performed on the X-chromosome, by using fluorescent microsatellite markers (10-cM intervals). Parametric linkage analysis was performed by using two disease models, assuming either recessive or dominant X-linked transmission by the MLINK/ILINK and FASTLINK (version 4.1P) programs (http:www.hgmp.mrc.ac.uk/; provided in the public domain by the Human Genome Mapping Project Resources Centre, Cambridge, UK). The NHS gene at the linked region was screened for mutation. By fine mapping, the disease gene was localized to Xp22.13. Multipoint analysis placed the peak LOD of 4.46 at DSX987. The NHS gene mapped to this region. Mutational screening in all the affected males and carrier females (heterozygous form) revealed a truncating mutation 115C-->T in exon 1, resulting in conversion of glutamine to stop codon (Q39X), but was not observed in unaffected individuals and control subjects. conclusions. A family with X-linked Nance-Horan syndrome had severe ocular, but mild to moderate nonocular, features. The clinical phenotype of the truncating mutation (Q39X) in the NHS gene suggests allelic heterogeneity at the NHS locus or the presence of modifier genes. X-linked families with cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.

Development and implementation of a Bayesian-based aquifer vulnerability assessment in Florida

USGS Publications Warehouse

Arthur, J.D.; Wood, H.A.R.; Baker, A.E.; Cichon, J.R.; Raines, G.L.

2007-01-01

The Florida Aquifer Vulnerability Assessment (FAVA) was designed to provide a tool for environmental, regulatory, resource management, and planning professionals to facilitate protection of groundwater resources from surface sources of contamination. The FAVA project implements weights-of-evidence (WofE), a data-driven, Bayesian-probabilistic model to generate a series of maps reflecting relative aquifer vulnerability of Florida's principal aquifer systems. The vulnerability assessment process, from project design to map implementation is described herein in reference to the Floridan aquifer system (FAS). The WofE model calculates weighted relationships between hydrogeologic data layers that influence aquifer vulnerability and ambient groundwater parameters in wells that reflect relative degrees of vulnerability. Statewide model input data layers (evidential themes) include soil hydraulic conductivity, density of karst features, thickness of aquifer confinement, and hydraulic head difference between the FAS and the watertable. Wells with median dissolved nitrogen concentrations exceeding statistically established thresholds serve as training points in the WofE model. The resulting vulnerability map (response theme) reflects classified posterior probabilities based on spatial relationships between the evidential themes and training points. The response theme is subjected to extensive sensitivity and validation testing. Among the model validation techniques is calculation of a response theme based on a different water-quality indicator of relative recharge or vulnerability: dissolved oxygen. Successful implementation of the FAVA maps was facilitated by the overall project design, which included a needs assessment and iterative technical advisory committee input and review. Ongoing programs to protect Florida's springsheds have led to development of larger-scale WofE-based vulnerability assessments. Additional applications of the maps include land-use planning amendments and prioritization of land purchases to protect groundwater resources. ?? International Association for Mathematical Geology 2007.

Bayesian mapping of HIV infection among women of reproductive age in Rwanda.

PubMed

Niragire, François; Achia, Thomas N O; Lyambabaje, Alexandre; Ntaganira, Joseph

2015-01-01

HIV prevalence is rising and has been consistently higher among women in Rwanda whereas a decreasing national HIV prevalence rate in the adult population has stabilised since 2005. Factors explaining the increased vulnerability of women to HIV infection are not currently well understood. A statistical mapping at smaller geographic units and the identification of key HIV risk factors are crucial for pragmatic and more efficient interventions. The data used in this study were extracted from the 2010 Rwanda Demographic and Health Survey data for 6952 women. A full Bayesian geo-additive logistic regression model was fitted to data in order to assess the effect of key risk factors and map district-level spatial effects on the risk of HIV infection. The results showed that women who had STIs, concurrent sexual partners in the 12 months prior to the survey, a sex debut at earlier age than 19 years, were living in a woman-headed or high-economic status household were significantly associated with a higher risk of HIV infection. There was a protective effect of high HIV knowledge and perception. Women occupied in agriculture, and those residing in rural areas were also associated with lower risk of being infected. This study provides district-level maps of the variation of HIV infection among women of child-bearing age in Rwanda. The maps highlight areas where women are at a higher risk of infection; the aspect that proximate and distal factors alone could not uncover. There are distinctive geographic patterns, although statistically insignificant, of the risk of HIV infection suggesting potential effectiveness of district specific interventions. The results also suggest that changes in sexual behaviour can yield significant results in controlling HIV infection in Rwanda.

Bayesian Mapping of HIV Infection among Women of Reproductive Age in Rwanda

PubMed Central

Niragire, François; Achia, Thomas N. O.; Lyambabaje, Alexandre; Ntaganira, Joseph

2015-01-01

HIV prevalence is rising and has been consistently higher among women in Rwanda whereas a decreasing national HIV prevalence rate in the adult population has stabilised since 2005. Factors explaining the increased vulnerability of women to HIV infection are not currently well understood. A statistical mapping at smaller geographic units and the identification of key HIV risk factors are crucial for pragmatic and more efficient interventions. The data used in this study were extracted from the 2010 Rwanda Demographic and Health Survey data for 6952 women. A full Bayesian geo-additive logistic regression model was fitted to data in order to assess the effect of key risk factors and map district-level spatial effects on the risk of HIV infection. The results showed that women who had STIs, concurrent sexual partners in the 12 months prior to the survey, a sex debut at earlier age than 19 years, were living in a woman-headed or high-economic status household were significantly associated with a higher risk of HIV infection. There was a protective effect of high HIV knowledge and perception. Women occupied in agriculture, and those residing in rural areas were also associated with lower risk of being infected. This study provides district-level maps of the variation of HIV infection among women of child-bearing age in Rwanda. The maps highlight areas where women are at a higher risk of infection; the aspect that proximate and distal factors alone could not uncover. There are distinctive geographic patterns, although statistically insignificant, of the risk of HIV infection suggesting potential effectiveness of district specific interventions. The results also suggest that changes in sexual behaviour can yield significant results in controlling HIV infection in Rwanda. PMID:25811462

A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations.

PubMed

Munford, V; Castro, L P; Souto, R; Lerner, L K; Vilar, J B; Quayle, C; Asif, H; Schuch, A P; de Souza, T A; Ienne, S; Alves, F I A; Moura, L M S; Galante, P A F; Camargo, A A; Liboredo, R; Pena, S D J; Sarasin, A; Chaibub, S C; Menck, C F M

2017-05-01

Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants). To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe. © 2016 British Association of Dermatologists.

Fast Homozygosity Mapping and Identification of a Zebrafish ENU-Induced Mutation by Whole-Genome Sequencing

PubMed Central

Voz, Marianne L.; Coppieters, Wouter; Manfroid, Isabelle; Baudhuin, Ariane; Von Berg, Virginie; Charlier, Carole; Meyer, Dirk; Driever, Wolfgang; Martial, Joseph A.; Peers, Bernard

2012-01-01

Forward genetics using zebrafish is a powerful tool for studying vertebrate development through large-scale mutagenesis. Nonetheless, the identification of the molecular lesion is still laborious and involves time-consuming genetic mapping. Here, we show that high-throughput sequencing of the whole zebrafish genome can directly locate the interval carrying the causative mutation and at the same time pinpoint the molecular lesion. The feasibility of this approach was validated by sequencing the m1045 mutant line that displays a severe hypoplasia of the exocrine pancreas. We generated 13 Gb of sequence, equivalent to an eightfold genomic coverage, from a pool of 50 mutant embryos obtained from a map-cross between the AB mutant carrier and the WIK polymorphic strain. The chromosomal region carrying the causal mutation was localized based on its unique property to display high levels of homozygosity among sequence reads as it derives exclusively from the initial AB mutated allele. We developed an algorithm identifying such a region by calculating a homozygosity score along all chromosomes. This highlighted an 8-Mb window on chromosome 5 with a score close to 1 in the m1045 mutants. The sequence analysis of all genes within this interval revealed a nonsense mutation in the snapc4 gene. Knockdown experiments confirmed the assertion that snapc4 is the gene whose mutation leads to exocrine pancreas hypoplasia. In conclusion, this study constitutes a proof-of-concept that whole-genome sequencing is a fast and effective alternative to the classical positional cloning strategies in zebrafish. PMID:22496837

Improved Determination of the Myelin Water Fraction in Human Brain using Magnetic Resonance Imaging through Bayesian Analysis of mcDESPOT

PubMed Central

Bouhrara, Mustapha; Spencer, Richard G.

2015-01-01

Myelin water fraction (MWF) mapping with magnetic resonance imaging has led to the ability to directly observe myelination and demyelination in both the developing brain and in disease. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has been proposed as a rapid approach for multicomponent relaxometry and has been applied to map MWF in human brain. However, even for the simplest two-pool signal model consisting of MWF and non-myelin-associated water, the dimensionality of the parameter space for obtaining MWF estimates remains high. This renders parameter estimation difficult, especially at low-to-moderate signal-to-noise ratios (SNR), due to the presence of local minima and the flatness of the fit residual energy surface used for parameter determination using conventional nonlinear least squares (NLLS)-based algorithms. In this study, we introduce three Bayesian approaches for analysis of the mcDESPOT signal model to determine MWF. Given the high dimensional nature of mcDESPOT signal model, and, thereby, the high dimensional marginalizations over nuisance parameters needed to derive the posterior probability distribution of MWF parameter, the introduced Bayesian analyses use different approaches to reduce the dimensionality of the parameter space. The first approach uses normalization by average signal amplitude, and assumes that noise can be accurately estimated from signal-free regions of the image. The second approach likewise uses average amplitude normalization, but incorporates a full treatment of noise as an unknown variable through marginalization. The third approach does not use amplitude normalization and incorporates marginalization over both noise and signal amplitude. Through extensive Monte Carlo numerical simulations and analysis of in-vivo human brain datasets exhibiting a range of SNR and spatial resolution, we demonstrated the markedly improved accuracy and precision in the estimation of MWF using these Bayesian methods as compared to the stochastic region contraction (SRC) implementation of NLLS. PMID:26499810

PCR-RFLP to Detect Codon 248 Mutation in Exon 7 of "p53" Tumor Suppressor Gene

ERIC Educational Resources Information Center

Ouyang, Liming; Ge, Chongtao; Wu, Haizhen; Li, Suxia; Zhang, Huizhan

2009-01-01

Individual genome DNA was extracted fast from oral swab and followed up with PCR specific for codon 248 of "p53" tumor suppressor gene. "Msp"I restriction mapping showed the G-C mutation in codon 248, which closely relates to cancer susceptibility. Students learn the concepts, detection techniques, and research significance of point mutations or…

MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation.

PubMed

Kalay, Ersan; Uzumcu, Abdullah; Krieger, Elmar; Caylan, Refik; Uyguner, Oya; Ulubil-Emiroglu, Melike; Erdol, Hidayet; Kayserili, Hülya; Hafiz, Gunter; Başerer, Nermin; Heister, Angelien J G M; Hennies, Hans C; Nürnberg, Peter; Başaran, Seher; Brunner, Han G; Cremers, Cor W R J; Karaguzel, Ahmet; Wollnik, Bernd; Kremer, Hannie

2007-10-15

Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harboring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-->T (p.Gly1831Val) and a novel splice site mutation, c.8968-1G-->C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain. Copyright (c) 2007 Wiley-Liss, Inc.

Wavelet-Bayesian inference of cosmic strings embedded in the cosmic microwave background

NASA Astrophysics Data System (ADS)

McEwen, J. D.; Feeney, S. M.; Peiris, H. V.; Wiaux, Y.; Ringeval, C.; Bouchet, F. R.

2017-12-01

Cosmic strings are a well-motivated extension to the standard cosmological model and could induce a subdominant component in the anisotropies of the cosmic microwave background (CMB), in addition to the standard inflationary component. The detection of strings, while observationally challenging, would provide a direct probe of physics at very high-energy scales. We develop a framework for cosmic string inference from observations of the CMB made over the celestial sphere, performing a Bayesian analysis in wavelet space where the string-induced CMB component has distinct statistical properties to the standard inflationary component. Our wavelet-Bayesian framework provides a principled approach to compute the posterior distribution of the string tension Gμ and the Bayesian evidence ratio comparing the string model to the standard inflationary model. Furthermore, we present a technique to recover an estimate of any string-induced CMB map embedded in observational data. Using Planck-like simulations, we demonstrate the application of our framework and evaluate its performance. The method is sensitive to Gμ ∼ 5 × 10-7 for Nambu-Goto string simulations that include an integrated Sachs-Wolfe contribution only and do not include any recombination effects, before any parameters of the analysis are optimized. The sensitivity of the method compares favourably with other techniques applied to the same simulations.

Spatially constrained Bayesian inversion of frequency- and time-domain electromagnetic data from the Tellus projects

NASA Astrophysics Data System (ADS)

Kiyan, Duygu; Rath, Volker; Delhaye, Robert

2017-04-01

The frequency- and time-domain airborne electromagnetic (AEM) data collected under the Tellus projects of the Geological Survey of Ireland (GSI) which represent a wealth of information on the multi-dimensional electrical structure of Ireland's near-surface. Our project, which was funded by GSI under the framework of their Short Call Research Programme, aims to develop and implement inverse techniques based on various Bayesian methods for these densely sampled data. We have developed a highly flexible toolbox using Python language for the one-dimensional inversion of AEM data along the flight lines. The computational core is based on an adapted frequency- and time-domain forward modelling core derived from the well-tested open-source code AirBeo, which was developed by the CSIRO (Australia) and the AMIRA consortium. Three different inversion methods have been implemented: (i) Tikhonov-type inversion including optimal regularisation methods (Aster el al., 2012; Zhdanov, 2015), (ii) Bayesian MAP inversion in parameter and data space (e.g. Tarantola, 2005), and (iii) Full Bayesian inversion with Markov Chain Monte Carlo (Sambridge and Mosegaard, 2002; Mosegaard and Sambridge, 2002), all including different forms of spatial constraints. The methods have been tested on synthetic and field data. This contribution will introduce the toolbox and present case studies on the AEM data from the Tellus projects.

Planetary micro-rover operations on Mars using a Bayesian framework for inference and control

NASA Astrophysics Data System (ADS)

Post, Mark A.; Li, Junquan; Quine, Brendan M.

2016-03-01

With the recent progress toward the application of commercially-available hardware to small-scale space missions, it is now becoming feasible for groups of small, efficient robots based on low-power embedded hardware to perform simple tasks on other planets in the place of large-scale, heavy and expensive robots. In this paper, we describe design and programming of the Beaver micro-rover developed for Northern Light, a Canadian initiative to send a small lander and rover to Mars to study the Martian surface and subsurface. For a small, hardware-limited rover to handle an uncertain and mostly unknown environment without constant management by human operators, we use a Bayesian network of discrete random variables as an abstraction of expert knowledge about the rover and its environment, and inference operations for control. A framework for efficient construction and inference into a Bayesian network using only the C language and fixed-point mathematics on embedded hardware has been developed for the Beaver to make intelligent decisions with minimal sensor data. We study the performance of the Beaver as it probabilistically maps a simple outdoor environment with sensor models that include uncertainty. Results indicate that the Beaver and other small and simple robotic platforms can make use of a Bayesian network to make intelligent decisions in uncertain planetary environments.

Receptive Field Inference with Localized Priors

PubMed Central

Park, Mijung; Pillow, Jonathan W.

2011-01-01

The linear receptive field describes a mapping from sensory stimuli to a one-dimensional variable governing a neuron's spike response. However, traditional receptive field estimators such as the spike-triggered average converge slowly and often require large amounts of data. Bayesian methods seek to overcome this problem by biasing estimates towards solutions that are more likely a priori, typically those with small, smooth, or sparse coefficients. Here we introduce a novel Bayesian receptive field estimator designed to incorporate locality, a powerful form of prior information about receptive field structure. The key to our approach is a hierarchical receptive field model that flexibly adapts to localized structure in both spacetime and spatiotemporal frequency, using an inference method known as empirical Bayes. We refer to our method as automatic locality determination (ALD), and show that it can accurately recover various types of smooth, sparse, and localized receptive fields. We apply ALD to neural data from retinal ganglion cells and V1 simple cells, and find it achieves error rates several times lower than standard estimators. Thus, estimates of comparable accuracy can be achieved with substantially less data. Finally, we introduce a computationally efficient Markov Chain Monte Carlo (MCMC) algorithm for fully Bayesian inference under the ALD prior, yielding accurate Bayesian confidence intervals for small or noisy datasets. PMID:22046110

[Cardiofaciocutaneous syndrome, a Noonan syndrome related disorder: clinical and molecular findings in 11 patients].

PubMed

Carcavilla, Atilano; García-Miñaúr, Sixto; Pérez-Aytés, Antonio; Vendrell, Teresa; Pinto, Isabel; Guillén-Navarro, Encarna; González-Meneses, Antonio; Aoki, Yoko; Grinberg, Daniel; Ezquieta, Begoña

2015-01-20

To describe 11 patients with cardiofaciocutaneous syndrome (CFC) and compare them with 130 patients with other RAS-MAPK syndromes (111 Noonan syndrome patients [NS] and 19 patients with LEOPARD syndrome). Clinical data from patients submitted for genetic analysis were collected. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, and MAP2K1 focused on exons carrying recurrent mutations, and of all KRAS exons were performed. Six different mutations in BRAF were identified in 9 patients, as well as 2 MAP2K1 mutations. Short stature, developmental delay, language difficulties and ectodermal anomalies were more frequent in CFC patients when compared with other neuro-cardio-faciocutaneous syndromes (P<.05). In at least 2 cases molecular testing helped reconsider the diagnosis. CFC patients showed a rather severe phenotype but at least one patient with BRAF mutation showed no developmental delay, which illustrates the variability of the phenotypic spectrum caused by BRAF mutations. Molecular genetic testing is a valuable tool for differential diagnosis of CFC and NS related disorders. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

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

Fan, L.; Fuss, J.O.; Cheng, Q.J.

2009-05-18

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

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

Tainer, John; Fan, Li; Fuss, Jill O.

2008-06-02

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

Application of In Vitro Transposon Mutagenesis to Erythromycin Strain Improvement in Saccharopolyspora erythraea.

PubMed

Weber, J Mark; Reeves, Andrew; Cernota, William H; Wesley, Roy K

2017-01-01

Transposon mutagenesis is an invaluable technique in molecular biology for the creation of random mutations that can be easily identified and mapped. However, in the field of microbial strain improvement, transposon mutagenesis has scarcely been used; instead, chemical and physical mutagenic methods have been traditionally favored. Transposons have the advantage of creating single mutations in the genome, making phenotype to genotype assignments less challenging than with traditional mutagens which commonly create multiple mutations in the genome. The site of a transposon mutation can also be readily mapped using DNA sequencing primer sites engineered into the transposon termini. In this chapter an in vitro method for transposon mutagenesis of Saccharopolyspora erythraea is presented. Since in vivo transposon tools are not available for most actinomycetes including S. erythraea, an in vitro method was developed. The in vitro method involves a significant investment in time and effort to create the mutants, but once the mutants are made and screened, a large number of highly relevant mutations of direct interest to erythromycin production can be found.

A Parallel and Incremental Approach for Data-Intensive Learning of Bayesian Networks.

PubMed

Yue, Kun; Fang, Qiyu; Wang, Xiaoling; Li, Jin; Liu, Weiyi

2015-12-01

Bayesian network (BN) has been adopted as the underlying model for representing and inferring uncertain knowledge. As the basis of realistic applications centered on probabilistic inferences, learning a BN from data is a critical subject of machine learning, artificial intelligence, and big data paradigms. Currently, it is necessary to extend the classical methods for learning BNs with respect to data-intensive computing or in cloud environments. In this paper, we propose a parallel and incremental approach for data-intensive learning of BNs from massive, distributed, and dynamically changing data by extending the classical scoring and search algorithm and using MapReduce. First, we adopt the minimum description length as the scoring metric and give the two-pass MapReduce-based algorithms for computing the required marginal probabilities and scoring the candidate graphical model from sample data. Then, we give the corresponding strategy for extending the classical hill-climbing algorithm to obtain the optimal structure, as well as that for storing a BN by pairs. Further, in view of the dynamic characteristics of the changing data, we give the concept of influence degree to measure the coincidence of the current BN with new data, and then propose the corresponding two-pass MapReduce-based algorithms for BNs incremental learning. Experimental results show the efficiency, scalability, and effectiveness of our methods.

Bayesian validation of a serum and milk ELISA for antibodies against Mycobacterium avium subspecies paratuberculosis in Greek dairy goats across lactation.

PubMed

Angelidou, E; Kostoulas, P; Leontides, L

2014-02-01

We validated a commercial (Idexx Pourquier, Montpellier, France) serum and milk indirect ELISA that detects antibodies against Mycobacterium avium ssp. paratuberculosis (MAP) in Greek dairy goats. Each goat was sampled 4 times, starting from kidding and covering early, mid, and late lactation. A total of 1,268 paired milk (or colostrum) and serum samples were collected during the 7-mo lactation period. Bayesian latent class models, which allow for the continuous interpretation of test results, were used to derive the distribution of the serum and milk ELISA response for healthy and MAP-infected individuals at each lactation stage. Both serum and milk ELISA, in all lactation stages, had average and similar overall discriminatory ability as measured by the area under the curve (AUC). For each test, the smallest overlap between the distribution of the healthy and MAP-infected does was in late lactation. At this stage, the AUC was 0.89 (95% credible interval: 0.70; 0.98) and 0.92 (0.74; 0.99) for the milk and serum ELISA, respectively. Both tests had comparable sensitivities and specificities at the recommended cutoffs across lactation. Lowering the cutoffs led to an increase in sensitivity without serious loss in specificity. In conclusion, the milk ELISA was as accurate as the serum ELISA. Therefore, it could serve as the diagnostic tool of choice, especially during the implementation of MAP control programs that require frequent testing, because milk sampling is a noninvasive, rapid, and easy process. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Cosmological parameters, shear maps and power spectra from CFHTLenS using Bayesian hierarchical inference

NASA Astrophysics Data System (ADS)

Alsing, Justin; Heavens, Alan; Jaffe, Andrew H.

2017-04-01

We apply two Bayesian hierarchical inference schemes to infer shear power spectra, shear maps and cosmological parameters from the Canada-France-Hawaii Telescope (CFHTLenS) weak lensing survey - the first application of this method to data. In the first approach, we sample the joint posterior distribution of the shear maps and power spectra by Gibbs sampling, with minimal model assumptions. In the second approach, we sample the joint posterior of the shear maps and cosmological parameters, providing a new, accurate and principled approach to cosmological parameter inference from cosmic shear data. As a first demonstration on data, we perform a two-bin tomographic analysis to constrain cosmological parameters and investigate the possibility of photometric redshift bias in the CFHTLenS data. Under the baseline ΛCDM (Λ cold dark matter) model, we constrain S_8 = σ _8(Ω _m/0.3)^{0.5} = 0.67+0.03-0.03 (68 per cent), consistent with previous CFHTLenS analyses but in tension with Planck. Adding neutrino mass as a free parameter, we are able to constrain ∑mν < 4.6 eV (95 per cent) using CFHTLenS data alone. Including a linear redshift-dependent photo-z bias Δz = p2(z - p1), we find p_1=-0.25+0.53-0.60 and p_2 = -0.15+0.17-0.15, and tension with Planck is only alleviated under very conservative prior assumptions. Neither the non-minimal neutrino mass nor photo-z bias models are significantly preferred by the CFHTLenS (two-bin tomography) data.

Exploring links between juvenile offenders and social disorganization at a large map scale: a Bayesian spatial modeling approach

NASA Astrophysics Data System (ADS)

Law, Jane; Quick, Matthew

2013-01-01

This paper adopts a Bayesian spatial modeling approach to investigate the distribution of young offender residences in York Region, Southern Ontario, Canada, at the census dissemination area level. Few geographic researches have analyzed offender (as opposed to offense) data at a large map scale (i.e., using a relatively small areal unit of analysis) to minimize aggregation effects. Providing context is the social disorganization theory, which hypothesizes that areas with economic deprivation, high population turnover, and high ethnic heterogeneity exhibit social disorganization and are expected to facilitate higher instances of young offenders. Non-spatial and spatial Poisson models indicate that spatial methods are superior to non-spatial models with respect to model fit and that index of ethnic heterogeneity, residential mobility (1 year moving rate), and percentage of residents receiving government transfer payments are, respectively, the most significant explanatory variables related to young offender location. These findings provide overwhelming support for social disorganization theory as it applies to offender location in York Region, Ontario. Targeting areas where prevalence of young offenders could or could not be explained by social disorganization through decomposing the estimated risk map are helpful for dealing with juvenile offenders in the region. Results prompt discussion into geographically targeted police services and young offender placement pertaining to risk of recidivism. We discuss possible reasons for differences and similarities between the previous findings (that analyzed offense data and/or were conducted at a smaller map scale) and our findings, limitations of our study, and practical outcomes of this research from a law enforcement perspective.

The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse chromosome 10 homologous to 19p13.3

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

Kapfhamer, D.; Sufalko, D.; Warren, S.

1996-08-01

Jittery (ji) is a recessive mouse mutation on Chromosome 10 characterized by progressive ataxic gait, dystonic movements, spontaneus seizures, and death by dehydration/starvation before fertility. Recently, a viable neurological recessive mutation, hesitant, was discovered. It is characterized by hesitant, uncoordinated movements, exaggerated stepping of the hind limbs, and reduced fertility in males. In a complementation test and by genetic mapping we have shown here that hesitant and jittery are allelic. Using several large intersubspecific backcrosses and intercrosses we have genetically mapped ji near the marker Amh and microsatellite markers D10Mit7, D10Mit21, and D10Mit23. The linked region of mouse Chromosome 10more » is homologous to human 19p13.3, to which several human ataxia loci have recently been mapped. By excluding genes that map to human 21q22.3 (Pfkl) and 12q23 (Nfyb), we conclude that jittery is not likely to be a genetic mouse model for human Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) on 21q22.3 nor for spinocerebellar ataxia II (SCA2) on 12q22-q24. The closely linked markers presented here will facilitate positional cloning of the ji gene. 31 refs., 2 figs.« less

The BRAF{sup T1799A} mutation confers sensitivity of thyroid cancer cells to the BRAF{sup V600E} inhibitor PLX4032 (RG7204)

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

Xing, Joanna; Liu, Ruixin; Xing, Mingzhao

2011-01-28

Research highlights: {yields} Exciting therapeutic potential has been recently reported for the BRAF{sup V600E} inhibitor PLX4032 in melanoma. {yields} We tested the effects of PLX4032 on the growth of thyroid cancer cells which often harbor the BRAF{sup V600E} mutation. {yields} We observed a potent BRAF{sup V600E}-dependent inhibition of thyroid cancer cells by PLX4032. {yields} We thus demonstrated an important therapeutic potential of PLX4032 for thyroid cancer. -- Abstract: Aberrant signaling of the Ras-Raf-MEK-ERK (MAP kinase) pathway driven by the mutant kinase BRAF{sup V600E}, as a result of the BRAF{sup T1799A} mutation, plays a fundamental role in thyroid tumorigenesis. This studymore » investigated the therapeutic potential of a BRAF{sup V600E}-selective inhibitor, PLX4032 (RG7204), for thyroid cancer by examining its effects on the MAP kinase signaling and proliferation of 10 thyroid cancer cell lines with wild-type BRAF or BRAF{sup T1799A} mutation. We found that PLX4032 could effectively inhibit the MAP kinase signaling, as reflected by the suppression of ERK phosphorylation, in cells harboring the BRAF{sup T1799A} mutation. PLX4032 also showed a potent and BRAF mutation-selective inhibition of cell proliferation in a concentration-dependent manner. PLX4032 displayed low IC{sub 50} values (0.115-1.156 {mu}M) in BRAF{sup V600E} mutant cells, in contrast with wild-type BRAF cells that showed resistance to the inhibitor with high IC{sub 50} values (56.674-1349.788 {mu}M). Interestingly, cells with Ras mutations were also sensitive to PLX4032, albeit moderately. Thus, this study has confirmed that the BRAF{sup T1799A} mutation confers cancer cells sensitivity to PLX4032 and demonstrated its specific potential as an effective and BRAF{sup T1799A} mutation-selective therapeutic agent for thyroid cancer.« less

Gene mapping in an anophthalmic pedigree of a consanguineous Pakistani family opened new horizons for research

PubMed Central

Ajmal, M; Zafar, S; Hameed, A

2016-01-01

ABSTRACT Clinical anophthalmia is a rare inherited disease of the eye and phenotype refers to the absence of ocular tissue in the orbit of eye. Patients may have unilateral or bilateral anophthalmia, and generally have short palpebral fissures and small orbits. Anophthalmia may be isolated or associated with a broader syndrome and may have genetic or environmental causes. However, genetic cause has been defined in only a small proportion of cases, therefore, a consanguineous Pakistani family of the Pashtoon ethnic group, with isolated clinical anophthalmia was investigated using linkage mapping. A family pedigree was created to trace the possible mode of inheritance of the disease. Blood samples were collected from affected as well as normal members of this family, and screened for disease-associated mutations. This family was analyzed for linkage to all the known loci of clinical anophthalmia, using microsatellite short tandem repeat (STR) markers. Direct sequencing was performed to find out disease-associated mutations in the candidate gene. This family with isolated clinical anophthalmia, was mapped to the SOX2 gene that is located at chromosome 3q26.3-q27. However, on exonic and regulatory regions mutation screening of the SOX2 gene, the disease-associated mutation was not identified. It showed that another gene responsible for development of the eye might be present at chromosome 3q26.3-q27 and needs to be identified and screened for the disease-associated mutation in this family. PMID:27785411

A multiscale Bayesian data integration approach for mapping air dose rates around the Fukushima Daiichi Nuclear Power Plant.

PubMed

Wainwright, Haruko M; Seki, Akiyuki; Chen, Jinsong; Saito, Kimiaki

2017-02-01

This paper presents a multiscale data integration method to estimate the spatial distribution of air dose rates in the regional scale around the Fukushima Daiichi Nuclear Power Plant. We integrate various types of datasets, such as ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. The Bayesian method allows us to quantify the uncertainty in the estimates, and to provide the confidence intervals that are critical for robust decision-making. Although this approach is primarily data-driven, it has great flexibility to include mechanistic models for representing radiation transport or other complex correlations. We demonstrate our approach using three types of datasets collected at the same time over Fukushima City in Japan: (1) coarse-resolution airborne surveys covering the entire area, (2) car surveys along major roads, and (3) walk surveys in multiple neighborhoods. Results show that the method can successfully integrate three types of datasets and create an integrated map (including the confidence intervals) of air dose rates over the domain in high resolution. Moreover, this study provides us with various insights into the characteristics of each dataset, as well as radiocaesium distribution. In particular, the urban areas show high heterogeneity in the contaminant distribution due to human activities as well as large discrepancy among different surveys due to such heterogeneity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of Yeast as an In Vivo Test Tube to Characterize a Broad Spectrum of p53 Mutations Associated with Breast Cancer

DTIC Science & Technology

2002-10-01

there is a mutation in the p53 gene itself (4, 5). Interestingly, -80% of p53 mutations are missense changes that lead to single amino acid...substitutions, a feature that distinguishes p53 from other tumor suppressor genes (e.g., APC, NF1, BRCAJ) (6). The incidence of p53 mutations and the types of...intronic promoter is contained within the human mutation hotspot maps of p53: correlation with p53 protein structural and mdm2 gene . Nucleic Acids Res

Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening

PubMed Central

Chen, Jianjun; Wang, Qiwei; Cabrera, Patricia E.; Zhong, Zilin; Sun, Wenmin; Jiao, Xiaodong; Chen, Yabin; Govindarajan, Gowthaman; Naeem, Muhammad Asif; Khan, Shaheen N.; Ali, Muhammad Hassaan; Assir, Muhammad Zaman; Rahman, Fawad Ur; Qazi, Zaheeruddin A.; Riazuddin, Sheikh; Akram, Javed; Riazuddin, S. Amer; Hejtmancik, J. Fielding

2017-01-01

Purpose To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population. PMID:28418495

Mutation Scanning in Wheat by Exon Capture and Next-Generation Sequencing.

PubMed

King, Robert; Bird, Nicholas; Ramirez-Gonzalez, Ricardo; Coghill, Jane A; Patil, Archana; Hassani-Pak, Keywan; Uauy, Cristobal; Phillips, Andrew L

2015-01-01

Targeted Induced Local Lesions in Genomes (TILLING) is a reverse genetics approach to identify novel sequence variation in genomes, with the aims of investigating gene function and/or developing useful alleles for breeding. Despite recent advances in wheat genomics, most current TILLING methods are low to medium in throughput, being based on PCR amplification of the target genes. We performed a pilot-scale evaluation of TILLING in wheat by next-generation sequencing through exon capture. An oligonucleotide-based enrichment array covering ~2 Mbp of wheat coding sequence was used to carry out exon capture and sequencing on three mutagenised lines of wheat containing previously-identified mutations in the TaGA20ox1 homoeologous genes. After testing different mapping algorithms and settings, candidate SNPs were identified by mapping to the IWGSC wheat Chromosome Survey Sequences. Where sequence data for all three homoeologues were found in the reference, mutant calls were unambiguous; however, where the reference lacked one or two of the homoeologues, captured reads from these genes were mis-mapped to other homoeologues, resulting either in dilution of the variant allele frequency or assignment of mutations to the wrong homoeologue. Competitive PCR assays were used to validate the putative SNPs and estimate cut-off levels for SNP filtering. At least 464 high-confidence SNPs were detected across the three mutagenized lines, including the three known alleles in TaGA20ox1, indicating a mutation rate of ~35 SNPs per Mb, similar to that estimated by PCR-based TILLING. This demonstrates the feasibility of using exon capture for genome re-sequencing as a method of mutation detection in polyploid wheat, but accurate mutation calling will require an improved genomic reference with more comprehensive coverage of homoeologues.

Mapping of chloroplast mutations conferring resistance to antibiotics in Chlamydomonas: evidence for a novel site of streptomycin resistance in the small subunit rRNA.

PubMed

Gauthier, A; Turmel, M; Lemieux, C

1988-10-01

A major obstacle to our understanding of the mechanisms governing the inheritance, recombination and segregation of chloroplast genes in Chlamydomonas is that the majority of antibiotic resistance mutations that have been used to gain insights into such mechanisms have not been physically localized on the chloroplast genome. We report here the physical mapping of two chloroplast antibiotic resistance mutations: one conferring cross-resistance to erythromycin and spiramycin in Chlamydomonas moewusii (er-nM1) and the other conferring resistance to streptomycin in the interfertile species C. eugametos (sr-2). The er-nM1 mutation results from a C to G transversion at a well-known site of macrolide resistance within the peptidyl transferase loop region of the large subunit rRNA gene. This locus, designated rib-2 in yeast mitochondrial DNA, corresponds to residue C-2611 in the 23 S rRNA of Escherichia coli. The sr-2 locus maps within the small subunit (SSU) rRNA gene at a site that has not been described previously. The mutation results from an A to C transversion at a position equivalent to residue A-523 in the E. coli 16 S rRNA. Although this region of the E. coli SSU rRNA has no binding affinity for streptomycin, it binds to ribosomal protein S4, a protein that has long been associated with the response of bacterial cells to this antibiotic. We propose that the sr-2 mutation indirectly affects the nearest streptomycin binding site through an altered interaction between a ribosomal protein and the SSU rRNA.

Staying green postharvest: how three mutations in the Arabidopsis chlorophyll b reductase gene NYC1 delay degreening by distinct mechanisms.

PubMed

Jibran, Rubina; Sullivan, Kerry L; Crowhurst, Ross; Erridge, Zoe A; Chagné, David; McLachlan, Andrew R G; Brummell, David A; Dijkwel, Paul P; Hunter, Donald A

2015-11-01

Stresses such as energy deprivation, wounding and water-supply disruption often contribute to rapid deterioration of harvested tissues. To uncover the genetic regulation behind such stresses, a simple assessment system was used to detect senescence mutants in conjunction with two rapid mapping techniques to identify the causal mutations. To demonstrate the power of this approach, immature inflorescences of Arabidopsis plants that contained ethyl methanesulfonate-induced lesions were detached and screened for altered timing of dark-induced senescence. Numerous mutant lines displaying accelerated or delayed timing of senescence relative to wild type were discovered. The underlying mutations in three of these were identified using High Resolution Melting analysis to map to a chromosomal arm followed by a whole-genome sequencing-based mapping method, termed 'Needle in the K-Stack', to identify the causal lesions. All three mutations were single base pair changes and occurred in the same gene, NON-YELLOW COLORING1 (NYC1), a chlorophyll b reductase of the short-chain dehydrogenase/reductase (SDR) superfamily. This was consistent with the mutants preferentially retaining chlorophyll b, although substantial amounts of chlorophyll b were still lost. The single base pair mutations disrupted NYC1 function by three distinct mechanisms, one by producing a termination codon, the second by interfering with correct intron splicing and the third by replacing a highly conserved proline with a non-equivalent serine residue. This non-synonymous amino acid change, which occurred in the NADPH binding domain of NYC1, is the first example of such a mutation in an SDR protein inhibiting a physiological response in plants. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma

PubMed Central

Ramkissoon, Shakti H.; Bi, Wenya Linda; Schumacher, Steven E.; Ramkissoon, Lori A.; Haidar, Sam; Knoff, David; Dubuc, Adrian; Brown, Loreal; Burns, Margot; Cryan, Jane B.; Abedalthagafi, Malak; Kang, Yun Jee; Schultz, Nikolaus; Reardon, David A.; Lee, Eudocia Q.; Rinne, Mikael L.; Norden, Andrew D.; Nayak, Lakshmi; Ruland, Sandra; Doherty, Lisa M.; LaFrankie, Debra C.; Horvath, Margaret; Aizer, Ayal A.; Russo, Andrea; Arvold, Nils D.; Claus, Elizabeth B.; Al-Mefty, Ossama; Johnson, Mark D.; Golby, Alexandra J.; Dunn, Ian F.; Chiocca, E. Antonio; Trippa, Lorenzo; Santagata, Sandro; Folkerth, Rebecca D.; Kantoff, Philip; Rollins, Barrett J.; Lindeman, Neal I.; Wen, Patrick Y.; Ligon, Azra H.; Beroukhim, Rameen; Alexander, Brian M.; Ligon, Keith L.

2015-01-01

Background Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry–based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma. PMID:25754088

A population of deletion mutants and an integrated mapping and Exome-seq pipeline for gene discovery in maize

USDA-ARS?s Scientific Manuscript database

To better understand maize endosperm filling and maturation, we developed a novel functional genomics platform that combined Bulked Segregant RNA and Exome sequencing (BSREx-seq) to map causative mutations and identify candidate genes within mapping intervals. Using gamma-irradiation of B73 maize to...

Aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16

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

Montagutelli, X.; Lalouette, A.; Guenet, J.L.

1994-01-01

Alkaptonuria is a human hereditary metabolic disease characterized by a very high urinary excretion of homogentisic acid, an intermediary product in the metabolism of tyrosine, in association with ochronosis and arthritis. This disease is due to a deficiency in the enzyme homogentisic acid oxidase and is inherited as an autosomal recessive condition. The authors have found a new recessive mutation (aku) in the mouse that is homologous to human alkaptonuria, during a mutagenesis program with ethylnitrosourea. Affected mice show high levels of urinary homogentisic acid without signs of ochronosis or arthritis. This mutation has been mapped to Chr 16 closemore » to the D16Mit4 locus, in a region of synteny with human 3q. 22 refs., 1 fig., 1 tab.« less

Extreme-Scale Bayesian Inference for Uncertainty Quantification of Complex Simulations

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

Biros, George

Uncertainty quantification (UQ)—that is, quantifying uncertainties in complex mathematical models and their large-scale computational implementations—is widely viewed as one of the outstanding challenges facing the field of CS&E over the coming decade. The EUREKA project set to address the most difficult class of UQ problems: those for which both the underlying PDE model as well as the uncertain parameters are of extreme scale. In the project we worked on these extreme-scale challenges in the following four areas: 1. Scalable parallel algorithms for sampling and characterizing the posterior distribution that exploit the structure of the underlying PDEs and parameter-to-observable map. Thesemore » include structure-exploiting versions of the randomized maximum likelihood method, which aims to overcome the intractability of employing conventional MCMC methods for solving extreme-scale Bayesian inversion problems by appealing to and adapting ideas from large-scale PDE-constrained optimization, which have been very successful at exploring high-dimensional spaces. 2. Scalable parallel algorithms for construction of prior and likelihood functions based on learning methods and non-parametric density estimation. Constructing problem-specific priors remains a critical challenge in Bayesian inference, and more so in high dimensions. Another challenge is construction of likelihood functions that capture unmodeled couplings between observations and parameters. We will create parallel algorithms for non-parametric density estimation using high dimensional N-body methods and combine them with supervised learning techniques for the construction of priors and likelihood functions. 3. Bayesian inadequacy models, which augment physics models with stochastic models that represent their imperfections. The success of the Bayesian inference framework depends on the ability to represent the uncertainty due to imperfections of the mathematical model of the phenomena of interest. This is a central challenge in UQ, especially for large-scale models. We propose to develop the mathematical tools to address these challenges in the context of extreme-scale problems. 4. Parallel scalable algorithms for Bayesian optimal experimental design (OED). Bayesian inversion yields quantified uncertainties in the model parameters, which can be propagated forward through the model to yield uncertainty in outputs of interest. This opens the way for designing new experiments to reduce the uncertainties in the model parameters and model predictions. Such experimental design problems have been intractable for large-scale problems using conventional methods; we will create OED algorithms that exploit the structure of the PDE model and the parameter-to-output map to overcome these challenges. Parallel algorithms for these four problems were created, analyzed, prototyped, implemented, tuned, and scaled up for leading-edge supercomputers, including UT-Austin’s own 10 petaflops Stampede system, ANL’s Mira system, and ORNL’s Titan system. While our focus is on fundamental mathematical/computational methods and algorithms, we will assess our methods on model problems derived from several DOE mission applications, including multiscale mechanics and ice sheet dynamics.« less

Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.

PubMed Central

Drummond, Alexei J; Nicholls, Geoff K; Rodrigo, Allen G; Solomon, Wiremu

2002-01-01

Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences. PMID:12136032

Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data.

PubMed

Drummond, Alexei J; Nicholls, Geoff K; Rodrigo, Allen G; Solomon, Wiremu

2002-07-01

Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences.

Distinguishing between Selective Sweeps from Standing Variation and from a De Novo Mutation

PubMed Central

Peter, Benjamin M.; Huerta-Sanchez, Emilia; Nielsen, Rasmus

2012-01-01

An outstanding question in human genetics has been the degree to which adaptation occurs from standing genetic variation or from de novo mutations. Here, we combine several common statistics used to detect selection in an Approximate Bayesian Computation (ABC) framework, with the goal of discriminating between models of selection and providing estimates of the age of selected alleles and the selection coefficients acting on them. We use simulations to assess the power and accuracy of our method and apply it to seven of the strongest sweeps currently known in humans. We identify two genes, ASPM and PSCA, that are most likely affected by selection on standing variation; and we find three genes, ADH1B, LCT, and EDAR, in which the adaptive alleles seem to have swept from a new mutation. We also confirm evidence of selection for one further gene, TRPV6. In one gene, G6PD, neither neutral models nor models of selective sweeps fit the data, presumably because this locus has been subject to balancing selection. PMID:23071458

Population dynamics and in vitro antibody pressure of porcine parvovirus indicate a decrease in variability.

PubMed

Streck, André Felipe; Homeier, Timo; Foerster, Tessa; Truyen, Uwe

2013-09-01

To estimate the impact of porcine parvovirus (PPV) vaccines on the emergence of new phenotypes, the population dynamic history of the virus was calculated using the Bayesian Markov chain Monte Carlo method with a Bayesian skyline coalescent model. Additionally, an in vitro model was performed with consecutive passages of the 'Challenge' strain (a virulent field strain) and NADL2 strain (a vaccine strain) in a PK-15 cell line supplemented with polyclonal antibodies raised against the vaccine strain. A decrease in genetic diversity was observed in the presence of antibodies in vitro or after vaccination (as estimated by the in silico model). We hypothesized that the antibodies induced a selective pressure that may reduce the incidence of neutral selection, which should play a major role in the emergence of new mutations. In this scenario, vaccine failures and non-vaccinated populations (e.g. wild boars) may have an important impact in the emergence of new phenotypes.

Functional interactions at the interface between voltage-sensing and pore domains in the Shaker K(v) channel.

PubMed

Soler-Llavina, Gilberto J; Chang, Tsg-Hui; Swartz, Kenton J

2006-11-22

Voltage-activated potassium (K(v)) channels contain a central pore domain that is partially surrounded by four voltage-sensing domains. Recent X-ray structures suggest that the two domains lack extensive protein-protein contacts within presumed transmembrane regions, but whether this is the case for functional channels embedded in lipid membranes remains to be tested. We investigated domain interactions in the Shaker K(v) channel by systematically mutating the pore domain and assessing tolerance by examining channel maturation, S4 gating charge movement, and channel opening. When mapped onto the X-ray structure of the K(v)1.2 channel the large number of permissive mutations support the notion of relatively independent domains, consistent with crystallographic studies. Inspection of the maps also identifies portions of the interface where residues are sensitive to mutation, an external cluster where mutations hinder voltage sensor activation, and an internal cluster where domain interactions between S4 and S5 helices from adjacent subunits appear crucial for the concerted opening transition.

Use of multivariate analysis to suggest a new molecular classification of colorectal cancer

PubMed Central

Domingo, Enric; Ramamoorthy, Rajarajan; Oukrif, Dahmane; Rosmarin, Daniel; Presz, Michal; Wang, Haitao; Pulker, Hannah; Lockstone, Helen; Hveem, Tarjei; Cranston, Treena; Danielsen, Havard; Novelli, Marco; Davidson, Brian; Xu, Zheng-Zhou; Molloy, Peter; Johnstone, Elaine; Holmes, Christopher; Midgley, Rachel; Kerr, David; Sieber, Oliver; Tomlinson, Ian

2013-01-01

Abstract Molecular classification of colorectal cancer (CRC) is currently based on microsatellite instability (MSI), KRAS or BRAF mutation and, occasionally, chromosomal instability (CIN). Whilst useful, these categories may not fully represent the underlying molecular subgroups. We screened 906 stage II/III CRCs from the VICTOR clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between: CIN and TP53 mutation; MSI and BRAF mutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and NRAS mutation; and KRAS mutation, and each of NRAS, TP53 and BRAF mutations. Some complex relationships were elucidated: KRAS and TP53 mutations had both a direct negative association and a weaker, confounding, positive association via TP53–CIN–MSI–BRAF–KRAS. Our results suggested a new molecular classification of CRCs: (1) MSI+ and/or BRAF-mutant; (2) CIN+ and/or TP53– mutant, with wild-type KRAS and PIK3CA; (3) KRAS- and/or PIK3CA-mutant, CIN+, TP53-wild-type; (4) KRAS– and/or PIK3CA-mutant, CIN–, TP53-wild-type; (5) NRAS-mutant; (6) no mutations; (7) others. As expected, group 1 cancers were mostly proximal and poorly differentiated, usually occurring in women. Unexpectedly, two different types of CIN+ CRC were found: group 2 cancers were usually distal and occurred in men, whereas group 3 showed neither of these associations but were of higher stage. CIN+ cancers have conventionally been associated with all three of these variables, because they have been tested en masse. Our classification also showed potentially improved prognostic capabilities, with group 3, and possibly group 1, independently predicting disease-free survival. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:23165447

A bayesian approach for determining velocity and uncertainty estimates from seismic cone penetrometer testing or vertical seismic profiling data

USGS Publications Warehouse

Pidlisecky, Adam; Haines, S.S.

2011-01-01

Conventional processing methods for seismic cone penetrometer data present several shortcomings, most notably the absence of a robust velocity model uncertainty estimate. We propose a new seismic cone penetrometer testing (SCPT) data-processing approach that employs Bayesian methods to map measured data errors into quantitative estimates of model uncertainty. We first calculate travel-time differences for all permutations of seismic trace pairs. That is, we cross-correlate each trace at each measurement location with every trace at every other measurement location to determine travel-time differences that are not biased by the choice of any particular reference trace and to thoroughly characterize data error. We calculate a forward operator that accounts for the different ray paths for each measurement location, including refraction at layer boundaries. We then use a Bayesian inversion scheme to obtain the most likely slowness (the reciprocal of velocity) and a distribution of probable slowness values for each model layer. The result is a velocity model that is based on correct ray paths, with uncertainty bounds that are based on the data error. ?? NRC Research Press 2011.

An efficient method for model refinement in diffuse optical tomography

NASA Astrophysics Data System (ADS)

Zirak, A. R.; Khademi, M.

2007-11-01

Diffuse optical tomography (DOT) is a non-linear, ill-posed, boundary value and optimization problem which necessitates regularization. Also, Bayesian methods are suitable owing to measurements data are sparse and correlated. In such problems which are solved with iterative methods, for stabilization and better convergence, the solution space must be small. These constraints subject to extensive and overdetermined system of equations which model retrieving criteria specially total least squares (TLS) must to refine model error. Using TLS is limited to linear systems which is not achievable when applying traditional Bayesian methods. This paper presents an efficient method for model refinement using regularized total least squares (RTLS) for treating on linearized DOT problem, having maximum a posteriori (MAP) estimator and Tikhonov regulator. This is done with combination Bayesian and regularization tools as preconditioner matrices, applying them to equations and then using RTLS to the resulting linear equations. The preconditioning matrixes are guided by patient specific information as well as a priori knowledge gained from the training set. Simulation results illustrate that proposed method improves the image reconstruction performance and localize the abnormally well.

A Hierarchical Bayesian Model for Crowd Emotions

PubMed Central

Urizar, Oscar J.; Baig, Mirza S.; Barakova, Emilia I.; Regazzoni, Carlo S.; Marcenaro, Lucio; Rauterberg, Matthias

2016-01-01

Estimation of emotions is an essential aspect in developing intelligent systems intended for crowded environments. However, emotion estimation in crowds remains a challenging problem due to the complexity in which human emotions are manifested and the capability of a system to perceive them in such conditions. This paper proposes a hierarchical Bayesian model to learn in unsupervised manner the behavior of individuals and of the crowd as a single entity, and explore the relation between behavior and emotions to infer emotional states. Information about the motion patterns of individuals are described using a self-organizing map, and a hierarchical Bayesian network builds probabilistic models to identify behaviors and infer the emotional state of individuals and the crowd. This model is trained and tested using data produced from simulated scenarios that resemble real-life environments. The conducted experiments tested the efficiency of our method to learn, detect and associate behaviors with emotional states yielding accuracy levels of 74% for individuals and 81% for the crowd, similar in performance with existing methods for pedestrian behavior detection but with novel concepts regarding the analysis of crowds. PMID:27458366

Incorporating prior knowledge induced from stochastic differential equations in the classification of stochastic observations.

PubMed

Zollanvari, Amin; Dougherty, Edward R

2016-12-01

In classification, prior knowledge is incorporated in a Bayesian framework by assuming that the feature-label distribution belongs to an uncertainty class of feature-label distributions governed by a prior distribution. A posterior distribution is then derived from the prior and the sample data. An optimal Bayesian classifier (OBC) minimizes the expected misclassification error relative to the posterior distribution. From an application perspective, prior construction is critical. The prior distribution is formed by mapping a set of mathematical relations among the features and labels, the prior knowledge, into a distribution governing the probability mass across the uncertainty class. In this paper, we consider prior knowledge in the form of stochastic differential equations (SDEs). We consider a vector SDE in integral form involving a drift vector and dispersion matrix. Having constructed the prior, we develop the optimal Bayesian classifier between two models and examine, via synthetic experiments, the effects of uncertainty in the drift vector and dispersion matrix. We apply the theory to a set of SDEs for the purpose of differentiating the evolutionary history between two species.

Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex

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

Ipsaro, Jonathan J.; Harper, Sandra L.; Messick, Troy E.

2010-09-07

As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known clinically about the resulting conditions (hereditary elliptocytosis and pyropoikilocytosis), the detailed structural basis for spectrin tetramerization and its disruption by hereditary anemia mutations remains elusive. Thus, to provide further insights into spectrin assembly and tetramer site mutations, a crystal structure of the spectrin tetramerization domain complex has been determined. Architecturally, this complex shows striking resemblance to multirepeat spectrinmore » fragments, with the interacting tetramer site region forming a central, composite repeat. This structure identifies conformational changes in {alpha}-spectrin that occur upon binding to {beta}-spectrin, and it reports the first structure of the {beta}-spectrin tetramerization domain. Analysis of the interaction surfaces indicates an extensive interface dominated by hydrophobic contacts and supplemented by electrostatic complementarity. Analysis of evolutionarily conserved residues suggests additional surfaces that may form important interactions. Finally, mapping of hereditary anemia-related mutations onto the structure demonstrate that most, but not all, local hereditary anemia mutations map to the interacting domains. The potential molecular effects of these mutations are described.« less

Crystal Structure and Functional Interpretation of the Erythrocyte spectrin Tetramerization Domain Complex

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

J Ipsaro; S Harper; T Messick

2011-12-31

As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known clinically about the resulting conditions (hereditary elliptocytosis and pyropoikilocytosis), the detailed structural basis for spectrin tetramerization and its disruption by hereditary anemia mutations remains elusive. Thus, to provide further insights into spectrin assembly and tetramer site mutations, a crystal structure of the spectrin tetramerization domain complex has been determined. Architecturally, this complex shows striking resemblance to multirepeat spectrinmore » fragments, with the interacting tetramer site region forming a central, composite repeat. This structure identifies conformational changes in {alpha}-spectrin that occur upon binding to {beta}-spectrin, and it reports the first structure of the {beta}-spectrin tetramerization domain. Analysis of the interaction surfaces indicates an extensive interface dominated by hydrophobic contacts and supplemented by electrostatic complementarity. Analysis of evolutionarily conserved residues suggests additional surfaces that may form important interactions. Finally, mapping of hereditary anemia-related mutations onto the structure demonstrate that most, but not all, local hereditary anemia mutations map to the interacting domains. The potential molecular effects of these mutations are described.« less

The cld mutation: narrowing the critical chromosomal region and selecting candidate genes.

PubMed

Péterfy, Miklós; Mao, Hui Z; Doolittle, Mark H

2006-10-01

Combined lipase deficiency (cld) is a recessive, lethal mutation specific to the tw73 haplotype on mouse Chromosome 17. While the cld mutation results in lipase proteins that are inactive, aggregated, and retained in the endoplasmic reticulum (ER), it maps separately from the lipase structural genes. We have narrowed the gene critical region by about 50% using the tw18 haplotype for deletion mapping and a recombinant chromosome used originally to map cld with respect to the phenotypic marker tf. The region now extends from 22 to 25.6 Mbp on the wild-type chromosome, currently containing 149 genes and 50 expressed sequence tags (ESTs). To identify the affected gene, we have selected candidates based on their known role in associated biological processes, cellular components, and molecular functions that best fit with the predicted function of the cld gene. A secondary approach was based on differences in mRNA levels between mutant (cld/cld) and unaffected (+/cld) cells. Using both approaches, we have identified seven functional candidates with an ER localization and/or an involvement in protein maturation and folding that could explain the lipase deficiency, and six expression candidates that exhibit large differences in mRNA levels between mutant and unaffected cells. Significantly, two genes were found to be candidates with regard to both function and expression, thus emerging as the strongest candidates for cld. We discuss the implications of our mapping results and our selection of candidates with respect to other genes, deletions, and mutations occurring in the cld critical region.

Understanding mutagenesis through delineation of mutational signatures in human cancer

DOE PAGES

Petljak, Mia; Alexandrov, Ludmil B.

2016-05-04

Each individual cell within a human body acquires a certain number of somatic mutations during a course of its lifetime. These mutations originate from a wide spectra of both endogenous and exogenous mutational processes that leave distinct patterns of mutations, termed mutational signatures, embedded within the genomes of all cells. In recent years, the vast amount of data produced by sequencing of cancer genomes was coupled with novel mathematical models and computational tools to generate the first comprehensive map of mutational signatures in human cancer. Up to date, >30 distinct mutational signatures have been identified, and etiologies have been proposedmore » for many of them. This paper provides a brief historical background on examination of mutational patterns in human cancer, summarizes the knowledge accumulated since introducing the concept of mutational signatures and discusses their future potential applications and perspectives within the field.« less

KinSNP software for homozygosity mapping of disease genes using SNP microarrays.

PubMed

Amir, El-Ad David; Bartal, Ofer; Morad, Efrat; Nagar, Tal; Sheynin, Jony; Parvari, Ruti; Chalifa-Caspi, Vered

2010-08-01

Consanguineous families affected with a recessive genetic disease caused by homozygotisation of a mutation offer a unique advantage for positional cloning of rare diseases. Homozygosity mapping of patient genotypes is a powerful technique for the identification of the genomic locus harbouring the causing mutation. This strategy relies on the observation that in these patients a large region spanning the disease locus is also homozygous with high probability. The high marker density in single nucleotide polymorphism (SNP) arrays is extremely advantageous for homozygosity mapping. We present KinSNP, a user-friendly software tool for homozygosity mapping using SNP arrays. The software searches for stretches of SNPs which are homozygous to the same allele in all ascertained sick individuals. User-specified parameters control the number of allowed genotyping 'errors' within homozygous blocks. Candidate disease regions are then reported in a detailed, coloured Excel file, along with genotypes of family members and healthy controls. An interactive genome browser has been included which shows homozygous blocks, individual genotypes, genes and further annotations along the chromosomes, with zooming and scrolling capabilities. The software has been used to identify the location of a mutated gene causing insensitivity to pain in a large Bedouin family. KinSNP is freely available from.

KinSNP software for homozygosity mapping of disease genes using SNP microarrays

PubMed Central

2010-01-01

Consanguineous families affected with a recessive genetic disease caused by homozygotisation of a mutation offer a unique advantage for positional cloning of rare diseases. Homozygosity mapping of patient genotypes is a powerful technique for the identification of the genomic locus harbouring the causing mutation. This strategy relies on the observation that in these patients a large region spanning the disease locus is also homozygous with high probability. The high marker density in single nucleotide polymorphism (SNP) arrays is extremely advantageous for homozygosity mapping. We present KinSNP, a user-friendly software tool for homozygosity mapping using SNP arrays. The software searches for stretches of SNPs which are homozygous to the same allele in all ascertained sick individuals. User-specified parameters control the number of allowed genotyping 'errors' within homozygous blocks. Candidate disease regions are then reported in a detailed, coloured Excel file, along with genotypes of family members and healthy controls. An interactive genome browser has been included which shows homozygous blocks, individual genotypes, genes and further annotations along the chromosomes, with zooming and scrolling capabilities. The software has been used to identify the location of a mutated gene causing insensitivity to pain in a large Bedouin family. KinSNP is freely available from http://bioinfo.bgu.ac.il/bsu/software/kinSNP. PMID:20846928

Genome-wide SNP scan of pooled DNA reveals nonsense mutation in FGF20 in the scaleless line of featherless chickens

PubMed Central

2012-01-01

Background Scaleless (sc/sc) chickens carry a single recessive mutation that causes a lack of almost all body feathers, as well as foot scales and spurs, due to a failure of skin patterning during embryogenesis. This spontaneous mutant line, first described in the 1950s, has been used extensively to explore the tissue interactions involved in ectodermal appendage formation in embryonic skin. Moreover, the trait is potentially useful in tropical agriculture due to the ability of featherless chickens to tolerate heat, which is at present a major constraint to efficient poultry meat production in hot climates. In the interests of enhancing our understanding of feather placode development, and to provide the poultry industry with a strategy to breed heat-tolerant meat-type chickens (broilers), we mapped and identified the sc mutation. Results Through a cost-effective and labour-efficient SNP array mapping approach using DNA from sc/sc and sc/+ blood sample pools, we map the sc trait to chromosome 4 and show that a nonsense mutation in FGF20 is completely associated with the sc/sc phenotype. This mutation, common to all sc/sc individuals and absent from wild type, is predicted to lead to loss of a highly conserved region of the FGF20 protein important for FGF signalling. In situ hybridisation and quantitative RT-PCR studies reveal that FGF20 is epidermally expressed during the early stages of feather placode patterning. In addition, we describe a dCAPS genotyping assay based on the mutation, developed to facilitate discrimination between wild type and sc alleles. Conclusions This work represents the first loss of function genetic evidence supporting a role for FGF ligand signalling in feather development, and suggests FGF20 as a novel central player in the development of vertebrate skin appendages, including hair follicles and exocrine glands. In addition, this is to our knowledge the first report describing the use of the chicken SNP array to map genes based on genotyping of DNA samples from pooled whole blood. The identification of the sc mutation has important implications for the future breeding of this potentially useful trait for the poultry industry, and our genotyping assay can facilitate its rapid introgression into production lines. PMID:22712610

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps

PubMed Central

Zhang, Weihua; Collins, Andrew; Gibson, Jane; Tapper, William J.; Hunt, Sarah; Deloukas, Panos; Bentley, David R.; Morton, Newton E.

2004-01-01

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences. PMID:15604137

Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps.

PubMed

Zhang, Weihua; Collins, Andrew; Gibson, Jane; Tapper, William J; Hunt, Sarah; Deloukas, Panos; Bentley, David R; Morton, Newton E

2004-12-28

Genetic maps in linkage disequilibrium (LD) units play the same role for association mapping as maps in centimorgans provide at much lower resolution for linkage mapping. Association mapping of genes determining disease susceptibility and other phenotypes is based on the theory of LD, here applied to relations with three phenomena. To test the theory, markers at high density along a 10-Mb continuous segment of chromosome 20q were studied in African-American, Asian, and Caucasian samples. Population structure, whether created by pooling samples from divergent populations or by the mating pattern in a mixed population, is accurately bioassayed from genotype frequencies. The effective bottleneck time for Eurasians is substantially less than for migration out of Africa, reflecting later bottlenecks. The classical dependence of allele frequency on mutation age does not hold for the generally shorter time span of inbreeding and LD. Limitation of the classical theory to mutation age justifies the assumption of constant time in a LD map, except for alleles that were rare at the effective bottleneck time or have arisen since. This assumption is derived from the Malecot model and verified in all samples. Tested measures of relative efficiency, support intervals, and localization error determine the operating characteristics of LD maps that are applicable to every sexually reproducing species, with implications for association mapping, high-resolution linkage maps, evolutionary inference, and identification of recombinogenic sequences.

Selkirk Rex: Morphological and Genetic Characterization of a New Cat Breed

PubMed Central

2012-01-01

Rexoid, curly hair mutations have been selected to develop new domestic cat breeds. The Selkirk Rex is the most recently established curly-coated cat breed originating from a spontaneous mutation that was discovered in the United States in 1987. Unlike the earlier and well-established Cornish and Devon Rex breeds with curly-coat mutations, the Selkirk Rex mutation is suggested as autosomal dominant and has a different curl phenotype. This study provides a genetic analysis of the Selkirk Rex breed. An informal segregation analysis of genetically proven matings supported an autosomal, incomplete dominant expression of the curly trait in the Selkirk Rex. Homozygous curl cats can be distinguished from heterozygous cats by head and body type, as well as the presentation of the hair curl. Bayesian clustering of short tandem repeat (STR) genotypes from 31 cats that represent the future breeding stock supported the close relationship of the Selkirk Rex to the British Shorthair, Scottish Fold, Persian, and Exotic Shorthair, suggesting the Selkirk as part of the Persian breed family. The high heterozygosity of 0.630 and the low mean inbreeding coefficient of 0.057 suggest that Selkirk Rex has a diverse genetic foundation. A new locus for Selkirk autosomal dominant Rex, SADRE, is suggested for the curly trait. PMID:22837475

MIP-MAP: High-Throughput Mapping of Caenorhabditis elegans Temperature-Sensitive Mutants via Molecular Inversion Probes.

PubMed

Mok, Calvin A; Au, Vinci; Thompson, Owen A; Edgley, Mark L; Gevirtzman, Louis; Yochem, John; Lowry, Joshua; Memar, Nadin; Wallenfang, Matthew R; Rasoloson, Dominique; Bowerman, Bruce; Schnabel, Ralf; Seydoux, Geraldine; Moerman, Donald G; Waterston, Robert H

2017-10-01

Mutants remain a powerful means for dissecting gene function in model organisms such as Caenorhabditis elegans Massively parallel sequencing has simplified the detection of variants after mutagenesis but determining precisely which change is responsible for phenotypic perturbation remains a key step. Genetic mapping paradigms in C . elegans rely on bulk segregant populations produced by crosses with the problematic Hawaiian wild isolate and an excess of redundant information from whole-genome sequencing (WGS). To increase the repertoire of available mutants and to simplify identification of the causal change, we performed WGS on 173 temperature-sensitive (TS) lethal mutants and devised a novel mapping method. The mapping method uses molecular inversion probes (MIP-MAP) in a targeted sequencing approach to genetic mapping, and replaces the Hawaiian strain with a Million Mutation Project strain with high genomic and phenotypic similarity to the laboratory wild-type strain N2 We validated MIP-MAP on a subset of the TS mutants using a competitive selection approach to produce TS candidate mapping intervals with a mean size < 3 Mb. MIP-MAP successfully uses a non-Hawaiian mapping strain and multiplexed libraries are sequenced at a fraction of the cost of WGS mapping approaches. Our mapping results suggest that the collection of TS mutants contains a diverse library of TS alleles for genes essential to development and reproduction. MIP-MAP is a robust method to genetically map mutations in both viable and essential genes and should be adaptable to other organisms. It may also simplify tracking of individual genotypes within population mixtures. Copyright © 2017 by the Genetics Society of America.

MIP-MAP: High-Throughput Mapping of Caenorhabditis elegans Temperature-Sensitive Mutants via Molecular Inversion Probes

PubMed Central

Mok, Calvin A.; Au, Vinci; Thompson, Owen A.; Edgley, Mark L.; Gevirtzman, Louis; Yochem, John; Lowry, Joshua; Memar, Nadin; Wallenfang, Matthew R.; Rasoloson, Dominique; Bowerman, Bruce; Schnabel, Ralf; Seydoux, Geraldine; Moerman, Donald G.; Waterston, Robert H.

2017-01-01

Mutants remain a powerful means for dissecting gene function in model organisms such as Caenorhabditis elegans. Massively parallel sequencing has simplified the detection of variants after mutagenesis but determining precisely which change is responsible for phenotypic perturbation remains a key step. Genetic mapping paradigms in C. elegans rely on bulk segregant populations produced by crosses with the problematic Hawaiian wild isolate and an excess of redundant information from whole-genome sequencing (WGS). To increase the repertoire of available mutants and to simplify identification of the causal change, we performed WGS on 173 temperature-sensitive (TS) lethal mutants and devised a novel mapping method. The mapping method uses molecular inversion probes (MIP-MAP) in a targeted sequencing approach to genetic mapping, and replaces the Hawaiian strain with a Million Mutation Project strain with high genomic and phenotypic similarity to the laboratory wild-type strain N2. We validated MIP-MAP on a subset of the TS mutants using a competitive selection approach to produce TS candidate mapping intervals with a mean size < 3 Mb. MIP-MAP successfully uses a non-Hawaiian mapping strain and multiplexed libraries are sequenced at a fraction of the cost of WGS mapping approaches. Our mapping results suggest that the collection of TS mutants contains a diverse library of TS alleles for genes essential to development and reproduction. MIP-MAP is a robust method to genetically map mutations in both viable and essential genes and should be adaptable to other organisms. It may also simplify tracking of individual genotypes within population mixtures. PMID:28827289

Mapping pre-European settlement vegetation at fine resolutions using a hierarchical Bayesian model and GIS

Treesearch

Hong S. He; Daniel C. Dey; Xiuli Fan; Mevin B. Hooten; John M. Kabrick; Christopher K. Wikle; Zhaofei. Fan

2007-01-01

In the Midwestern United States, the GeneralLandOffice (GLO) survey records provide the only reasonably accurate data source of forest composition and tree species distribution at the time of pre-European settlement (circa late 1800 to early 1850). However, GLO data have two fundamental limitations: coarse spatial resolutions (the square mile section and half mile...

Assessment of Data Fusion Algorithms for Earth Observation Change Detection Processes.

PubMed

Molina, Iñigo; Martinez, Estibaliz; Morillo, Carmen; Velasco, Jesus; Jara, Alvaro

2016-09-30

In this work a parametric multi-sensor Bayesian data fusion approach and a Support Vector Machine (SVM) are used for a Change Detection problem. For this purpose two sets of SPOT5-PAN images have been used, which are in turn used for Change Detection Indices (CDIs) calculation. For minimizing radiometric differences, a methodology based on zonal "invariant features" is suggested. The choice of one or the other CDI for a change detection process is a subjective task as each CDI is probably more or less sensitive to certain types of changes. Likewise, this idea might be employed to create and improve a "change map", which can be accomplished by means of the CDI's informational content. For this purpose, information metrics such as the Shannon Entropy and "Specific Information" have been used to weight the changes and no-changes categories contained in a certain CDI and thus introduced in the Bayesian information fusion algorithm. Furthermore, the parameters of the probability density functions (pdf's) that best fit the involved categories have also been estimated. Conversely, these considerations are not necessary for mapping procedures based on the discriminant functions of a SVM. This work has confirmed the capabilities of probabilistic information fusion procedure under these circumstances.

Propagation of the velocity model uncertainties to the seismic event location

NASA Astrophysics Data System (ADS)

Gesret, A.; Desassis, N.; Noble, M.; Romary, T.; Maisons, C.

2015-01-01

Earthquake hypocentre locations are crucial in many domains of application (academic and industrial) as seismic event location maps are commonly used to delineate faults or fractures. The interpretation of these maps depends on location accuracy and on the reliability of the associated uncertainties. The largest contribution to location and uncertainty errors is due to the fact that the velocity model errors are usually not correctly taken into account. We propose a new Bayesian formulation that integrates properly the knowledge on the velocity model into the formulation of the probabilistic earthquake location. In this work, the velocity model uncertainties are first estimated with a Bayesian tomography of active shot data. We implement a sampling Monte Carlo type algorithm to generate velocity models distributed according to the posterior distribution. In a second step, we propagate the velocity model uncertainties to the seismic event location in a probabilistic framework. This enables to obtain more reliable hypocentre locations as well as their associated uncertainties accounting for picking and velocity model uncertainties. We illustrate the tomography results and the gain in accuracy of earthquake location for two synthetic examples and one real data case study in the context of induced microseismicity.

Bayesian Mapping Reveals That Attention Boosts Neural Responses to Predicted and Unpredicted Stimuli.

PubMed

Garrido, Marta I; Rowe, Elise G; Halász, Veronika; Mattingley, Jason B

2018-05-01

Predictive coding posits that the human brain continually monitors the environment for regularities and detects inconsistencies. It is unclear, however, what effect attention has on expectation processes, as there have been relatively few studies and the results of these have yielded contradictory findings. Here, we employed Bayesian model comparison to adjudicate between 2 alternative computational models. The "Opposition" model states that attention boosts neural responses equally to predicted and unpredicted stimuli, whereas the "Interaction" model assumes that attentional boosting of neural signals depends on the level of predictability. We designed a novel, audiospatial attention task that orthogonally manipulated attention and prediction by playing oddball sequences in either the attended or unattended ear. We observed sensory prediction error responses, with electroencephalography, across all attentional manipulations. Crucially, posterior probability maps revealed that, overall, the Opposition model better explained scalp and source data, suggesting that attention boosts responses to predicted and unpredicted stimuli equally. Furthermore, Dynamic Causal Modeling showed that these Opposition effects were expressed in plastic changes within the mismatch negativity network. Our findings provide empirical evidence for a computational model of the opposing interplay of attention and expectation in the brain.

Anaysis of the quality of image data required by the LANDSAT-4 Thematic Mapper and Multispectral Scanner. [agricultural and forest cover types in California

NASA Technical Reports Server (NTRS)

Colwell, R. N. (Principal Investigator)

1984-01-01

The spatial, geometric, and radiometric qualities of LANDSAT 4 thematic mapper (TM) and multispectral scanner (MSS) data were evaluated by interpreting, through visual and computer means, film and digital products for selected agricultural and forest cover types in California. Multispectral analyses employing Bayesian maximum likelihood, discrete relaxation, and unsupervised clustering algorithms were used to compare the usefulness of TM and MSS data for discriminating individual cover types. Some of the significant results are as follows: (1) for maximizing the interpretability of agricultural and forest resources, TM color composites should contain spectral bands in the visible, near-reflectance infrared, and middle-reflectance infrared regions, namely TM 4 and TM % and must contain TM 4 in all cases even at the expense of excluding TM 5; (2) using enlarged TM film products, planimetric accuracy of mapped poins was within 91 meters (RMSE east) and 117 meters (RMSE north); (3) using TM digital products, planimetric accuracy of mapped points was within 12.0 meters (RMSE east) and 13.7 meters (RMSE north); and (4) applying a contextual classification algorithm to TM data provided classification accuracies competitive with Bayesian maximum likelihood.

A Bayesian and Physics-Based Ground Motion Parameters Map Generation System

NASA Astrophysics Data System (ADS)

Ramirez-Guzman, L.; Quiroz, A.; Sandoval, H.; Perez-Yanez, C.; Ruiz, A. L.; Delgado, R.; Macias, M. A.; Alcántara, L.

2014-12-01

We present the Ground Motion Parameters Map Generation (GMPMG) system developed by the Institute of Engineering at the National Autonomous University of Mexico (UNAM). The system delivers estimates of information associated with the social impact of earthquakes, engineering ground motion parameters (gmp), and macroseismic intensity maps. The gmp calculated are peak ground acceleration and velocity (pga and pgv) and response spectral acceleration (SA). The GMPMG relies on real-time data received from strong ground motion stations belonging to UNAM's networks throughout Mexico. Data are gathered via satellite and internet service providers, and managed with the data acquisition software Earthworm. The system is self-contained and can perform all calculations required for estimating gmp and intensity maps due to earthquakes, automatically or manually. An initial data processing, by baseline correcting and removing records containing glitches or low signal-to-noise ratio, is performed. The system then assigns a hypocentral location using first arrivals and a simplified 3D model, followed by a moment tensor inversion, which is performed using a pre-calculated Receiver Green's Tensors (RGT) database for a realistic 3D model of Mexico. A backup system to compute epicentral location and magnitude is in place. A Bayesian Kriging is employed to combine recorded values with grids of computed gmp. The latter are obtained by using appropriate ground motion prediction equations (for pgv, pga and SA with T=0.3, 0.5, 1 and 1.5 s ) and numerical simulations performed in real time, using the aforementioned RGT database (for SA with T=2, 2.5 and 3 s). Estimated intensity maps are then computed using SA(T=2S) to Modified Mercalli Intensity correlations derived for central Mexico. The maps are made available to the institutions in charge of the disaster prevention systems. In order to analyze the accuracy of the maps, we compare them against observations not considered in the computations, and present some examples of recent earthquakes. We conclude that the system provides information with a fair goodness-of-fit against observations. This project is partially supported by DGAPA-PAPIIT (UNAM) project TB100313-RR170313.

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains.

PubMed

Miller, Martin L; Reznik, Ed; Gauthier, Nicholas P; Aksoy, Bülent Arman; Korkut, Anil; Gao, Jianjiong; Ciriello, Giovanni; Schultz, Nikolaus; Sander, Chris

2015-09-23

In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots, identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene, detect previously unknown mutation hotspots, and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype. Copyright © 2015 Elsevier Inc. All rights reserved.

Nucleotide sequences of Herpes Simplex Virus type 1 (HSV-1) affecting virus entry, cell fusion, and production of glycoprotein gB (VP7)

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

DeLuca, N.; Bzik, D.J.; Bond, V.C.

1982-10-30

The tsB5 strain of Herpes Simplex Virus type 1 (HSV-1) contains at least two mutations; one mutation specifies the syncytial phenotype and the other confers temperature sensitivity for virus growth. These functions are known to be located between the prototypic map coordinates 0.30 and 0.42. In this study it was demonstrated that tsB5 enters human embryonic lung (HEL) cells more rapidly than KOS, another strain of HSV-1. The EcoRI restriction fragment F from the KOS strain (map coordinates 0.315 to 0.421) was mapped with eight restriction endonucleases, and 16 recombinant plasmids were constructed which contained varying portions of the KOSmore » genome. Recombinant viruses were generated by marker-rescue and marker-transfer cotransfection procedures, using intact DNA from one strain and a recombinant plasmid containing DNA from the other strain. The region of the crossover between the two nonisogenic strains was inferred by the identification of restriction sites in the recombinants that were characteristic of the parental strains. The recombinants were subjected to phenotypic analysis. Syncytium formation, rate of virus entry, and the production of gB were all separable by the crossovers that produced the recombinants. The KOS sequences which rescue the syncytial phenotype of tsB5 were localized to 1.5 kb (map coordinates 0.345 to 0.355), and the temperature-sensitive mutation was localized to 1.2 kb (0.360 to 0.368), giving an average separation between the mutations of 2.5 kb on the 150-kb genome. DNA sequences that specify a functional domain for virus entry were localized to the nucleotide sequences between the two mutations. All three functions could be encoded by the virus gene specifying the gB glycoprotein.« less

Systems Analysis of Early Host Gene Expression Provides Clues for Transient Mycobacterium avium ssp avium vs. Persistent Mycobacterium avium ssp paratuberculosis Intestinal Infections

PubMed Central

Khare, Sangeeta; Drake, Kenneth L.; Lawhon, Sara D.; Nunes, Jairo E. S.; Figueiredo, Josely F.; Rossetti, Carlos A.; Gull, Tamara; Everts, Robin E.; Lewin, Harris. A.; Adams, Leslie Garry

2016-01-01

It has long been a quest in ruminants to understand how two very similar mycobacterial species, Mycobacterium avium ssp. paratuberculosis (MAP) and Mycobacterium avium ssp. avium (MAA) lead to either a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer’s patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrier weakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection. PMID:27653506

Systems Analysis of Early Host Gene Expression Provides Clues for Transient Mycobacterium avium ssp avium vs. Persistent Mycobacterium avium ssp paratuberculosis Intestinal Infections.

PubMed

Khare, Sangeeta; Drake, Kenneth L; Lawhon, Sara D; Nunes, Jairo E S; Figueiredo, Josely F; Rossetti, Carlos A; Gull, Tamara; Everts, Robin E; Lewin, Harris A; Adams, Leslie Garry

It has long been a quest in ruminants to understand how two very similar mycobacterial species, Mycobacterium avium ssp. paratuberculosis (MAP) and Mycobacterium avium ssp. avium (MAA) lead to either a chronic persistent infection or a rapid-transient infection, respectively. Here, we hypothesized that when the host immune response is activated by MAP or MAA, the outcome of the infection depends on the early activation of signaling molecules and host temporal gene expression. To test our hypothesis, ligated jejuno-ileal loops including Peyer's patches in neonatal calves were inoculated with PBS, MAP, or MAA. A temporal analysis of the host transcriptome profile was conducted at several times post-infection (0.5, 1, 2, 4, 8 and 12 hours). When comparing the transcriptional responses of calves infected with the MAA versus MAP, discordant patterns of mucosal expression were clearly evident, and the numbers of unique transcripts altered were moderately less for MAA-infected tissue than were mucosal tissues infected with the MAP. To interpret these complex data, changes in the gene expression were further analyzed by dynamic Bayesian analysis. Bayesian network modeling identified mechanistic genes, gene-to-gene relationships, pathways and Gene Ontologies (GO) biological processes that are involved in specific cell activation during infection. MAP and MAA had significant different pathway perturbation at 0.5 and 12 hours post inoculation. Inverse processes were observed between MAP and MAA response for epithelial cell proliferation, negative regulation of chemotaxis, cell-cell adhesion mediated by integrin and regulation of cytokine-mediated signaling. MAP inoculated tissue had significantly lower expression of phagocytosis receptors such as mannose receptor and complement receptors. This study reveals that perturbation of genes and cellular pathways during MAP infection resulted in host evasion by mucosal membrane barrier weakening to access entry in the ileum, inhibition of Ca signaling associated with decreased phagosome-lysosome fusion as well as phagocytosis inhibition, bias toward Th2 cell immune response accompanied by cell recruitment, cell proliferation and cell differentiation; leading to persistent infection. Contrarily, MAA infection was related to cellular responses associated with activation of molecular pathways that release chemicals and cytokines involved with containment of infection and a strong bias toward Th1 immune response, resulting in a transient infection.

GNE missense mutation in recessive familial amyotrophic lateral sclerosis.

PubMed

Köroğlu, Çiğdem; Yılmaz, Rezzak; Sorgun, Mine Hayriye; Solakoğlu, Seyhun; Şener, Özden

2017-12-01

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease eventually leading to death from respiratory failure. Recessive inheritance is very rare. Here, we describe the clinical findings in a consanguineous family with five men afflicted with recessive ALS and the identification of the homozygous mutation responsible for the disorder. The onset of the disease ranged from 12 to 35 years of age, with variable disease progressions. We performed clinical investigations including metabolic and paraneoplastic screening, cranial and cervical imaging, and electrophysiology. We mapped the disease gene to 9p21.1-p12 with a LOD score of 5.2 via linkage mapping using genotype data for single-nucleotide polymorphism markers and performed exome sequence analysis to identify the disease-causing gene variant. We also Sanger sequenced all coding sequences of SIGMAR1, a gene reported as responsible for juvenile ALS in a family. We did not find any mutation in SIGMAR1. Instead, we identified a novel homozygous missense mutation p.(His705Arg) in GNE which was predicted as damaging by online tools. GNE has been associated with inclusion body myopathy and is expressed in many tissues. We propose that the GNE mutation underlies the pathology in the family.

In Southern Africa, Brown Oculocutaneous Albinism (BOCA) Maps to the OCA2 Locus on Chromosome 15q: P-Gene Mutations Identified

PubMed Central

Manga, Prashiela; Kromberg, Jennifer G. R.; Turner, Angela; Jenkins, Trefor; Ramsay, Michele

2001-01-01

In southern Africa, brown oculocutaneous albinism (BOCA) is a distinct pigmentation phenotype. In at least two cases, it has occurred in the same families as tyrosinase-positive oculocutaneous albinism (OCA2), suggesting that it may be allelic, despite the fact that this phenotype was attributed to mutations in the TYRP1 gene in an American individual of mixed ancestry. Linkage analysis in five families mapped the BOCA locus to the same region as the OCA2 locus (maximum LOD 3.07; θ=0 using a six-marker haplotype). Mutation analysis of the human homologue of the mouse pink-eyed dilution gene (P), in 10 unrelated individuals with BOCA revealed that 9 had one copy of the 2.7-kb deletion. No other mutations were identified. Additional haplotype studies, based on closely linked markers (telomere to centromere: D15S1048, D15S1019, D15S1533, P-gene 2.7-kb deletion, D15S219, and D15S156) revealed several BOCA-associated P haplotypes. These could be divided into two core haplotypes, suggesting that a limited number of P-gene mutations give rise to this phenotype. PMID:11179026

Markov Chain Monte Carlo Inference of Parametric Dictionaries for Sparse Bayesian Approximations

PubMed Central

Chaspari, Theodora; Tsiartas, Andreas; Tsilifis, Panagiotis; Narayanan, Shrikanth

2016-01-01

Parametric dictionaries can increase the ability of sparse representations to meaningfully capture and interpret the underlying signal information, such as encountered in biomedical problems. Given a mapping function from the atom parameter space to the actual atoms, we propose a sparse Bayesian framework for learning the atom parameters, because of its ability to provide full posterior estimates, take uncertainty into account and generalize on unseen data. Inference is performed with Markov Chain Monte Carlo, that uses block sampling to generate the variables of the Bayesian problem. Since the parameterization of dictionary atoms results in posteriors that cannot be analytically computed, we use a Metropolis-Hastings-within-Gibbs framework, according to which variables with closed-form posteriors are generated with the Gibbs sampler, while the remaining ones with the Metropolis Hastings from appropriate candidate-generating densities. We further show that the corresponding Markov Chain is uniformly ergodic ensuring its convergence to a stationary distribution independently of the initial state. Results on synthetic data and real biomedical signals indicate that our approach offers advantages in terms of signal reconstruction compared to previously proposed Steepest Descent and Equiangular Tight Frame methods. This paper demonstrates the ability of Bayesian learning to generate parametric dictionaries that can reliably represent the exemplar data and provides the foundation towards inferring the entire variable set of the sparse approximation problem for signal denoising, adaptation and other applications. PMID:28649173

Mapping structural landmarks, ligand binding sites and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions and variation in phenotypes in inherited diseases affecting basement membranes

PubMed Central

Des Parkin, J.; San Antonio, James D.; Pedchenko, Vadim; Hudson, Billy; Jensen, Shane T.; Savige, Judy

2016-01-01

Collagen IV is the major protein found in basement membranes. It comprises 3 heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity. We constructed linear maps of the collagen IV heterotrimers (‘interactomes’) that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype-phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms and muscle Cramps (HANAC) syndrome, and early onset Alport syndrome respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets. PMID:21280145

Mapping mitochondrial heteroplasmy in a Leydig tumor by laser capture micro-dissection and cycling temperature capillary electrophoresis.

PubMed

Refinetti, Paulo; Arstad, Christian; Thilly, William G; Morgenthaler, Stephan; Ekstrøm, Per Olaf

2017-01-01

The growth of tumor cells is accompanied by mutations in nuclear and mitochondrial genomes creating marked genetic heterogeneity. Tumors also contain non-tumor cells of various origins. An observed somatic mitochondrial mutation would have occurred in a founding cell and spread through cell division. Micro-anatomical dissection of a tumor coupled with assays for mitochondrial point mutations permits new insights into this growth process. More generally, the ability to detect and trace, at a histological level, somatic mitochondrial mutations in human tissues and tumors, makes these mutations into markers for lineage tracing. A tumor was first sampled by a large punch biopsy and scanned for any significant degree of heteroplasmy in a set of sequences containing known mutational hotspots of the mitochondrial genome. A heteroplasmic tumor was sliced at a 12 μm thickness and placed on membranes. Laser capture micro-dissection was used to take 25000 μm 2 subsamples or spots. After DNA amplification, cycling temperature capillary electrophoresis (CTCE) was used on the laser captured samples to quantify mitochondrial mutant fractions. Of six testicular tumors studied, one, a Leydig tumor, was discovered to carry a detectable degree of heteroplasmy for two separate point mutations: a C → T mutation at bp 64 and a T → C mutation found at bp 152. From this tumor, 381 spots were sampled with laser capture micro-dissection. The ordered distribution of spots exhibited a wide range of fractions of the mutant sequences from 0 to 100% mutant copies. The two mutations co-distributed in the growing tumor indicating they were present on the same genome copies in the founding cell. Laser capture microdissection of sliced tumor samples coupled with CTCE-based point mutation assays provides an effective and practical means to obtain maps of mitochondrial mutational heteroplasmy within human tumors.

Selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) for direct, versatile, and accurate RNA structure analysis

PubMed Central

Smola, Matthew J.; Rice, Greggory M.; Busan, Steven; Siegfried, Nathan A.; Weeks, Kevin M.

2016-01-01

SHAPE chemistries exploit small electrophilic reagents that react with the 2′-hydroxyl group to interrogate RNA structure at single-nucleotide resolution. Mutational profiling (MaP) identifies modified residues based on the ability of reverse transcriptase to misread a SHAPE-modified nucleotide and then counting the resulting mutations by massively parallel sequencing. The SHAPE-MaP approach measures the structure of large and transcriptome-wide systems as accurately as for simple model RNAs. This protocol describes the experimental steps, implemented over three days, required to perform SHAPE probing and construct multiplexed SHAPE-MaP libraries suitable for deep sequencing. These steps include RNA folding and SHAPE structure probing, mutational profiling by reverse transcription, library construction, and sequencing. Automated processing of MaP sequencing data is accomplished using two software packages. ShapeMapper converts raw sequencing files into mutational profiles, creates SHAPE reactivity plots, and provides useful troubleshooting information, often within an hour. SuperFold uses these data to model RNA secondary structures, identify regions with well-defined structures, and visualize probable and alternative helices, often in under a day. We illustrate these algorithms with the E. coli thiamine pyrophosphate riboswitch, E. coli 16S rRNA, and HIV-1 genomic RNAs. SHAPE-MaP can be used to make nucleotide-resolution biophysical measurements of individual RNA motifs, rare components of complex RNA ensembles, and entire transcriptomes. The straightforward MaP strategy greatly expands the number, length, and complexity of analyzable RNA structures. PMID:26426499

Escherichia Coli Mutations That Prevent the Action of the T4 Unf/Alc Protein Map in an RNA Polymerase Gene

PubMed Central

Snyder, L.; Jorissen, L.

1988-01-01

Bacteriophage T4 has the substituted base hydroxymethylcytosine in its DNA and presumably shuts off host transcription by specifically blocking transcription of cytosine-containing DNA. When T4 incorporates cytosine into its own DNA, the shutoff mechanism is directed back at T4, blocking its late gene expression and phage production. Mutations which permit T4 multiplication with cytosine DNA should be in genes required for host shutoff. The only such mutations characterized thus far have been in the phage unf/alc gene. The product of this gene is also required for the unfolding of the host nucleoid after infection, hence its dual name unf/alc. As part of our investigation of the mechanism of action of unf/alc, we have isolated Escherichia coli mutants which propagate cytosine T4 even if the phage are genotypically alc(+). These same E. coli mutants are delayed in the T4-induced unfolding of their nucleoid, lending strong support to the conclusion that blocking transcription and unfolding the host nucleoid are but different manifestations of the same activity. We have mapped two of the mutations, called paf mutations for prevent alc function. They both map at about 90 min, probably in the rpoB gene encoding a subunit of RNA polymerase. From the behavior of Paf mutants, we hypothesize that the unf/alc gene product of T4 interacts somehow with the host RNA polymerase to block transcription of cytosine DNA and unfold the host nucleoid. PMID:3282983

APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

PubMed

Dussaillant, Catalina; Serrano, Valentina; Maiz, Alberto; Eyheramendy, Susana; Cataldo, Luis Rodrigo; Chavez, Matías; Smalley, Susan V; Fuentes, Marcela; Rigotti, Attilio; Rubio, Lorena; Lagos, Carlos F; Martinez, José Alfredo; Santos, José Luis

2012-11-15

Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

PubMed Central

2012-01-01

Background Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. Methods We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. Results A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. Conclusion The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family. PMID:23151256

Comprehensive mutation analysis of 17 Y-chromosomal short tandem repeat polymorphisms included in the AmpFlSTR Yfiler PCR amplification kit.

PubMed

Goedbloed, Miriam; Vermeulen, Mark; Fang, Rixun N; Lembring, Maria; Wollstein, Andreas; Ballantyne, Kaye; Lao, Oscar; Brauer, Silke; Krüger, Carmen; Roewer, Lutz; Lessig, Rüdiger; Ploski, Rafal; Dobosz, Tadeusz; Henke, Lotte; Henke, Jürgen; Furtado, Manohar R; Kayser, Manfred

2009-11-01

The Y-chromosomal short tandem repeat (Y-STR) polymorphisms included in the AmpFlSTR Yfiler polymerase chain reaction amplification kit have become widely used for forensic and evolutionary applications where a reliable knowledge on mutation properties is necessary for correct data interpretation. Therefore, we investigated the 17 Yfiler Y-STRs in 1,730-1,764 DNA-confirmed father-son pairs per locus and found 84 sequence-confirmed mutations among the 29,792 meiotic transfers covered. Of the 84 mutations, 83 (98.8%) were single-repeat changes and one (1.2%) was a double-repeat change (ratio, 1:0.01), as well as 43 (51.2%) were repeat gains and 41 (48.8%) repeat losses (ratio, 1:0.95). Medians from Bayesian estimation of locus-specific mutation rates ranged from 0.0003 for DYS448 to 0.0074 for DYS458, with a median rate across all 17 Y-STRs of 0.0025. The mean age (at the time of son's birth) of fathers with mutations was with 34.40 (+/-11.63) years higher than that of fathers without ones at 30.32 (+/-10.22) years, a difference that is highly statistically significant (p < 0.001). A Poisson-based modeling revealed that the Y-STR mutation rate increased with increasing father's age on a statistically significant level (alpha = 0.0294, 2.5% quantile = 0.0001). From combining our data with those previously published, considering all together 135,212 meiotic events and 331 mutations, we conclude for the Yfiler Y-STRs that (1) none had a mutation rate of >1%, 12 had mutation rates of >0.1% and four of <0.1%, (2) single-repeat changes were strongly favored over multiple-repeat ones for all loci but 1 and (3) considerable variation existed among loci in the ratio of repeat gains versus losses. Our finding of three Y-STR mutations in one father-son pair (and two pairs with two mutations each) has consequences for determining the threshold of allelic differences to conclude exclusion constellations in future applications of Y-STRs in paternity testing and pedigree analyses.

Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models.

PubMed

Lindor, Noralane M; Lindor, Rachel A; Apicella, Carmel; Dowty, James G; Ashley, Amanda; Hunt, Katherine; Mincey, Betty A; Wilson, Marcia; Smith, M Cathie; Hopper, John L

2007-01-01

Models have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is unclear. To compare the performance characteristics of four BRCA1/BRCA2 gene mutation prediction models: LAMBDA, based on a checklist and scores developed from data on Ashkenazi Jewish (AJ) women; BRCAPRO, a Bayesian computer program; modified Couch tables based on regression analyses; and Myriad II tables collated by Myriad Genetics Laboratories. Family cancer history data were analyzed from 200 probands from the Mayo Clinic Familial Cancer Program, in a multispecialty tertiary care group practice. All probands had clinical testing for BRCA1 and BRCA2 mutations conducted in a single laboratory. For each model, performance was assessed by the area under the receiver operator characteristic curve (ROC) and by tests of accuracy and dispersion. Cases "missed" by one or more models (model predicted less than 10% probability of mutation when a mutation was actually found) were compared across models. All models gave similar areas under the ROC curve of 0.71 to 0.76. All models except LAMBDA substantially under-predicted the numbers of carriers. All models were too dispersed. In terms of ranking, all prediction models performed reasonably well with similar performance characteristics. Model predictions were widely discrepant for some families. Review of cancer family histories by an experienced clinician continues to be vital to ensure that critical elements are not missed and that the most appropriate risk prediction figures are provided.

HELP: XID+, the probabilistic de-blender for Herschel SPIRE maps

NASA Astrophysics Data System (ADS)

Hurley, P. D.; Oliver, S.; Betancourt, M.; Clarke, C.; Cowley, W. I.; Duivenvoorden, S.; Farrah, D.; Griffin, M.; Lacey, C.; Le Floc'h, E.; Papadopoulos, A.; Sargent, M.; Scudder, J. M.; Vaccari, M.; Valtchanov, I.; Wang, L.

2017-01-01

We have developed a new prior-based source extraction tool, XID+, to carry out photometry in the Herschel SPIRE (Spectral and Photometric Imaging Receiver) maps at the positions of known sources. XID+ is developed using a probabilistic Bayesian framework that provides a natural framework in which to include prior information, and uses the Bayesian inference tool Stan to obtain the full posterior probability distribution on flux estimates. In this paper, we discuss the details of XID+ and demonstrate the basic capabilities and performance by running it on simulated SPIRE maps resembling the COSMOS field, and comparing to the current prior-based source extraction tool DESPHOT. Not only we show that XID+ performs better on metrics such as flux accuracy and flux uncertainty accuracy, but we also illustrate how obtaining the posterior probability distribution can help overcome some of the issues inherent with maximum-likelihood-based source extraction routines. We run XID+ on the COSMOS SPIRE maps from Herschel Multi-Tiered Extragalactic Survey using a 24-μm catalogue as a positional prior, and a uniform flux prior ranging from 0.01 to 1000 mJy. We show the marginalized SPIRE colour-colour plot and marginalized contribution to the cosmic infrared background at the SPIRE wavelengths. XID+ is a core tool arising from the Herschel Extragalactic Legacy Project (HELP) and we discuss how additional work within HELP providing prior information on fluxes can and will be utilized. The software is available at https://github.com/H-E-L-P/XID_plus. We also provide the data product for COSMOS. We believe this is the first time that the full posterior probability of galaxy photometry has been provided as a data product.

Bayesian analysis and classification of two Enzyme-Linked Immunosorbent Assay (ELISA) tests without a gold standard

PubMed Central

Zhang, Jingyang; Chaloner, Kathryn; McLinden, James H.; Stapleton, Jack T.

2013-01-01

Reconciling two quantitative ELISA tests for an antibody to an RNA virus, in a situation without a gold standard and where false negatives may occur, is the motivation for this work. False negatives occur when access of the antibody to the binding site is blocked. Based on the mechanism of the assay, a mixture of four bivariate normal distributions is proposed with the mixture probabilities depending on a two-stage latent variable model including the prevalence of the antibody in the population and the probabilities of blocking on each test. There is prior information on the prevalence of the antibody, and also on the probability of false negatives, and so a Bayesian analysis is used. The dependence between the two tests is modeled to be consistent with the biological mechanism. Bayesian decision theory is utilized for classification. The proposed method is applied to the motivating data set to classify the data into two groups: those with and those without the antibody. Simulation studies describe the properties of the estimation and the classification. Sensitivity to the choice of the prior distribution is also addressed by simulation. The same model with two levels of latent variables is applicable in other testing procedures such as quantitative polymerase chain reaction tests where false negatives occur when there is a mutation in the primer sequence. PMID:23592433

What affects the predictability of evolutionary constraints using a G-matrix? The relative effects of modular pleiotropy and mutational correlation.

PubMed

Chebib, Jobran; Guillaume, Frédéric

2017-10-01

Phenotypic traits do not always respond to selection independently from each other and often show correlated responses to selection. The structure of a genotype-phenotype map (GP map) determines trait covariation, which involves variation in the degree and strength of the pleiotropic effects of the underlying genes. It is still unclear, and debated, how much of that structure can be deduced from variational properties of quantitative traits that are inferred from their genetic (co) variance matrix (G-matrix). Here we aim to clarify how the extent of pleiotropy and the correlation among the pleiotropic effects of mutations differentially affect the structure of a G-matrix and our ability to detect genetic constraints from its eigen decomposition. We show that the eigenvectors of a G-matrix can be predictive of evolutionary constraints when they map to underlying pleiotropic modules with correlated mutational effects. Without mutational correlation, evolutionary constraints caused by the fitness costs associated with increased pleiotropy are harder to infer from evolutionary metrics based on a G-matrix's geometric properties because uncorrelated pleiotropic effects do not affect traits' genetic correlations. Correlational selection induces much weaker modular partitioning of traits' genetic correlations in absence then in presence of underlying modular pleiotropy. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity.

PubMed

Mao, Peng; Brown, Alexander J; Malc, Ewa P; Mieczkowski, Piotr A; Smerdon, Michael J; Roberts, Steven A; Wyrick, John J

2017-10-01

DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers. © 2017 Mao et al.; Published by Cold Spring Harbor Laboratory Press.

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

Wainwright, Haruko M.; Flores Orozco, Adrian; Bucker, Matthias

In floodplain environments, a naturally reduced zone (NRZ) is considered to be a common biogeochemical hot spot, having distinct microbial and geochemical characteristics. Although important for understanding their role in mediating floodplain biogeochemical processes, mapping the subsurface distribution of NRZs over the dimensions of a floodplain is challenging, as conventional wellbore data are typically spatially limited and the distribution of NRZs is heterogeneous. In this work, we present an innovative methodology for the probabilistic mapping of NRZs within a three-dimensional (3-D) subsurface domain using induced polarization imaging, which is a noninvasive geophysical technique. Measurements consist of surface geophysical surveys andmore » drilling-recovered sediments at the U.S. Department of Energy field site near Rifle, CO (USA). Inversion of surface time domain-induced polarization (TDIP) data yielded 3-D images of the complex electrical resistivity, in terms of magnitude and phase, which are associated with mineral precipitation and other lithological properties. By extracting the TDIP data values colocated with wellbore lithological logs, we found that the NRZs have a different distribution of resistivity and polarization from the other aquifer sediments. To estimate the spatial distribution of NRZs, we developed a Bayesian hierarchical model to integrate the geophysical and wellbore data. In addition, the resistivity images were used to estimate hydrostratigraphic interfaces under the floodplain. Validation results showed that the integration of electrical imaging and wellbore data using a Bayesian hierarchical model was capable of mapping spatially heterogeneous interfaces and NRZ distributions thereby providing a minimally invasive means to parameterize a hydrobiogeochemical model of the floodplain.« less

Reconstruction of metabolic pathways by combining probabilistic graphical model-based and knowledge-based methods

PubMed Central

2014-01-01

Automatic reconstruction of metabolic pathways for an organism from genomics and transcriptomics data has been a challenging and important problem in bioinformatics. Traditionally, known reference pathways can be mapped into an organism-specific ones based on its genome annotation and protein homology. However, this simple knowledge-based mapping method might produce incomplete pathways and generally cannot predict unknown new relations and reactions. In contrast, ab initio metabolic network construction methods can predict novel reactions and interactions, but its accuracy tends to be low leading to a lot of false positives. Here we combine existing pathway knowledge and a new ab initio Bayesian probabilistic graphical model together in a novel fashion to improve automatic reconstruction of metabolic networks. Specifically, we built a knowledge database containing known, individual gene / protein interactions and metabolic reactions extracted from existing reference pathways. Known reactions and interactions were then used as constraints for Bayesian network learning methods to predict metabolic pathways. Using individual reactions and interactions extracted from different pathways of many organisms to guide pathway construction is new and improves both the coverage and accuracy of metabolic pathway construction. We applied this probabilistic knowledge-based approach to construct the metabolic networks from yeast gene expression data and compared its results with 62 known metabolic networks in the KEGG database. The experiment showed that the method improved the coverage of metabolic network construction over the traditional reference pathway mapping method and was more accurate than pure ab initio methods. PMID:25374614

Bayesian analysis of anisotropic cosmologies: Bianchi VIIh and WMAP

NASA Astrophysics Data System (ADS)

McEwen, J. D.; Josset, T.; Feeney, S. M.; Peiris, H. V.; Lasenby, A. N.

2013-12-01

We perform a definitive analysis of Bianchi VIIh cosmologies with Wilkinson Microwave Anisotropy Probe (WMAP) observations of the cosmic microwave background (CMB) temperature anisotropies. Bayesian analysis techniques are developed to study anisotropic cosmologies using full-sky and partial-sky masked CMB temperature data. We apply these techniques to analyse the full-sky internal linear combination (ILC) map and a partial-sky masked W-band map of WMAP 9 yr observations. In addition to the physically motivated Bianchi VIIh model, we examine phenomenological models considered in previous studies, in which the Bianchi VIIh parameters are decoupled from the standard cosmological parameters. In the two phenomenological models considered, Bayes factors of 1.7 and 1.1 units of log-evidence favouring a Bianchi component are found in full-sky ILC data. The corresponding best-fitting Bianchi maps recovered are similar for both phenomenological models and are very close to those found in previous studies using earlier WMAP data releases. However, no evidence for a phenomenological Bianchi component is found in the partial-sky W-band data. In the physical Bianchi VIIh model, we find no evidence for a Bianchi component: WMAP data thus do not favour Bianchi VIIh cosmologies over the standard Λ cold dark matter (ΛCDM) cosmology. It is not possible to discount Bianchi VIIh cosmologies in favour of ΛCDM completely, but we are able to constrain the vorticity of physical Bianchi VIIh cosmologies at (ω/H)0 < 8.6 × 10-10 with 95 per cent confidence.

A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice.

PubMed

Calvert, Jennifer A; Dedos, Skarlatos G; Hawker, Kelvin; Fleming, Michelle; Lewis, Morag A; Steel, Karen P

2011-06-01

The hush puppy mouse mutant has been shown previously to have skull and outer, middle, and inner ear defects, and an increase in hearing threshold. The fibroblast growth factor receptor 1 (Fgfr1) gene is located in the region of chromosome 8 containing the mutation. Sequencing of the gene in hush puppy heterozygotes revealed a missense mutation in the kinase domain of the protein (W691R). Homozygotes were found to die during development, at approximately embryonic day 8.5, and displayed a phenotype similar to null mutants. Reverse transcription PCR indicated a decrease in Fgfr1 transcript in heterozygotes and homozygotes. Generation of a construct containing the mutation allowed the function of the mutated receptor to be studied. Immunocytochemistry showed that the mutant receptor protein was present at the cell membrane, suggesting normal expression and trafficking. Measurements of changes in intracellular calcium concentration showed that the mutated receptor could not activate the IP(3) pathway, in contrast to the wild-type receptor, nor could it initiate activation of the Ras/MAP kinase pathway. Thus, the hush puppy mutation in fibroblast growth factor receptor 1 appears to cause a loss of receptor function. The mutant protein appears to have a dominant negative effect, which could be due to it dimerising with the wild-type protein and inhibiting its activity, thus further reducing the levels of functional protein. A dominant modifier, Mhspy, which reduces the effect of the hush puppy mutation on pinna and stapes development, has been mapped to the distal end of chromosome 7 and may show imprinting.

A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.

PubMed

Khateb, Samer; Zelinger, Lina; Mizrahi-Meissonnier, Liliana; Ayuso, Carmen; Koenekoop, Robert K; Laxer, Uri; Gross, Menachem; Banin, Eyal; Sharon, Dror

2014-07-01

Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes. Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping and whole exome sequencing (WES). A combination of homozygosity mapping and WES in a large consanguineous family of Iranian Jewish origin revealed nonsense mutations in two ciliary genes: c.3289C>T (p.Q1097*) in C2orf71 and c.3463C>T (p.R1155*) in centrosome-associated protein CEP250 (C-Nap1). The latter has not been associated with any inherited disease and the c.3463C>T mutation was absent in control chromosomes. Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration. No ciliary structural abnormalities in the respiratory system were evident by electron microscopy analysis. CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region. A homozygous nonsense CEP250 mutation, in combination with a heterozygous C2orf71 nonsense mutation, causes an atypical form of USH, characterised by early-onset SNHL and a relatively mild RP. The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins. 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.

Generative Topographic Mapping (GTM): Universal Tool for Data Visualization, Structure-Activity Modeling and Dataset Comparison.

PubMed

Kireeva, N; Baskin, I I; Gaspar, H A; Horvath, D; Marcou, G; Varnek, A

2012-04-01

Here, the utility of Generative Topographic Maps (GTM) for data visualization, structure-activity modeling and database comparison is evaluated, on hand of subsets of the Database of Useful Decoys (DUD). Unlike other popular dimensionality reduction approaches like Principal Component Analysis, Sammon Mapping or Self-Organizing Maps, the great advantage of GTMs is providing data probability distribution functions (PDF), both in the high-dimensional space defined by molecular descriptors and in 2D latent space. PDFs for the molecules of different activity classes were successfully used to build classification models in the framework of the Bayesian approach. Because PDFs are represented by a mixture of Gaussian functions, the Bhattacharyya kernel has been proposed as a measure of the overlap of datasets, which leads to an elegant method of global comparison of chemical libraries. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

9. international mouse genome conference

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

NONE

This conference was held November 12--16, 1995 in Ann Arbor, Michigan. The purpose of this conference was to provide a multidisciplinary forum for exchange of state-of-the-art information on genetic mapping in mice. This report contains abstracts of presentations, focusing on the following areas: mutation identification; comparative mapping; informatics and complex traits; mutagenesis; gene identification and new technology; and genetic and physical mapping.

Fine Structure Genetic and Physical Map of the Gene 3 to 10 Region of the Bacteriophage P22 Chromosome

PubMed Central

Casjens, S.; Eppler, K.; Sampson, L.; Parr, R.; Wyckoff, E.

1991-01-01

The mechanism by which dsDNA is packaged by viruses is not yet understood in any system. Bacteriophage P22 has been a productive system in which to study the molecular genetics of virus particle assembly and DNA packaging. Only five phage encoded proteins, the products of genes 3, 2, 1, 8 and 5, are required for packaging the virus chromosome inside the coat protein shell. We report here the construction of a detailed genetic and physical map of these genes, the neighboring gene 4 and a portion of gene 10, in which 289 conditional lethal amber, opal, temperature sensitive and cold sensitive mutations are mapped into 44 small (several hundred base pair) intervals of known sequence. Knowledge of missense mutant phenotypes and information on the location of these mutations allows us to begin the assignment of partial protein functions to portions of these genes. The map and mapping strains will be of use in the further genetic dissection of the P22 DNA packaging and prohead assembly processes. PMID:2029965

Assessing Vermont's stream health and biological integrity using artificial neural networks and Bayesian methods

NASA Astrophysics Data System (ADS)

Rizzo, D. M.; Fytilis, N.; Stevens, L.

2012-12-01

Environmental managers are increasingly required to monitor and forecast long-term effects and vulnerability of biophysical systems to human-generated stresses. Ideally, a study involving both physical and biological assessments conducted concurrently (in space and time) could provide a better understanding of the mechanisms and complex relationships. However, costs and resources associated with monitoring the complex linkages between the physical, geomorphic and habitat conditions and the biological integrity of stream reaches are prohibitive. Researchers have used classification techniques to place individual streams and rivers into a broader spatial context (hydrologic or health condition). Such efforts require environmental managers to gather multiple forms of information - quantitative, qualitative and subjective. We research and develop a novel classification tool that combines self-organizing maps with a Naïve Bayesian classifier to direct resources to stream reaches most in need. The Vermont Agency of Natural Resources has developed and adopted protocols for physical stream geomorphic and habitat assessments throughout the state of Vermont. Separate from these assessments, the Vermont Department of Environmental Conservation monitors the biological communities and the water quality in streams. Our initial hypothesis is that the geomorphic reach assessments and water quality data may be leveraged to reduce error and uncertainty associated with predictions of biological integrity and stream health. We test our hypothesis using over 2500 Vermont stream reaches (~1371 stream miles) assessed by the two agencies. In the development of this work, we combine a Naïve Bayesian classifier with a modified Kohonen Self-Organizing Map (SOM). The SOM is an unsupervised artificial neural network that autonomously analyzes inherent dataset properties using input data only. It is typically used to cluster data into similar categories when a priori classes do not exist. The incorporation of a Bayesian classifier allows one to explicitly incorporate existing knowledge and expert opinion into the data analysis. Since classification plays a leading role in the future development of data-enabled science and engineering, such a computational tool is applicable to a variety of proactive adaptive watershed management applications.

Molecular genetic analysis of retinitis pigmentosa in Indonesia using genome-wide homozygosity mapping

PubMed Central

Siemiatkowska, Anna M.; Arimadyo, Kentar; Moruz, Luminita M.; Astuti, Galuh D.N.; de Castro-Miro, Marta; Zonneveld, Marijke N.; Strom, Tim M.; de Wijs, Ilse J.; Hoefsloot, Lies H.; Faradz, Sultana M.H.; Cremers, Frans P.M.; den Hollander, Anneke I.

2011-01-01

Purpose Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous retinal disorder. Despite tremendous knowledge about the genes involved in RP, little is known about the genetic causes of RP in Indonesia. Here, we aim to identify the molecular genetic causes underlying RP in a small cohort of Indonesian patients, using genome-wide homozygosity mapping. Methods DNA samples from affected and healthy individuals from 14 Indonesian families segregating autosomal recessive, X-linked, or isolated RP were collected. Homozygosity mapping was conducted using Illumina 6k or Affymetrix 5.0 single nucleotide polymorphism (SNP) arrays. Known autosomal recessive RP (arRP) genes residing in homozygous regions and X-linked RP genes were sequenced for mutations. Results In ten out of the 14 families, homozygous regions were identified that contained genes known to be involved in the pathogenesis of RP. Sequence analysis of these genes revealed seven novel homozygous mutations in ATP-binding cassette, sub-family A, member 4 (ABCA4), crumbs homolog 1 (CRB1), eyes shut homolog (Drosophila) (EYS), c-mer proto-oncogene tyrosine kinase (MERTK), nuclear receptor subfamily 2, group E, member 3 (NR2E3) and phosphodiesterase 6A, cGMP-specific, rod, alpha (PDE6A), all segregating in the respective families. No mutations were identified in the X-linked genes retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (X-linked recessive; RP2). Conclusions Homozygosity mapping is a powerful tool to identify the genetic defects underlying RP in the Indonesian population. Compared to studies involving patients from other populations, the same genes appear to be implicated in the etiology of recessive RP in Indonesia, although all mutations that were discovered are novel and as such may be unique for this population. PMID:22128245

Next Generation MUT-MAP, a High-Sensitivity High-Throughput Microfluidics Chip-Based Mutation Analysis Panel

PubMed Central

Patel, Rajesh; Tsan, Alison; Sumiyoshi, Teiko; Fu, Ling; Desai, Rupal; Schoenbrunner, Nancy; Myers, Thomas W.; Bauer, Keith; Smith, Edward; Raja, Rajiv

2014-01-01

Molecular profiling of tumor tissue to detect alterations, such as oncogenic mutations, plays a vital role in determining treatment options in oncology. Hence, there is an increasing need for a robust and high-throughput technology to detect oncogenic hotspot mutations. Although commercial assays are available to detect genetic alterations in single genes, only a limited amount of tissue is often available from patients, requiring multiplexing to allow for simultaneous detection of mutations in many genes using low DNA input. Even though next-generation sequencing (NGS) platforms provide powerful tools for this purpose, they face challenges such as high cost, large DNA input requirement, complex data analysis, and long turnaround times, limiting their use in clinical settings. We report the development of the next generation mutation multi-analyte panel (MUT-MAP), a high-throughput microfluidic, panel for detecting 120 somatic mutations across eleven genes of therapeutic interest (AKT1, BRAF, EGFR, FGFR3, FLT3, HRAS, KIT, KRAS, MET, NRAS, and PIK3CA) using allele-specific PCR (AS-PCR) and Taqman technology. This mutation panel requires as little as 2 ng of high quality DNA from fresh frozen or 100 ng of DNA from formalin-fixed paraffin-embedded (FFPE) tissues. Mutation calls, including an automated data analysis process, have been implemented to run 88 samples per day. Validation of this platform using plasmids showed robust signal and low cross-reactivity in all of the newly added assays and mutation calls in cell line samples were found to be consistent with the Catalogue of Somatic Mutations in Cancer (COSMIC) database allowing for direct comparison of our platform to Sanger sequencing. High correlation with NGS when compared to the SuraSeq500 panel run on the Ion Torrent platform in a FFPE dilution experiment showed assay sensitivity down to 0.45%. This multiplexed mutation panel is a valuable tool for high-throughput biomarker discovery in personalized medicine and cancer drug development. PMID:24658394

Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: evidence for differences and commonalities in size distributions and size restrictions

PubMed Central

2013-01-01

Background Macrosatellite repeats (MSRs), usually spanning hundreds of kilobases of genomic DNA, comprise a significant proportion of the human genome. Because of their highly polymorphic nature, MSRs represent an extreme example of copy number variation, but their structure and function is largely understudied. Here, we describe a detailed study of six autosomal and two X chromosomal MSRs among 270 HapMap individuals from Central Europe, Asia and Africa. Copy number variation, stability and genetic heterogeneity of the autosomal macrosatellite repeats RS447 (chromosome 4p), MSR5p (5p), FLJ40296 (13q), RNU2 (17q) and D4Z4 (4q and 10q) and X chromosomal DXZ4 and CT47 were investigated. Results Repeat array size distribution analysis shows that all of these MSRs are highly polymorphic with the most genetic variation among Africans and the least among Asians. A mitotic mutation rate of 0.4-2.2% was observed, exceeding meiotic mutation rates and possibly explaining the large size variability found for these MSRs. By means of a novel Bayesian approach, statistical support for a distinct multimodal rather than a uniform allele size distribution was detected in seven out of eight MSRs, with evidence for equidistant intervals between the modes. Conclusions The multimodal distributions with evidence for equidistant intervals, in combination with the observation of MSR-specific constraints on minimum array size, suggest that MSRs are limited in their configurations and that deviations thereof may cause disease, as is the case for facioscapulohumeral muscular dystrophy. However, at present we cannot exclude that there are mechanistic constraints for MSRs that are not directly disease-related. This study represents the first comprehensive study of MSRs in different human populations by applying novel statistical methods and identifies commonalities and differences in their organization and function in the human genome. PMID:23496858

A novel approach for choosing summary statistics in approximate Bayesian computation.

PubMed

Aeschbacher, Simon; Beaumont, Mark A; Futschik, Andreas

2012-11-01

The choice of summary statistics is a crucial step in approximate Bayesian computation (ABC). Since statistics are often not sufficient, this choice involves a trade-off between loss of information and reduction of dimensionality. The latter may increase the efficiency of ABC. Here, we propose an approach for choosing summary statistics based on boosting, a technique from the machine-learning literature. We consider different types of boosting and compare them to partial least-squares regression as an alternative. To mitigate the lack of sufficiency, we also propose an approach for choosing summary statistics locally, in the putative neighborhood of the true parameter value. We study a demographic model motivated by the reintroduction of Alpine ibex (Capra ibex) into the Swiss Alps. The parameters of interest are the mean and standard deviation across microsatellites of the scaled ancestral mutation rate (θ(anc) = 4N(e)u) and the proportion of males obtaining access to matings per breeding season (ω). By simulation, we assess the properties of the posterior distribution obtained with the various methods. According to our criteria, ABC with summary statistics chosen locally via boosting with the L(2)-loss performs best. Applying that method to the ibex data, we estimate θ(anc)≈ 1.288 and find that most of the variation across loci of the ancestral mutation rate u is between 7.7 × 10(-4) and 3.5 × 10(-3) per locus per generation. The proportion of males with access to matings is estimated as ω≈ 0.21, which is in good agreement with recent independent estimates.

A Novel Approach for Choosing Summary Statistics in Approximate Bayesian Computation

PubMed Central

Aeschbacher, Simon; Beaumont, Mark A.; Futschik, Andreas

2012-01-01

The choice of summary statistics is a crucial step in approximate Bayesian computation (ABC). Since statistics are often not sufficient, this choice involves a trade-off between loss of information and reduction of dimensionality. The latter may increase the efficiency of ABC. Here, we propose an approach for choosing summary statistics based on boosting, a technique from the machine-learning literature. We consider different types of boosting and compare them to partial least-squares regression as an alternative. To mitigate the lack of sufficiency, we also propose an approach for choosing summary statistics locally, in the putative neighborhood of the true parameter value. We study a demographic model motivated by the reintroduction of Alpine ibex (Capra ibex) into the Swiss Alps. The parameters of interest are the mean and standard deviation across microsatellites of the scaled ancestral mutation rate (θanc = 4Neu) and the proportion of males obtaining access to matings per breeding season (ω). By simulation, we assess the properties of the posterior distribution obtained with the various methods. According to our criteria, ABC with summary statistics chosen locally via boosting with the L2-loss performs best. Applying that method to the ibex data, we estimate θ^anc≈1.288 and find that most of the variation across loci of the ancestral mutation rate u is between 7.7 × 10−4 and 3.5 × 10−3 per locus per generation. The proportion of males with access to matings is estimated as ω^≈0.21, which is in good agreement with recent independent estimates. PMID:22960215

Narrowing the wingless-2 mutation to a 227 kb candidate region on chicken chromosome 12

PubMed Central

Webb, A E; Youngworth, I A; Kaya, M; Gitter, C L; O’Hare, E A; May, B; Cheng, H H; Delany, M E

2018-01-01

ABSTRACT Wingless-2 (wg-2) is an autosomal recessive mutation in chicken that results in an embryonic lethal condition. Affected individuals exhibit a multisystem syndrome characterized by absent wings, truncated legs, and craniofacial, kidney, and feather malformations. Previously, work focused on phenotype description, establishing the autosomal recessive pattern of Mendelian inheritance and placing the mutation on an inbred genetic background to create the congenic line UCD Wingless-2.331. The research described in this paper employed the complementary tools of breeding, genetics, and genomics to map the chromosomal location of the mutation and successively narrow the size of the region for analysis of the causative element. Specifically, the wg-2 mutation was initially mapped to a 7 Mb region of chromosome 12 using an Illumina 3 K SNP array. Subsequent SNP genotyping and exon sequencing combined with analysis from improved genome assemblies narrowed the region of interest to a maximum size of 227 kb. Within this region, 3 validated and 3 predicted candidate genes are found, and these are described. The wg-2 mutation is a valuable resource to contribute to an improved understanding of the developmental pathways involved in chicken and avian limb development as well as serving as a model for human development, as the resulting syndrome shares features with human congenital disorders. PMID:29562287

Bayesian LASSO, scale space and decision making in association genetics.

PubMed

Pasanen, Leena; Holmström, Lasse; Sillanpää, Mikko J

2015-01-01

LASSO is a penalized regression method that facilitates model fitting in situations where there are as many, or even more explanatory variables than observations, and only a few variables are relevant in explaining the data. We focus on the Bayesian version of LASSO and consider four problems that need special attention: (i) controlling false positives, (ii) multiple comparisons, (iii) collinearity among explanatory variables, and (iv) the choice of the tuning parameter that controls the amount of shrinkage and the sparsity of the estimates. The particular application considered is association genetics, where LASSO regression can be used to find links between chromosome locations and phenotypic traits in a biological organism. However, the proposed techniques are relevant also in other contexts where LASSO is used for variable selection. We separate the true associations from false positives using the posterior distribution of the effects (regression coefficients) provided by Bayesian LASSO. We propose to solve the multiple comparisons problem by using simultaneous inference based on the joint posterior distribution of the effects. Bayesian LASSO also tends to distribute an effect among collinear variables, making detection of an association difficult. We propose to solve this problem by considering not only individual effects but also their functionals (i.e. sums and differences). Finally, whereas in Bayesian LASSO the tuning parameter is often regarded as a random variable, we adopt a scale space view and consider a whole range of fixed tuning parameters, instead. The effect estimates and the associated inference are considered for all tuning parameters in the selected range and the results are visualized with color maps that provide useful insights into data and the association problem considered. The methods are illustrated using two sets of artificial data and one real data set, all representing typical settings in association genetics.

Can I Order a Burger at rnacdonalds.com? Visual Similarity Effects of Multi-Letter Combinations at the Early Stages of Word Recognition

ERIC Educational Resources Information Center

Marcet, Ana; Perea, Manuel

2018-01-01

Previous research has shown that early in the word recognition process, there is some degree of uncertainty concerning letter identity and letter position. Here, we examined whether this uncertainty also extends to the mapping of letter features onto letters, as predicted by the Bayesian Reader (Norris & Kinoshita, 2012). Indeed, anecdotal…

Bayesian Aggregation of Evidence for Detection and Characterization of Patterns in Multiple Noisy Observations

DTIC Science & Technology

2015-07-01

undergraduate student coauthors Aashish Jindia, Parag Srivastava, and Jay Jin for help with the research. In addition, thank you to the numerous...103 A.1.1 Sacramento Data Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 A.1.2 RadMap and SUNS Data Sets...parameters in a joint hypothesis space. We develop scalable branch and bound and pruning mechanisms for searching (at multiple resolutions) over source

Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas: Mutational signature associated with MUTYH deficiency in cancers

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

Pilati, Camilla; Shinde, Jayendra; Alexandrov, Ludmil B.

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signaturemore » also presenting germline MUTYH mutations. Altogether, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types.« less

Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas: Mutational signature associated with MUTYH deficiency in cancers

DOE PAGES

Pilati, Camilla; Shinde, Jayendra; Alexandrov, Ludmil B.; ...

2017-03-29

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signaturemore » also presenting germline MUTYH mutations. Altogether, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types.« less

Efficient fractal-based mutation in evolutionary algorithms from iterated function systems

NASA Astrophysics Data System (ADS)

Salcedo-Sanz, S.; Aybar-Ruíz, A.; Camacho-Gómez, C.; Pereira, E.

2018-03-01

In this paper we present a new mutation procedure for Evolutionary Programming (EP) approaches, based on Iterated Function Systems (IFSs). The new mutation procedure proposed consists of considering a set of IFS which are able to generate fractal structures in a two-dimensional phase space, and use them to modify a current individual of the EP algorithm, instead of using random numbers from different probability density functions. We test this new proposal in a set of benchmark functions for continuous optimization problems. In this case, we compare the proposed mutation against classical Evolutionary Programming approaches, with mutations based on Gaussian, Cauchy and chaotic maps. We also include a discussion on the IFS-based mutation in a real application of Tuned Mass Dumper (TMD) location and optimization for vibration cancellation in buildings. In both practical cases, the proposed EP with the IFS-based mutation obtained extremely competitive results compared to alternative classical mutation operators.

Cloning and Characterization of a Critical Regulator for Preharvest Sprouting in Wheat

PubMed Central

Liu, Shubing; Sehgal, Sunish K.; Li, Jiarui; Lin, Meng; Trick, Harold N.; Yu, Jianming; Gill, Bikram S.; Bai, Guihua

2013-01-01

Sprouting of grains in mature spikes before harvest is a major problem in wheat (Triticum aestivum) production worldwide. We cloned and characterized a gene underlying a wheat quantitative trait locus (QTL) on the short arm of chromosome 3A for preharvest sprouting (PHS) resistance in white wheat using comparative mapping and map-based cloning. This gene, designated TaPHS1, is a wheat homolog of a MOTHER OF FLOWERING TIME (TaMFT)-like gene. RNA interference-mediated knockdown of the gene confirmed that TaPHS1 positively regulates PHS resistance. We discovered two causal mutations in TaPHS1 that jointly altered PHS resistance in wheat. One GT-to-AT mutation generates a mis-splicing site, and the other A-to-T mutation creates a premature stop codon that results in a truncated nonfunctional transcript. Association analysis of a set of wheat cultivars validated the role of the two mutations on PHS resistance. The molecular characterization of TaPHS1 is significant for expediting breeding for PHS resistance to protect grain yield and quality in wheat production. PMID:23821595

A Bayesian-Based Novel Methodology to Generate Reliable Site Response Mapping Sensitive to Data Uncertainties

NASA Astrophysics Data System (ADS)

Chakraborty, A.; Goto, H.

2017-12-01

The 2011 off the Pacific coast of Tohoku earthquake caused severe damage in many areas further inside the mainland because of site-amplification. Furukawa district in Miyagi Prefecture, Japan recorded significant spatial differences in ground motion even at sub-kilometer scales. The site responses in the damage zone far exceeded the levels in the hazard maps. A reason why the mismatch occurred is that mapping follow only the mean value at the measurement locations with no regard to the data uncertainties and thus are not always reliable. Our research objective is to develop a methodology to incorporate data uncertainties in mapping and propose a reliable map. The methodology is based on a hierarchical Bayesian modeling of normally-distributed site responses in space where the mean (μ), site-specific variance (σ2) and between-sites variance(s2) parameters are treated as unknowns with a prior distribution. The observation data is artificially created site responses with varying means and variances for 150 seismic events across 50 locations in one-dimensional space. Spatially auto-correlated random effects were added to the mean (μ) using a conditionally autoregressive (CAR) prior. The inferences on the unknown parameters are done using Markov Chain Monte Carlo methods from the posterior distribution. The goal is to find reliable estimates of μ sensitive to uncertainties. During initial trials, we observed that the tau (=1/s2) parameter of CAR prior controls the μ estimation. Using a constraint, s = 1/(k×σ), five spatial models with varying k-values were created. We define reliability to be measured by the model likelihood and propose the maximum likelihood model to be highly reliable. The model with maximum likelihood was selected using a 5-fold cross-validation technique. The results show that the maximum likelihood model (μ*) follows the site-specific mean at low uncertainties and converges to the model-mean at higher uncertainties (Fig.1). This result is highly significant as it successfully incorporates the effect of data uncertainties in mapping. This novel approach can be applied to any research field using mapping techniques. The methodology is now being applied to real records from a very dense seismic network in Furukawa district, Miyagi Prefecture, Japan to generate a reliable map of the site responses.

A cis-Regulatory Mutation of PDSS2 Causes Silky-Feather in Chickens

PubMed Central

Feng, Chungang; Gao, Yu; Dorshorst, Ben; Song, Chi; Gu, Xiaorong; Li, Qingyuan; Li, Jinxiu; Liu, Tongxin; Rubin, Carl-Johan; Zhao, Yiqiang; Wang, Yanqiang; Fei, Jing; Li, Huifang; Chen, Kuanwei; Qu, Hao; Shu, Dingming; Ashwell, Chris; Da, Yang; Andersson, Leif; Hu, Xiaoxiang; Li, Ning

2014-01-01

Silky-feather has been selected and fixed in some breeds due to its unique appearance. This phenotype is caused by a single recessive gene (hookless, h). Here we map the silky-feather locus to chromosome 3 by linkage analysis and subsequently fine-map it to an 18.9 kb interval using the identical by descent (IBD) method. Further analysis reveals that a C to G transversion located upstream of the prenyl (decaprenyl) diphosphate synthase, subunit 2 (PDSS2) gene is causing silky-feather. All silky-feather birds are homozygous for the G allele. The silky-feather mutation significantly decreases the expression of PDSS2 during feather development in vivo. Consistent with the regulatory effect, the C to G transversion is shown to remarkably reduce PDSS2 promoter activity in vitro. We report a new example of feather structure variation associated with a spontaneous mutation and provide new insight into the PDSS2 function. PMID:25166907

The major origin of seedless grapes is associated with a missense mutation in the MADS-box gene VviAGL11.

PubMed

Royo, Carolina; Torres-Pérez, Rafael; Mauri, Nuria; Diestro, Nieves; Cabezas, José Antonio; Marchal, Cécile; Lacombe, Thierry; Ibáñez, Javier; Tornel, Manuel; Carreño, Juan; Martínez-Zapater, José M; Carbonell-Bejerano, Pablo

2018-05-31

Seedlessness is greatly prized by consumers of fresh grapes. While stenospermocarpic seed abortion determined by the SEED DEVELOPMENT INHIBITOR (SDI) locus is the usual source of seedlessness in commercial grapevine (Vitis vinifera) cultivars, the underlying sdi mutation remains unknown. Here, we undertook an integrative approach to identify the causal mutation. Quantitative genetics and fine mapping in two 'Crimson Seedless' (CS)-derived F1 mapping populations confirmed the major effect of the SDI locus and delimited the sdi mutation to a 323-kb region on chromosome 18. RNA-seq comparing seed traces of seedless and seeds of seeded F1 individuals identified processes triggered during sdi-determined seed abortion, including activation of salicylic acid-dependent defenses. The RNA-seq dataset was investigated for candidate genes and, while no evidence for causal cis-acting regulatory mutations was detected, deleterious nucleotide changes in coding sequences of the seedless haplotype were predicted in two genes within the sdi fine mapping interval. Targeted re-sequencing of the two genes in a collection of 124 grapevine cultivars showed that only the point variation causing the Arg197Leu substitution in the seed morphogenesis regulator gene AGAMOUS-LIKE 11 (VviAGL11) was fully linked with stenospermocarpy. The concurrent post-zygotic variation identified for this missense polymorphism and seedlessness phenotype in seeded somatic variants of the original stenospermocarpic cultivar supports a causal effect. We postulate that seed abortion caused by this amino acid substitution in VviAGL11 is the major cause of seedlessness in cultivated grapevine. This information can be exploited to boost seedless grape breeding. {copyright, serif} 2018 American Society of Plant Biologists. All rights reserved.

Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites

PubMed Central

2010-01-01

Background Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum. Results A lineage of isogenic in vivo drug-selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (Illumina® Solexa) defined the point mutations, insertions, deletions and copy-number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme. Conclusions This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. PMID:20846421

Whole genome association study identifies regions of the bovine genome and biological pathways involved in carcass trait performance in Holstein-Friesian cattle.

PubMed

Doran, Anthony G; Berry, Donagh P; Creevey, Christopher J

2014-10-01

Four traits related to carcass performance have been identified as economically important in beef production: carcass weight, carcass fat, carcass conformation of progeny and cull cow carcass weight. Although Holstein-Friesian cattle are primarily utilized for milk production, they are also an important source of meat for beef production and export. Because of this, there is great interest in understanding the underlying genomic structure influencing these traits. Several genome-wide association studies have identified regions of the bovine genome associated with growth or carcass traits, however, little is known about the mechanisms or underlying biological pathways involved. This study aims to detect regions of the bovine genome associated with carcass performance traits (employing a panel of 54,001 SNPs) using measures of genetic merit (as predicted transmitting abilities) for 5,705 Irish Holstein-Friesian animals. Candidate genes and biological pathways were then identified for each trait under investigation. Following adjustment for false discovery (q-value < 0.05), 479 quantitative trait loci (QTL) were associated with at least one of the four carcass traits using a single SNP regression approach. Using a Bayesian approach, 46 QTL were associated (posterior probability > 0.5) with at least one of the four traits. In total, 557 unique bovine genes, which mapped to 426 human orthologs, were within 500kbs of QTL found associated with a trait using the Bayesian approach. Using this information, 24 significantly over-represented pathways were identified across all traits. The most significantly over-represented biological pathway was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. A large number of genomic regions putatively associated with bovine carcass traits were detected using two different statistical approaches. Notably, several significant associations were detected in close proximity to genes with a known role in animal growth such as glucagon and leptin. Several biological pathways, including PPAR signaling, were shown to be involved in various aspects of bovine carcass performance. These core genes and biological processes may form the foundation for further investigation to identify causative mutations involved in each trait. Results reported here support previous findings suggesting conservation of key biological processes involved in growth and metabolism.

Radiation Source Mapping with Bayesian Inverse Methods

DOE PAGES

Hykes, Joshua M.; Azmy, Yousry Y.

2017-03-22

In this work, we present a method to map the spectral and spatial distributions of radioactive sources using a limited number of detectors. Locating and identifying radioactive materials is important for border monitoring, in accounting for special nuclear material in processing facilities, and in cleanup operations following a radioactive material spill. Most methods to analyze these types of problems make restrictive assumptions about the distribution of the source. In contrast, the source mapping method presented here allows an arbitrary three-dimensional distribution in space and a gamma peak distribution in energy. To apply the method, the problem is cast as anmore » inverse problem where the system’s geometry and material composition are known and fixed, while the radiation source distribution is sought. A probabilistic Bayesian approach is used to solve the resulting inverse problem since the system of equations is ill-posed. The posterior is maximized with a Newton optimization method. The probabilistic approach also provides estimates of the confidence in the final source map prediction. A set of adjoint, discrete ordinates flux solutions, obtained in this work by the Denovo code, is required to efficiently compute detector responses from a candidate source distribution. These adjoint fluxes form the linear mapping from the state space to the response space. The test of the method’s success is simultaneously locating a set of 137Cs and 60Co gamma sources in a room. This test problem is solved using experimental measurements that we collected for this purpose. Because of the weak sources available for use in the experiment, some of the expected photopeaks were not distinguishable from the Compton continuum. However, by supplanting 14 flawed measurements (out of a total of 69) with synthetic responses computed by MCNP, the proof-of-principle source mapping was successful. The locations of the sources were predicted within 25 cm for two of the sources and 90 cm for the third, in a room with an ~4-x 4-m floor plan. Finally, the predicted source intensities were within a factor of ten of their true value.« less

Exome Capture and Massively Parallel Sequencing Identifies a Novel HPSE2 Mutation in a Saudi Arabian Child with Ochoa (Urofacial) Syndrome

PubMed Central

Al Badr, Wisam; Al Bader, Suha; Otto, Edgar; Hildebrandt, Friedhelm; Ackley, Todd; Peng, Weiping; Xu, Jishu; Li, Jun; Owens, Kailey M.; Bloom, David; Innis, Jeffrey W.

2011-01-01

We describe a child of Middle Eastern descent by first-cousin mating with idiopathic neurogenic bladder and high grade vesicoureteral reflux at 1 year of age, whose characteristic facial grimace led to the diagnosis of Ochoa (Urofacial) syndrome at age 5 years. We used homozygosity mapping, exome capture and paired end sequencing to identify the disease causing mutation in the proband. We reviewed the literature with respect to the urologic manifestations of Ochoa syndrome. A large region of marker homozygosity was observed at 10q24, consistent with known autosomal recessive inheritance, family consanguinity and previous genetic mapping in other families with Ochoa syndrome. A homozygous mutation was identified in the proband in HPSE2: c.1374_1378delTGTGC, a deletion of 5 nucleotides in exon 10 that is predicted to lead to a frameshift followed by replacement of 132 C-terminal amino acids with 153 novel amino acids (p.Ala458Alafsdel132ins153). This mutation is novel relative to very recently published mutations in HPSE2 in other families. Early intervention and recognition of Ochoa syndrome with control of risk factors and close surveillance will decrease complications and renal failure. PMID:21450525

Rapid identification of causal mutations in tomato EMS populations via mapping-by-sequencing.

PubMed

Garcia, Virginie; Bres, Cécile; Just, Daniel; Fernandez, Lucie; Tai, Fabienne Wong Jun; Mauxion, Jean-Philippe; Le Paslier, Marie-Christine; Bérard, Aurélie; Brunel, Dominique; Aoki, Koh; Alseekh, Saleh; Fernie, Alisdair R; Fraser, Paul D; Rothan, Christophe

2016-12-01

The tomato is the model species of choice for fleshy fruit development and for the Solanaceae family. Ethyl methanesulfonate (EMS) mutants of tomato have already proven their utility for analysis of gene function in plants, leading to improved breeding stocks and superior tomato varieties. However, until recently, the identification of causal mutations that underlie particular phenotypes has been a very lengthy task that many laboratories could not afford because of spatial and technical limitations. Here, we describe a simple protocol for identifying causal mutations in tomato using a mapping-by-sequencing strategy. Plants displaying phenotypes of interest are first isolated by screening an EMS mutant collection generated in the miniature cultivar Micro-Tom. A recombinant F 2 population is then produced by crossing the mutant with a wild-type (WT; non-mutagenized) genotype, and F 2 segregants displaying the same phenotype are subsequently pooled. Finally, whole-genome sequencing and analysis of allele distributions in the pools allow for the identification of the causal mutation. The whole process, from the isolation of the tomato mutant to the identification of the causal mutation, takes 6-12 months. This strategy overcomes many previous limitations, is simple to use and can be applied in most laboratories with limited facilities for plant culture and genotyping.

In cell mutational interference mapping experiment (in cell MIME) identifies the 5' polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging.

PubMed

Smyth, Redmond P; Smith, Maureen R; Jousset, Anne-Caroline; Despons, Laurence; Laumond, Géraldine; Decoville, Thomas; Cattenoz, Pierre; Moog, Christiane; Jossinet, Fabrice; Mougel, Marylène; Paillart, Jean-Christophe; von Kleist, Max; Marquet, Roland

2018-05-18

Non-coding RNA regulatory elements are important for viral replication, making them promising targets for therapeutic intervention. However, regulatory RNA is challenging to detect and characterise using classical structure-function assays. Here, we present in cell Mutational Interference Mapping Experiment (in cell MIME) as a way to define RNA regulatory landscapes at single nucleotide resolution under native conditions. In cell MIME is based on (i) random mutation of an RNA target, (ii) expression of mutated RNA in cells, (iii) physical separation of RNA into functional and non-functional populations, and (iv) high-throughput sequencing to identify mutations affecting function. We used in cell MIME to define RNA elements within the 5' region of the HIV-1 genomic RNA (gRNA) that are important for viral replication in cells. We identified three distinct RNA motifs controlling intracellular gRNA production, and two distinct motifs required for gRNA packaging into virions. Our analysis reveals the 73AAUAAA78 polyadenylation motif within the 5' PolyA domain as a dual regulator of gRNA production and gRNA packaging, and demonstrates that a functional polyadenylation signal is required for viral packaging even though it negatively affects gRNA production.

In cell mutational interference mapping experiment (in cell MIME) identifies the 5′ polyadenylation signal as a dual regulator of HIV-1 genomic RNA production and packaging

PubMed Central

Smith, Maureen R; Jousset, Anne-Caroline; Despons, Laurence; Laumond, Géraldine; Decoville, Thomas; Cattenoz, Pierre; Moog, Christiane; Jossinet, Fabrice; Mougel, Marylène; Paillart, Jean-Christophe

2018-01-01

Abstract Non-coding RNA regulatory elements are important for viral replication, making them promising targets for therapeutic intervention. However, regulatory RNA is challenging to detect and characterise using classical structure-function assays. Here, we present in cell Mutational Interference Mapping Experiment (in cell MIME) as a way to define RNA regulatory landscapes at single nucleotide resolution under native conditions. In cell MIME is based on (i) random mutation of an RNA target, (ii) expression of mutated RNA in cells, (iii) physical separation of RNA into functional and non-functional populations, and (iv) high-throughput sequencing to identify mutations affecting function. We used in cell MIME to define RNA elements within the 5′ region of the HIV-1 genomic RNA (gRNA) that are important for viral replication in cells. We identified three distinct RNA motifs controlling intracellular gRNA production, and two distinct motifs required for gRNA packaging into virions. Our analysis reveals the 73AAUAAA78 polyadenylation motif within the 5′ PolyA domain as a dual regulator of gRNA production and gRNA packaging, and demonstrates that a functional polyadenylation signal is required for viral packaging even though it negatively affects gRNA production. PMID:29514260

Quantitative trait nucleotide analysis using Bayesian model selection.

PubMed

Blangero, John; Goring, Harald H H; Kent, Jack W; Williams, Jeff T; Peterson, Charles P; Almasy, Laura; Dyer, Thomas D

2005-10-01

Although much attention has been given to statistical genetic methods for the initial localization and fine mapping of quantitative trait loci (QTLs), little methodological work has been done to date on the problem of statistically identifying the most likely functional polymorphisms using sequence data. In this paper we provide a general statistical genetic framework, called Bayesian quantitative trait nucleotide (BQTN) analysis, for assessing the likely functional status of genetic variants. The approach requires the initial enumeration of all genetic variants in a set of resequenced individuals. These polymorphisms are then typed in a large number of individuals (potentially in families), and marker variation is related to quantitative phenotypic variation using Bayesian model selection and averaging. For each sequence variant a posterior probability of effect is obtained and can be used to prioritize additional molecular functional experiments. An example of this quantitative nucleotide analysis is provided using the GAW12 simulated data. The results show that the BQTN method may be useful for choosing the most likely functional variants within a gene (or set of genes). We also include instructions on how to use our computer program, SOLAR, for association analysis and BQTN analysis.

Fuzzy Bayesian Network-Bow-Tie Analysis of Gas Leakage during Biomass Gasification

PubMed Central

Yan, Fang; Xu, Kaili; Yao, Xiwen; Li, Yang

2016-01-01

Biomass gasification technology has been rapidly developed recently. But fire and poisoning accidents caused by gas leakage restrict the development and promotion of biomass gasification. Therefore, probabilistic safety assessment (PSA) is necessary for biomass gasification system. Subsequently, Bayesian network-bow-tie (BN-bow-tie) analysis was proposed by mapping bow-tie analysis into Bayesian network (BN). Causes of gas leakage and the accidents triggered by gas leakage can be obtained by bow-tie analysis, and BN was used to confirm the critical nodes of accidents by introducing corresponding three importance measures. Meanwhile, certain occurrence probability of failure was needed in PSA. In view of the insufficient failure data of biomass gasification, the occurrence probability of failure which cannot be obtained from standard reliability data sources was confirmed by fuzzy methods based on expert judgment. An improved approach considered expert weighting to aggregate fuzzy numbers included triangular and trapezoidal numbers was proposed, and the occurrence probability of failure was obtained. Finally, safety measures were indicated based on the obtained critical nodes. The theoretical occurrence probabilities in one year of gas leakage and the accidents caused by it were reduced to 1/10.3 of the original values by these safety measures. PMID:27463975

Potential uses of Bayesian networks as tools for synthesis of systematic reviews of complex interventions.

PubMed

Stewart, G B; Mengersen, K; Meader, N

2014-03-01

Bayesian networks (BNs) are tools for representing expert knowledge or evidence. They are especially useful for synthesising evidence or belief concerning a complex intervention, assessing the sensitivity of outcomes to different situations or contextual frameworks and framing decision problems that involve alternative types of intervention. Bayesian networks are useful extensions to logic maps when initiating a review or to facilitate synthesis and bridge the gap between evidence acquisition and decision-making. Formal elicitation techniques allow development of BNs on the basis of expert opinion. Such applications are useful alternatives to 'empty' reviews, which identify knowledge gaps but fail to support decision-making. Where review evidence exists, it can inform the development of a BN. We illustrate the construction of a BN using a motivating example that demonstrates how BNs can ensure coherence, transparently structure the problem addressed by a complex intervention and assess sensitivity to context, all of which are critical components of robust reviews of complex interventions. We suggest that BNs should be utilised to routinely synthesise reviews of complex interventions or empty reviews where decisions must be made despite poor evidence. Copyright © 2013 John Wiley & Sons, Ltd.

In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype.

PubMed

Saleha, Shamim; Ajmal, Muhammad; Jamil, Muhammad; Nasir, Muhammad; Hameed, Abdul

2016-01-01

To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

PubMed Central

Antoniou, Antonis C.; Spurdle, Amanda B.; Sinilnikova, Olga M.; Healey, Sue; Pooley, Karen A.; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Arnold, Norbert; Hofmann, Wera; Sutter, Christian; Niederacher, Dieter; Deissler, Helmut; Caldes, Trinidad; Kämpjärvi, Kati; Nevanlinna, Heli; Simard, Jacques; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Rebbeck, Timothy R.; Wagner, Theresa; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Ganz, Patricia A.; Daly, Mary B.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Blum, Joanne L.; Couch, Fergus J.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Szabo, Csilla I.; Pereira, Lutecia H. Mateus; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Barnett-Griness, Ofra; Andrulis, Irene L.; Ozcelik, Hilmi; Gerdes, Anne-Marie; Caligo, Maria A.; Laitman, Yael; Kaufman, Bella; Milgrom, Roni; Friedman, Eitan; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Llort, Gemma; Milne, Roger L.; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; Manders, Peggy; Ligtenberg, Marjolijn J.L.; van den Ouweland, Ans M.W.; Peock, Susan; Cook, Margaret; Platte, Radka; Evans, D. Gareth; Eeles, Rosalind; Pichert, Gabriella; Chu, Carol; Eccles, Diana; Davidson, Rosemarie; Douglas, Fiona; Godwin, Andrew K.; Barjhoux, Laure; Mazoyer, Sylvie; Sobol, Hagay; Bourdon, Violaine; Eisinger, François; Chompret, Agnès; Capoulade, Corinne; Bressac-de Paillerets, Brigitte; Lenoir, Gilbert M.; Gauthier-Villars, Marion; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.

2008-01-01

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20–1.45, ptrend = 1.7 × 10−8 and HR = 1.12, 95% CI: 1.02–1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06–1.20, ptrend = 5 × 10−5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers. PMID:18355772

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

PubMed Central

Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

2016-01-01

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

Breast cancer risk factors differ between Asian and white women with BRCA1/2 mutations.

PubMed

de Bruin, Monique A; Kwong, Ava; Goldstein, Benjamin A; Lipson, Jafi A; Ikeda, Debra M; McPherson, Lisa; Sharma, Bhavna; Kardashian, Ani; Schackmann, Elizabeth; Kingham, Kerry E; Mills, Meredith A; West, Dee W; Ford, James M; Kurian, Allison W

2012-09-01

The prevalence and penetrance of BRCA1 and BRCA2 (BRCA1/2) mutations may differ between Asians and whites. We investigated BRCA1/2 mutations and cancer risk factors in a clinic-based sample. BRCA1/2 mutation carriers were enrolled from cancer genetics clinics in Hong Kong and California according to standardized entry criteria. We compared BRCA mutation position, cancer history, hormonal and reproductive exposures. We analyzed DNA samples for single-nucleotide polymorphisms reported to modify breast cancer risk. We performed logistic regression to identify independent predictors of breast cancer. Fifty Asian women and forty-nine white American women were enrolled. BRCA1 mutations were more common among whites (67 vs. 42 %, p = 0.02), and BRCA2 mutations among Asians (58 vs. 37 %, p = 0.04). More Asians had breast cancer (76 vs. 53 %, p = 0.03); more whites had relatives with breast cancer (86 vs. 50 %, p = 0.0003). More whites than Asians had breastfed (71 vs. 42 %, p = 0.005), had high BMI (median 24.3 vs. 21.2, p = 0.04), consumed alcohol (2 drinks/week vs. 0, p < 0.001), and had oophorectomy (61 vs. 34 %, p = 0.01). Asians had a higher frequency of risk-associated alleles in MAP3K1 (88 vs. 59 %, p = 0.005) and TOX3/TNRC9 (88 vs. 55 %, p = 0.0002). On logistic regression, MAP3K1 was associated with increased breast cancer risk for BRCA2, but not BRCA1 mutation carriers; breast density was associated with increased risk among Asians but not whites. We found significant differences in breast cancer risk factors between Asian and white BRCA1/2 mutation carriers. Further investigation of racial differences in BRCA1/2 mutation epidemiology could inform targeted cancer risk-reduction strategies.

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

PubMed

Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

2016-01-01

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Rapid evolution of the human mutation spectrum

PubMed Central

Harris, Kelley; Pritchard, Jonathan K

2017-01-01

DNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely related populations. Close examination of one signal, an increased TCC→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers. DOI: http://dx.doi.org/10.7554/eLife.24284.001 PMID:28440220

Different approaches for identifying important concepts in probabilistic biomedical text summarization.

PubMed

Moradi, Milad; Ghadiri, Nasser

2018-01-01

Automatic text summarization tools help users in the biomedical domain to acquire their intended information from various textual resources more efficiently. Some of biomedical text summarization systems put the basis of their sentence selection approach on the frequency of concepts extracted from the input text. However, it seems that exploring other measures rather than the raw frequency for identifying valuable contents within an input document, or considering correlations existing between concepts, may be more useful for this type of summarization. In this paper, we describe a Bayesian summarization method for biomedical text documents. The Bayesian summarizer initially maps the input text to the Unified Medical Language System (UMLS) concepts; then it selects the important ones to be used as classification features. We introduce six different feature selection approaches to identify the most important concepts of the text and select the most informative contents according to the distribution of these concepts. We show that with the use of an appropriate feature selection approach, the Bayesian summarizer can improve the performance of biomedical summarization. Using the Recall-Oriented Understudy for Gisting Evaluation (ROUGE) toolkit, we perform extensive evaluations on a corpus of scientific papers in the biomedical domain. The results show that when the Bayesian summarizer utilizes the feature selection methods that do not use the raw frequency, it can outperform the biomedical summarizers that rely on the frequency of concepts, domain-independent and baseline methods. Copyright © 2017 Elsevier B.V. All rights reserved.

Exoplanet Biosignatures: A Framework for Their Assessment.

PubMed

Catling, David C; Krissansen-Totton, Joshua; Kiang, Nancy Y; Crisp, David; Robinson, Tyler D; DasSarma, Shiladitya; Rushby, Andrew J; Del Genio, Anthony; Bains, William; Domagal-Goldman, Shawn

2018-04-20

Finding life on exoplanets from telescopic observations is an ultimate goal of exoplanet science. Life produces gases and other substances, such as pigments, which can have distinct spectral or photometric signatures. Whether or not life is found with future data must be expressed with probabilities, requiring a framework of biosignature assessment. We present a framework in which we advocate using biogeochemical "Exo-Earth System" models to simulate potential biosignatures in spectra or photometry. Given actual observations, simulations are used to find the Bayesian likelihoods of those data occurring for scenarios with and without life. The latter includes "false positives" wherein abiotic sources mimic biosignatures. Prior knowledge of factors influencing planetary inhabitation, including previous observations, is combined with the likelihoods to give the Bayesian posterior probability of life existing on a given exoplanet. Four components of observation and analysis are necessary. (1) Characterization of stellar (e.g., age and spectrum) and exoplanetary system properties, including "external" exoplanet parameters (e.g., mass and radius), to determine an exoplanet's suitability for life. (2) Characterization of "internal" exoplanet parameters (e.g., climate) to evaluate habitability. (3) Assessment of potential biosignatures within the environmental context (components 1-2), including corroborating evidence. (4) Exclusion of false positives. We propose that resulting posterior Bayesian probabilities of life's existence map to five confidence levels, ranging from "very likely" (90-100%) to "very unlikely" (<10%) inhabited. Key Words: Bayesian statistics-Biosignatures-Drake equation-Exoplanets-Habitability-Planetary science. Astrobiology 18, xxx-xxx.

Homozygosity Mapping and Whole Exome Sequencing to Detect SLC45A2 and G6PC3 Mutations in a Single Patient with Oculocutaneous Albinism and Neutropenia

PubMed Central

Cullinane, Andrew R.; Vilboux, Thierry; O’Brien, Kevin; Curry, James A.; Maynard, Dawn M.; Carlson-Donohoe, Hannah; Ciccone, Carla; Markello, Thomas C.; Gunay-Aygun, Meral; Huizing, Marjan; Gahl, William A.

2011-01-01

We evaluated a 32 year-old woman whose oculocutaneous albinism, bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky-Pudlak syndrome type 2 (HPS-2). This was ruled out due to the presence of platelet delta granules and absence of AP3B1 mutations. Since parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional di-deoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with oculocutaneous albinism type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient’s melanocytes caused the mis-localization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient’s G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under ER stress. This report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping followed by whole exome sequencing to identify disease-causing mutations in multiple genes in a single affected individual. PMID:21677667

Efficient Detection of Copy Number Mutations in PMS2 Exons with a Close Homolog.

PubMed

Herman, Daniel S; Smith, Christina; Liu, Chang; Vaughn, Cecily P; Palaniappan, Selvi; Pritchard, Colin C; Shirts, Brian H

2018-07-01

Detection of 3' PMS2 copy-number mutations that cause Lynch syndrome is difficult because of highly homologous pseudogenes. To improve the accuracy and efficiency of clinical screening for these mutations, we developed a new method to analyze standard capture-based, next-generation sequencing data to identify deletions and duplications in PMS2 exons 9 to 15. The approach captures sequences using PMS2 targets, maps sequences randomly among regions with equal mapping quality, counts reads aligned to homologous exons and introns, and flags read count ratios outside of empirically derived reference ranges. The method was trained on 1352 samples, including 8 known positives, and tested on 719 samples, including 17 known positives. Clinical implementation of the first version of this method detected new mutations in the training (N = 7) and test (N = 2) sets that had not been identified by our initial clinical testing pipeline. The described final method showed complete sensitivity in both sample sets and false-positive rates of 5% (training) and 7% (test), dramatically decreasing the number of cases needing additional mutation evaluation. This approach leveraged the differences between gene and pseudogene to distinguish between PMS2 and PMS2CL copy-number mutations. These methods enable efficient and sensitive Lynch syndrome screening for 3' PMS2 copy-number mutations and may be applied similarly to other genomic regions with highly homologous pseudogenes. Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism

PubMed Central

Salvatori, Roberto; Radian, Serban; Diekmann, Yoan; Iacovazzo, Donato; David, Alessia; Gabrovska, Plamena; Grassi, Giorgia; Bussell, Anna-Marie; Stals, Karen; Weber, Astrid; Quinton, Richard; Crowne, Elizabeth C; Corazzini, Valentina; Metherell, Lou; Kearney, Tara; Du Plessis, Daniel; Sinha, Ajay Kumar; Baborie, Atik; Lecoq, Anne-Lise; Chanson, Philippe; Ansorge, Olaf; Ellard, Sian; Trainer, Peter J; Balding, David; Thomas, Mark G

2017-01-01

Objective Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Design and methods Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Results Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. Conclusions The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability. PMID:28634279

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

PubMed

Salvatori, Roberto; Radian, Serban; Diekmann, Yoan; Iacovazzo, Donato; David, Alessia; Gabrovska, Plamena; Grassi, Giorgia; Bussell, Anna-Marie; Stals, Karen; Weber, Astrid; Quinton, Richard; Crowne, Elizabeth C; Corazzini, Valentina; Metherell, Lou; Kearney, Tara; Du Plessis, Daniel; Sinha, Ajay Kumar; Baborie, Atik; Lecoq, Anne-Lise; Chanson, Philippe; Ansorge, Olaf; Ellard, Sian; Trainer, Peter J; Balding, David; Thomas, Mark G; Korbonits, Márta

2017-09-01

Mutations in the aryl hydrocarbon receptor-interacting protein ( AIP ) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP -region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability. © 2017 The authors.

The center for causal discovery of biomedical knowledge from big data.

PubMed

Cooper, Gregory F; Bahar, Ivet; Becich, Michael J; Benos, Panayiotis V; Berg, Jeremy; Espino, Jeremy U; Glymour, Clark; Jacobson, Rebecca Crowley; Kienholz, Michelle; Lee, Adrian V; Lu, Xinghua; Scheines, Richard

2015-11-01

The Big Data to Knowledge (BD2K) Center for Causal Discovery is developing and disseminating an integrated set of open source tools that support causal modeling and discovery of biomedical knowledge from large and complex biomedical datasets. The Center integrates teams of biomedical and data scientists focused on the refinement of existing and the development of new constraint-based and Bayesian algorithms based on causal Bayesian networks, the optimization of software for efficient operation in a supercomputing environment, and the testing of algorithms and software developed using real data from 3 representative driving biomedical projects: cancer driver mutations, lung disease, and the functional connectome of the human brain. Associated training activities provide both biomedical and data scientists with the knowledge and skills needed to apply and extend these tools. Collaborative activities with the BD2K Consortium further advance causal discovery tools and integrate tools and resources developed by other centers. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mapping mutational effects along the evolutionary landscape of HIV envelope

PubMed Central

Hilton, Sarah K; Overbaugh, Julie

2018-01-01

The immediate evolutionary space accessible to HIV is largely determined by how single amino acid mutations affect fitness. These mutational effects can shift as the virus evolves. However, the prevalence of such shifts in mutational effects remains unclear. Here, we quantify the effects on viral growth of all amino acid mutations to two HIV envelope (Env) proteins that differ at >100 residues. Most mutations similarly affect both Envs, but the amino acid preferences of a minority of sites have clearly shifted. These shifted sites usually prefer a specific amino acid in one Env, but tolerate many amino acids in the other. Surprisingly, shifts are only slightly enriched at sites that have substituted between the Envs—and many occur at residues that do not even contact substitutions. Therefore, long-range epistasis can unpredictably shift Env’s mutational tolerance during HIV evolution, although the amino acid preferences of most sites are conserved between moderately diverged viral strains. PMID:29590010

Updating categorical soil maps using limited survey data by Bayesian Markov chain cosimulation.

PubMed

Li, Weidong; Zhang, Chuanrong; Dey, Dipak K; Willig, Michael R

2013-01-01

Updating categorical soil maps is necessary for providing current, higher-quality soil data to agricultural and environmental management but may not require a costly thorough field survey because latest legacy maps may only need limited corrections. This study suggests a Markov chain random field (MCRF) sequential cosimulation (Co-MCSS) method for updating categorical soil maps using limited survey data provided that qualified legacy maps are available. A case study using synthetic data demonstrates that Co-MCSS can appreciably improve simulation accuracy of soil types with both contributions from a legacy map and limited sample data. The method indicates the following characteristics: (1) if a soil type indicates no change in an update survey or it has been reclassified into another type that similarly evinces no change, it will be simply reproduced in the updated map; (2) if a soil type has changes in some places, it will be simulated with uncertainty quantified by occurrence probability maps; (3) if a soil type has no change in an area but evinces changes in other distant areas, it still can be captured in the area with unobvious uncertainty. We concluded that Co-MCSS might be a practical method for updating categorical soil maps with limited survey data.

Updating Categorical Soil Maps Using Limited Survey Data by Bayesian Markov Chain Cosimulation

PubMed Central

Dey, Dipak K.; Willig, Michael R.

2013-01-01

Updating categorical soil maps is necessary for providing current, higher-quality soil data to agricultural and environmental management but may not require a costly thorough field survey because latest legacy maps may only need limited corrections. This study suggests a Markov chain random field (MCRF) sequential cosimulation (Co-MCSS) method for updating categorical soil maps using limited survey data provided that qualified legacy maps are available. A case study using synthetic data demonstrates that Co-MCSS can appreciably improve simulation accuracy of soil types with both contributions from a legacy map and limited sample data. The method indicates the following characteristics: (1) if a soil type indicates no change in an update survey or it has been reclassified into another type that similarly evinces no change, it will be simply reproduced in the updated map; (2) if a soil type has changes in some places, it will be simulated with uncertainty quantified by occurrence probability maps; (3) if a soil type has no change in an area but evinces changes in other distant areas, it still can be captured in the area with unobvious uncertainty. We concluded that Co-MCSS might be a practical method for updating categorical soil maps with limited survey data. PMID:24027447

Efficient, adaptive estimation of two-dimensional firing rate surfaces via Gaussian process methods.

PubMed

Rad, Kamiar Rahnama; Paninski, Liam

2010-01-01

Estimating two-dimensional firing rate maps is a common problem, arising in a number of contexts: the estimation of place fields in hippocampus, the analysis of temporally nonstationary tuning curves in sensory and motor areas, the estimation of firing rates following spike-triggered covariance analyses, etc. Here we introduce methods based on Gaussian process nonparametric Bayesian techniques for estimating these two-dimensional rate maps. These techniques offer a number of advantages: the estimates may be computed efficiently, come equipped with natural errorbars, adapt their smoothness automatically to the local density and informativeness of the observed data, and permit direct fitting of the model hyperparameters (e.g., the prior smoothness of the rate map) via maximum marginal likelihood. We illustrate the method's flexibility and performance on a variety of simulated and real data.

Fine-structure mapping of the firA gene, a locus involved in the phenotypic expression of rifampin resistance in Escherichia.

PubMed

Lathe, R

1977-09-01

The firA (Ts)200 mutation not only eliminates the resistance to rifampin of certain genetically resistant strains, but, moreover, renders ribonucleic acid synthesis thermolabile. The firA gene has been mapped by P1 tranduction and is located extremely close to the structural gene for deoxyribonucleic acid polymerase III at 4 min on the Escherichia coli linkage map.

Mannosyltransferase is required for cell wall biosynthesis, morphology and control of asexual development in Neurospora crassa.

PubMed

Bowman, Shaun M; Piwowar, Amy; Ciocca, Maria; Free, Stephen J

2005-01-01

Two Neurospora mutants with a phenotype that includes a tight colonial growth pattern, an inability to form conidia and an inability to form protoperithecia have been isolated and characterized. The relevant mutations were mapped to the same locus on the sequenced Neurospora genome. The mutations responsible for the mutant phenotype then were identified by examining likely candidate genes from the mutant genomes at the mapped locus with PCR amplification and a sequencing assay. The results demonstrate that a map and sequence strategy is a feasible way to identify mutant genes in Neurospora. The gene responsible for the phenotype is a putative alpha-1,2-mannosyltransferase gene. The mutant cell wall has an altered composition demonstrating that the gene functions in cell wall biosynthesis. The results demonstrate that the mnt-1 gene is required for normal cell wall biosynthesis, morphology and for the regulation of asexual development.

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

Manem, V; Paganetti, H

Purpose: Evaluate the excess relative risk (ERR) induced by photons and protons in each voxel of the lung, and display it as a three-dimensional map, known as the ERRM (i.e. excess relative risk map) along with the dose distribution map. In addition, we also study the effect of variations in the linear energy transfer (LET) distribution on ERRM for a given proton plan. Methods: The excess relative risk due to radiation is estimated using the initiation-inactivation-proliferation formalism. This framework accounts for three biological phenomenon: mutation induction, cell kill and proliferation. Cell kill and mutation induction are taken as a functionmore » of LET using experimental data. LET distributions are calculated using a Monte Carlo algorithm. ERR is then estimated for each voxel in the organ, and displayed as a three dimensional carcinogenic map. Results: The differences in the ERR’s between photons and protons is seen from the three-dimensional ERR map. In addition, we also varied the LET of a proton plan and observed the differences in the corresponding ERR maps demonstrating variations in the ERR maps depend on features of a proton plan. Additionally, our results suggest that any two proton plans that have the same integral dose does not necessarily imply identical ERR maps, and these changes are due to the variations in the LET distribution map. Conclusion: Clinically, it is important to have a three dimensional display of biological end points. This study is an effort to introduce 3D ERR maps into the treatment planning workflow for certain sites such as pediatric head and neck tumors.« less

Frameshift Suppression in SACCHAROMYCES CEREVISIAE. IV. New Suppressors among Spontaneous Co-Revertants of the Group II HIS4-206 and LEU2-3 Frameshift Mutations

PubMed Central

Gaber, Richard F.; Culbertson, Michael R.

1982-01-01

ICR-induced frameshift mutations at the his4 locus in Saccharomyces cerevisiae have been classified into several groups on the basis of their reversion and suppression properties. One group of externally suppressible his4 mutations, designated Group II, have been shown to contain +1 G:C insertions in glycine codons and are suppressed by any one of five suppressor mutations described previously (SUF1, SUF3, SUF4, SUF5, and SUF6). The suppressor genes are believed to encode glycine tRNAs containing four base anticodons.—An analysis of spontaneous co-revertants of the Group II frameshift mutations his4-206 and leu2-3 has revealed the existence of eleven new Group II-specific suppressor genes (SUF15 through SUF25). The locations of the new suppressor loci on the yeast genetic map have been determined.—By comparing the ability or inability of Group II-specific suppressors mapping at 16 different loci to suppress different Group II his4 mutations, two subclasses of suppressors have been defined. One subclass suppresses his4-38 and his4-519, which contain the altered four base mRNA codons 5'-GGGU-3' and 5'-GGGG-3', respectively. The other subclass suppresses his4-38, but fails to suppress his4-519. The mechanism of tRNA-mediated frameshift suppression and the molecular basis for this division of the suppressors into two subclasses is discussed. PMID:6757051

Identification of an EMS-induced causal mutation in a gene required for boron-mediated root development by low-coverage genome re-sequencing in Arabidopsis

PubMed Central

Tabata, Ryo; Kamiya, Takehiro; Shigenobu, Shuji; Yamaguchi, Katsushi; Yamada, Masashi; Hasebe, Mitsuyasu; Fujiwara, Toru; Sawa, Shinichiro

2013-01-01

Next-generation sequencing (NGS) technologies enable the rapid production of an enormous quantity of sequence data. These powerful new technologies allow the identification of mutations by whole-genome sequencing. However, most reported NGS-based mapping methods, which are based on bulked segregant analysis, are costly and laborious. To address these limitations, we designed a versatile NGS-based mapping method that consists of a combination of low- to medium-coverage multiplex SOLiD (Sequencing by Oligonucleotide Ligation and Detection) and classical genetic rough mapping. Using only low to medium coverage reduces the SOLiD sequencing costs and, since just 10 to 20 mutant F2 plants are required for rough mapping, the operation is simple enough to handle in a laboratory with limited space and funding. As a proof of principle, we successfully applied this method to identify the CTR1, which is involved in boron-mediated root development, from among a population of high boron requiring Arabidopsis thaliana mutants. Our work demonstrates that this NGS-based mapping method is a moderately priced and versatile method that can readily be applied to other model organisms. PMID:23104114

Detecting Adaptation in Protein-Coding Genes Using a Bayesian Site-Heterogeneous Mutation-Selection Codon Substitution Model.

PubMed

Rodrigue, Nicolas; Lartillot, Nicolas

2017-01-01

Codon substitution models have traditionally attempted to uncover signatures of adaptation within protein-coding genes by contrasting the rates of synonymous and non-synonymous substitutions. Another modeling approach, known as the mutation-selection framework, attempts to explicitly account for selective patterns at the amino acid level, with some approaches allowing for heterogeneity in these patterns across codon sites. Under such a model, substitutions at a given position occur at the neutral or nearly neutral rate when they are synonymous, or when they correspond to replacements between amino acids of similar fitness; substitutions from high to low (low to high) fitness amino acids have comparatively low (high) rates. Here, we study the use of such a mutation-selection framework as a null model for the detection of adaptation. Following previous works in this direction, we include a deviation parameter that has the effect of capturing the surplus, or deficit, in non-synonymous rates, relative to what would be expected under a mutation-selection modeling framework that includes a Dirichlet process approach to account for across-codon-site variation in amino acid fitness profiles. We use simulations, along with a few real data sets, to study the behavior of the approach, and find it to have good power with a low false-positive rate. Altogether, we emphasize the potential of recent mutation-selection models in the detection of adaptation, calling for further model refinements as well as large-scale applications. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

High-Throughput Gene Mapping in Caenorhabditis elegans

PubMed Central

Swan, Kathryn A.; Curtis, Damian E.; McKusick, Kathleen B.; Voinov, Alexander V.; Mapa, Felipa A.; Cancilla, Michael R.

2002-01-01

Positional cloning of mutations in model genetic systems is a powerful method for the identification of targets of medical and agricultural importance. To facilitate the high-throughput mapping of mutations in Caenorhabditis elegans, we have identified a further 9602 putative new single nucleotide polymorphisms (SNPs) between two C. elegans strains, Bristol N2 and the Hawaiian mapping strain CB4856, by sequencing inserts from a CB4856 genomic DNA library and using an informatics pipeline to compare sequences with the canonical N2 genomic sequence. When combined with data from other laboratories, our marker set of 17,189 SNPs provides even coverage of the complete worm genome. To date, we have confirmed >1099 evenly spaced SNPs (one every 91 ± 56 kb) across the six chromosomes and validated the utility of our SNP marker set and new fluorescence polarization-based genotyping methods for systematic and high-throughput identification of genes in C. elegans by cloning several proprietary genes. We illustrate our approach by recombination mapping and confirmation of the mutation in the cloned gene, dpy-18. [The sequence data described in this paper have been submitted to the NCBI dbSNP data library under accession nos. 4388625–4389689 and GenBank dbSTS under accession nos. 973810–974874. The following individuals and institutions kindly provided reagents, samples, or unpublished information as indicated in the paper: The C. elegans Sequencing Consortium and The Caenorhabditis Genetics Center.] PMID:12097347

How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin.

PubMed

Doud, Michael B; Lee, Juhye M; Bloom, Jesse D

2018-04-11

Influenza virus can escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if there was strong pressure to do so. Here, we map all single amino-acid mutations that increase resistance to broad antibodies to H1 hemagglutinin. Our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody to hemagglutinin's receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies to hemagglutinin's stalk only select mutations with small effects. Therefore, among the antibodies we examine, breadth is an imperfect indicator of the potential for viral escape via single mutations. Antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.

Homozygosity Mapping and Candidate Prioritization Identify Mutations, Missed by Whole-Exome Sequencing, in SMOC2, Causing Major Dental Developmental Defects

PubMed Central

Bloch-Zupan, Agnès; Jamet, Xavier; Etard, Christelle; Laugel, Virginie; Muller, Jean; Geoffroy, Véronique; Strauss, Jean-Pierre; Pelletier, Valérie; Marion, Vincent; Poch, Olivier; Strahle, Uwe; Stoetzel, Corinne; Dollfus, Hélène

2011-01-01

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2. PMID:22152679

More about the Viking hypothesis of origin of the delta32 mutation in the CCR5 gene conferring resistance to HIV-1 infection.

PubMed

Lucotte, Gérard; Dieterlen, Florent

2003-11-01

The chemokine receptor CCR5 constitutes the major coreceptor for the HIV-1, because a mutant allele of the CCR5 gene named delta32 was shown to provide to homozygotes a strong resistance against infection. In the present study the frequency of the delta32 allele was collected in 36 European populations and in Cyprus, and the highest allele frequencies were found in Nordic countries. We constructed an allele map of delta32 frequencies in Europe; the map is in accordance to the Vikings hypothesis of the origin of the mutation and his dissemination during the eighth to the tenth centuries.

Local coexistence of VO 2 phases revealed by deep data analysis

DOE PAGES

Strelcov, Evgheni; Ievlev, Anton; Tselev, Alexander; ...

2016-07-07

We report a synergistic approach of micro-Raman spectroscopic mapping and deep data analysis to study the distribution of crystallographic phases and ferroelastic domains in a defected Al-doped VO 2 microcrystal. Bayesian linear unmixing revealed an uneven distribution of the T phase, which is stabilized by the surface defects and uneven local doping that went undetectable by other classical analysis techniques such as PCA and SIMPLISMA. This work demonstrates the impact of information recovery via statistical analysis and full mapping in spectroscopic studies of vanadium dioxide systems, which is commonly substituted by averaging or single point-probing approaches, both of which suffermore » from information misinterpretation due to low resolving power.« less

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.

PubMed

Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

2015-04-01

Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. Copyright © 2015 Tun et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker

PubMed Central

Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

2015-01-01

Summary Background Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. PMID:25704894

An unbiased adaptive sampling algorithm for the exploration of RNA mutational landscapes under evolutionary pressure.

PubMed

Waldispühl, Jérôme; Ponty, Yann

2011-11-01

The analysis of the relationship between sequences and structures (i.e., how mutations affect structures and reciprocally how structures influence mutations) is essential to decipher the principles driving molecular evolution, to infer the origins of genetic diseases, and to develop bioengineering applications such as the design of artificial molecules. Because their structures can be predicted from the sequence data only, RNA molecules provide a good framework to study this sequence-structure relationship. We recently introduced a suite of algorithms called RNAmutants which allows a complete exploration of RNA sequence-structure maps in polynomial time and space. Formally, RNAmutants takes an input sequence (or seed) to compute the Boltzmann-weighted ensembles of mutants with exactly k mutations, and sample mutations from these ensembles. However, this approach suffers from major limitations. Indeed, since the Boltzmann probabilities of the mutations depend of the free energy of the structures, RNAmutants has difficulties to sample mutant sequences with low G+C-contents. In this article, we introduce an unbiased adaptive sampling algorithm that enables RNAmutants to sample regions of the mutational landscape poorly covered by classical algorithms. We applied these methods to sample mutations with low G+C-contents. These adaptive sampling techniques can be easily adapted to explore other regions of the sequence and structural landscapes which are difficult to sample. Importantly, these algorithms come at a minimal computational cost. We demonstrate the insights offered by these techniques on studies of complete RNA sequence structures maps of sizes up to 40 nucleotides. Our results indicate that the G+C-content has a strong influence on the size and shape of the evolutionary accessible sequence and structural spaces. In particular, we show that low G+C-contents favor the apparition of internal loops and thus possibly the synthesis of tertiary structure motifs. On the other hand, high G+C-contents significantly reduce the size of the evolutionary accessible mutational landscapes.

Detecting negative selection on recurrent mutations using gene genealogy

PubMed Central

2013-01-01

Background Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such “recurrent mutations” might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. Results Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. Conclusions With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID:23651527

Selective 2'-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) for direct, versatile and accurate RNA structure analysis.

PubMed

Smola, Matthew J; Rice, Greggory M; Busan, Steven; Siegfried, Nathan A; Weeks, Kevin M

2015-11-01

Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) chemistries exploit small electrophilic reagents that react with 2'-hydroxyl groups to interrogate RNA structure at single-nucleotide resolution. Mutational profiling (MaP) identifies modified residues by using reverse transcriptase to misread a SHAPE-modified nucleotide and then counting the resulting mutations by massively parallel sequencing. The SHAPE-MaP approach measures the structure of large and transcriptome-wide systems as accurately as can be done for simple model RNAs. This protocol describes the experimental steps, implemented over 3 d, that are required to perform SHAPE probing and to construct multiplexed SHAPE-MaP libraries suitable for deep sequencing. Automated processing of MaP sequencing data is accomplished using two software packages. ShapeMapper converts raw sequencing files into mutational profiles, creates SHAPE reactivity plots and provides useful troubleshooting information. SuperFold uses these data to model RNA secondary structures, identify regions with well-defined structures and visualize probable and alternative helices, often in under 1 d. SHAPE-MaP can be used to make nucleotide-resolution biophysical measurements of individual RNA motifs, rare components of complex RNA ensembles and entire transcriptomes.

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.

PubMed

McGregor, Lesley; Makela, Ville; Darling, Susan M; Vrontou, Sofia; Chalepakis, Georges; Roberts, Catherine; Smart, Nicola; Rutland, Paul; Prescott, Natalie; Hopkins, Jason; Bentley, Elizabeth; Shaw, Alison; Roberts, Emma; Mueller, Robert; Jadeja, Shalini; Philip, Nicole; Nelson, John; Francannet, Christine; Perez-Aytes, Antonio; Megarbane, Andre; Kerr, Bronwyn; Wainwright, Brandon; Woolf, Adrian S; Winter, Robin M; Scambler, Peter J

2003-06-01

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Mapping Flexibility and the Assembly Switch of Cell Division Protein FtsZ by Computational and Mutational Approaches*♦

PubMed Central

Martín-Galiano, Antonio J.; Buey, Rubén M.; Cabezas, Marta; Andreu, José M.

2010-01-01

The molecular switch for nucleotide-regulated assembly and disassembly of the main prokaryotic cell division protein FtsZ is unknown despite the numerous crystal structures that are available. We have characterized the functional motions in FtsZ with a computational consensus of essential dynamics, structural comparisons, sequence conservation, and networks of co-evolving residues. Employing this information, we have constructed 17 mutants, which alter the FtsZ functional cycle at different stages, to modify FtsZ flexibility. The mutant phenotypes ranged from benign to total inactivation and included increased GTPase, reduced assembly, and stabilized assembly. Six mutations clustering at the long cleft between the C-terminal β-sheet and core helix H7 deviated FtsZ assembly into curved filaments with inhibited GTPase, which still polymerize cooperatively. These mutations may perturb the predicted closure of the C-terminal domain onto H7 required for switching between curved and straight association modes and for GTPase activation. By mapping the FtsZ assembly switch, this work also gives insight into FtsZ druggability because the curved mutations delineate the putative binding site of the promising antibacterial FtsZ inhibitor PC190723. PMID:20472561

Mapping heat exchange in an allosteric protein.

PubMed

Gupta, Shaweta; Auerbach, Anthony

2011-02-16

Nicotinic acetylcholine receptors (AChRs) are synaptic ion channels that spontaneously isomerize (i.e., gate) between resting and active conformations. We used single-molecule electrophysiology to measure the temperature dependencies of mouse neuromuscular AChR gating rate and equilibrium constants. From these we estimated free energy, enthalpy, and entropy changes caused by mutations of amino acids located between the transmitter binding sites and the middle of the membrane domain. The range of equilibrium enthalpy change (13.4 kcal/mol) was larger than for free energy change (5.5 kcal/mol at 25°C). For two residues, the slope of the rate-equilibrium free energy relationship (Φ) was approximately constant with temperature. Mutant cycle analysis showed that both free energies and enthalpies are additive for energetically independent mutations. We hypothesize that changes in energy associated with changes in structure mainly occur close to the site of the mutation, and, hence, that it is possible to make a residue-by-residue map of heat exchange in the AChR gating isomerization. The structural correlates of enthalpy changes are discussed for 12 different mutations in the protein. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Mapping flexibility and the assembly switch of cell division protein FtsZ by computational and mutational approaches.

PubMed

Martín-Galiano, Antonio J; Buey, Rubén M; Cabezas, Marta; Andreu, José M

2010-07-16

The molecular switch for nucleotide-regulated assembly and disassembly of the main prokaryotic cell division protein FtsZ is unknown despite the numerous crystal structures that are available. We have characterized the functional motions in FtsZ with a computational consensus of essential dynamics, structural comparisons, sequence conservation, and networks of co-evolving residues. Employing this information, we have constructed 17 mutants, which alter the FtsZ functional cycle at different stages, to modify FtsZ flexibility. The mutant phenotypes ranged from benign to total inactivation and included increased GTPase, reduced assembly, and stabilized assembly. Six mutations clustering at the long cleft between the C-terminal beta-sheet and core helix H7 deviated FtsZ assembly into curved filaments with inhibited GTPase, which still polymerize cooperatively. These mutations may perturb the predicted closure of the C-terminal domain onto H7 required for switching between curved and straight association modes and for GTPase activation. By mapping the FtsZ assembly switch, this work also gives insight into FtsZ druggability because the curved mutations delineate the putative binding site of the promising antibacterial FtsZ inhibitor PC190723.

Mapping the Structural and Dynamical Features of Multiple p53 DNA Binding Domains: Insights into Loop 1 Intrinsic Dynamics

PubMed Central

Lukman, Suryani; Lane, David P.; Verma, Chandra S.

2013-01-01

The transcription factor p53 regulates cellular integrity in response to stress. p53 is mutated in more than half of cancerous cells, with a majority of the mutations localized to the DNA binding domain (DBD). In order to map the structural and dynamical features of the DBD, we carried out multiple copy molecular dynamics simulations (totaling 0.8 μs). Simulations show the loop 1 to be the most dynamic element among the DNA-contacting loops (loops 1-3). Loop 1 occupies two major conformational states: extended and recessed; the former but not the latter displays correlations in atomic fluctuations with those of loop 2 (~24 Å apart). Since loop 1 binds to the major groove whereas loop 2 binds to the minor groove of DNA, our results begin to provide some insight into the possible mechanism underpinning the cooperative nature of DBD binding to DNA. We propose (1) a novel mechanism underlying the dynamics of loop 1 and the possible tread-milling of p53 on DNA and (2) possible mutations on loop 1 residues to restore the transcriptional activity of an oncogenic mutation at a distant site. PMID:24324553

A Bayesian modelling framework for tornado occurrences in North America

NASA Astrophysics Data System (ADS)

Cheng, Vincent Y. S.; Arhonditsis, George B.; Sills, David M. L.; Gough, William A.; Auld, Heather

2015-03-01

Tornadoes represent one of nature’s most hazardous phenomena that have been responsible for significant destruction and devastating fatalities. Here we present a Bayesian modelling approach for elucidating the spatiotemporal patterns of tornado activity in North America. Our analysis shows a significant increase in the Canadian Prairies and the Northern Great Plains during the summer, indicating a clear transition of tornado activity from the United States to Canada. The linkage between monthly-averaged atmospheric variables and likelihood of tornado events is characterized by distinct seasonality; the convective available potential energy is the predominant factor in the summer; vertical wind shear appears to have a strong signature primarily in the winter and secondarily in the summer; and storm relative environmental helicity is most influential in the spring. The present probabilistic mapping can be used to draw inference on the likelihood of tornado occurrence in any location in North America within a selected time period of the year.

A Bayesian modelling framework for tornado occurrences in North America.

PubMed

Cheng, Vincent Y S; Arhonditsis, George B; Sills, David M L; Gough, William A; Auld, Heather

2015-03-25

Tornadoes represent one of nature's most hazardous phenomena that have been responsible for significant destruction and devastating fatalities. Here we present a Bayesian modelling approach for elucidating the spatiotemporal patterns of tornado activity in North America. Our analysis shows a significant increase in the Canadian Prairies and the Northern Great Plains during the summer, indicating a clear transition of tornado activity from the United States to Canada. The linkage between monthly-averaged atmospheric variables and likelihood of tornado events is characterized by distinct seasonality; the convective available potential energy is the predominant factor in the summer; vertical wind shear appears to have a strong signature primarily in the winter and secondarily in the summer; and storm relative environmental helicity is most influential in the spring. The present probabilistic mapping can be used to draw inference on the likelihood of tornado occurrence in any location in North America within a selected time period of the year.

Brain white matter fiber estimation and tractography using Q-ball imaging and Bayesian MODEL.

PubMed

Lu, Meng

2015-01-01

Diffusion tensor imaging allows for the non-invasive in vivo mapping of the brain tractography. However, fiber bundles have complex structures such as fiber crossings, fiber branchings and fibers with large curvatures that tensor imaging (DTI) cannot accurately handle. This study presents a novel brain white matter tractography method using Q-ball imaging as the data source instead of DTI, because QBI can provide accurate information about multiple fiber crossings and branchings in a single voxel using an orientation distribution function (ODF). The presented method also uses graph theory to construct the Bayesian model-based graph, so that the fiber tracking between two voxels can be represented as the shortest path in a graph. Our experiment showed that our new method can accurately handle brain white matter fiber crossings and branchings, and reconstruct brain tractograhpy both in phantom data and real brain data.

Contour-Driven Atlas-Based Segmentation

PubMed Central

Wachinger, Christian; Fritscher, Karl; Sharp, Greg; Golland, Polina

2016-01-01

We propose new methods for automatic segmentation of images based on an atlas of manually labeled scans and contours in the image. First, we introduce a Bayesian framework for creating initial label maps from manually annotated training images. Within this framework, we model various registration- and patch-based segmentation techniques by changing the deformation field prior. Second, we perform contour-driven regression on the created label maps to refine the segmentation. Image contours and image parcellations give rise to non-stationary kernel functions that model the relationship between image locations. Setting the kernel to the covariance function in a Gaussian process establishes a distribution over label maps supported by image structures. Maximum a posteriori estimation of the distribution over label maps conditioned on the outcome of the atlas-based segmentation yields the refined segmentation. We evaluate the segmentation in two clinical applications: the segmentation of parotid glands in head and neck CT scans and the segmentation of the left atrium in cardiac MR angiography images. PMID:26068202

Mapping Interactive Cancer Susceptibility Genes in Prostate Cancer

DTIC Science & Technology

2007-04-01

interval within intron 5 of FHIT. Since non- exonic causative mutations are difficult to identify, we employed an approach looking for signatures of...natural selection in this region within human populations to better understand the potential nature of any disease mutation(s). Since non- exonic ...0.523 0.126 CYP3A4 7 98.999-99.026 D7S647 199496 0.79 98.913 195 0.510 0.300 EZH2 7 147.961-147.982 D7S688 199984 0.84 147.981 49 0.478 0.687 PTEN 10

Malaria Risk Mapping for Control in the Republic of Sudan

PubMed Central

Noor, Abdisalan M.; ElMardi, Khalid A.; Abdelgader, Tarig M.; Patil, Anand P.; Amine, Ahmed A. A.; Bakhiet, Sahar; Mukhtar, Maowia M.; Snow, Robert W.

2012-01-01

Evidence shows that malaria risk maps are rarely tailored to address national control program ambitions. Here, we generate a malaria risk map adapted for malaria control in Sudan. Community Plasmodium falciparum parasite rate (PfPR) data from 2000 to 2010 were assembled and were standardized to 2–10 years of age (PfPR2–10). Space-time Bayesian geostatistical methods were used to generate a map of malaria risk for 2010. Surfaces of aridity, urbanization, irrigation schemes, and refugee camps were combined with the PfPR2–10 map to tailor the epidemiological stratification for appropriate intervention design. In 2010, a majority of the geographical area of the Sudan had risk of < 1% PfPR2–10. Areas of meso- and hyperendemic risk were located in the south. About 80% of Sudan's population in 2011 was in the areas in the desert, urban centers, or where risk was < 1% PfPR2–10. Aggregated data suggest reducing risks in some high transmission areas since the 1960s. PMID:23033400

Mineral Potential in India Using Airborne Visible/Infrared Imaging Spectrometer-Next Generation (AVIRIS-NG) Data

NASA Astrophysics Data System (ADS)

Oommen, T.; Chatterjee, S.

2017-12-01

NASA and the Indian Space Research Organization (ISRO) are generating Earth surface features data using Airborne Visible/Infrared Imaging Spectrometer-Next Generation (AVIRIS-NG) within 380 to 2500 nm spectral range. This research focuses on the utilization of such data to better understand the mineral potential in India and to demonstrate the application of spectral data in rock type discrimination and mapping for mineral exploration by using automated mapping techniques. The primary focus area of this research is the Hutti-Maski greenstone belt, located in Karnataka, India. The AVIRIS-NG data was integrated with field analyzed data (laboratory scaled compositional analysis, mineralogy, and spectral library) to characterize minerals and rock types. An expert system was developed to produce mineral maps from AVIRIS-NG data automatically. The ground truth data from the study areas was obtained from the existing literature and collaborators from India. The Bayesian spectral unmixing algorithm was used in AVIRIS-NG data for endmember selection. The classification maps of the minerals and rock types were developed using support vector machine algorithm. The ground truth data was used to verify the mineral maps.

Genetic Map of Bacteriophage φX174

PubMed Central

Benbow, R. M.; Hutchison, C. A.; Fabricant, J. D.; Sinsheimer, R. L.

1971-01-01

Bacteriophage φX174 temperature-sensitive and nonsense mutations in eight cistrons were mapped by using two-, three-, and four-factor genetic crosses. The genetic map is circular with a total length of 24 × 10−4wt recombinants per progeny phage. The cistron order is D-E-F-G-H-A-B-C. High negative interference is seen, consistent with a small closed circular deoxyribonucleic acid molecule as a genome. PMID:16789129

Fine-structure mapping of the firA gene, a locus involved in the phenotypic expression of rifampin resistance in Escherichia.

PubMed Central

Lathe, R

1977-01-01

The firA (Ts)200 mutation not only eliminates the resistance to rifampin of certain genetically resistant strains, but, moreover, renders ribonucleic acid synthesis thermolabile. The firA gene has been mapped by P1 tranduction and is located extremely close to the structural gene for deoxyribonucleic acid polymerase III at 4 min on the Escherichia coli linkage map. PMID:330494

Genetic Studies of the Prp17 Gene of Saccharomyces Cerevisiae: A Domain Essential for Function Maps to a Nonconserved Region of the Protein

PubMed Central

Seshadri, V.; Vaidya, V. C.; Vijayraghavan, U.

1996-01-01

The PRP17 gene product is required for the second step of pre-mRNA splicing reactions. The C-terminal half of this protein bears four repeat units with homology to the β transducin repeat. Missense mutations in three temperature-sensitive prp17 mutants map to a region in the N-terminal half of the protein. We have generated, in vitro, 11 missense alleles at the β transducin repeat units and find that only one affects function in vivo. A phenotypically silent missense allele at the fourth repeat unit enhances the slow-growing phenotype conferred by an allele at the third repeat, suggesting an interaction between these domains. Although many missense mutations in highly conserved amino acids lack phenotypic effects, deletion analysis suggests an essential role for these units. Only mutations in the N-terminal nonconserved domain of PRP17 are synthetically lethal in combination with mutations in PRP16 and PRP18, two other gene products required for the second splicing reaction. A mutually allele-specific interaction between prp17 and snr7, with mutations in U5 snRNA, was observed. We therefore suggest that the functional region of Prp17p that interacts with Prp18p, Prp16p, and U5 snRNA is in the N terminal region of the protein. PMID:8722761

Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

PubMed

Harripaul, R; Vasli, N; Mikhailov, A; Rafiq, M A; Mittal, K; Windpassinger, C; Sheikh, T I; Noor, A; Mahmood, H; Downey, S; Johnson, M; Vleuten, K; Bell, L; Ilyas, M; Khan, F S; Khan, V; Moradi, M; Ayaz, M; Naeem, F; Heidari, A; Ahmed, I; Ghadami, S; Agha, Z; Zeinali, S; Qamar, R; Mozhdehipanah, H; John, P; Mir, A; Ansar, M; French, L; Ayub, M; Vincent, J B

2018-04-01

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.

PubMed

Wang, Jie; Wan, Ke; Sun, Jiayu; Li, Weihao; Liu, Hong; Han, Yuchi; Chen, Yucheng

2018-01-17

Limited data is available on phenotypic variations with the same genotype in hypertrophic cardiomyopathy (HCM). The present study aims to explore the relationship between genotype and phenotype characterized by cardiovascular magnetic resonance (CMR) in a large Chinese family. A proband diagnosed with HCM from a multigenerational family underwent next-generation sequencing based on a custom sureSelect panel, including 117 candidate pathogenic genes associated with cardiomyopathies. All genetic results were confirmed by the Sanger sequencing method. All confirmed mutation carriers underwent CMR exam and myocardial tissue characterization using T1 mapping and late gadolinium enhancement (LGE) on a 3T scanner (Siemens Trio, Gemany). After clinical and genetic screening of 36 (including the proband) members of a large Chinese family, nineteen family members are determined to carry the single p.T1377M (c.4130C>T) mutation in the MYH7 gene. Of these 19 mutation carriers, eight are diagnosed with HCM, one was considered as borderline affected and ten are not clinically or phenotypically affected. Different HCM phenotypes are present in the nine affected individuals in this family. In addition, we have found different tissue characteristics assessed by T1 mapping and LGE in these individuals. We describe a family that demonstrates the diverse HCM phenotypes associated with a single MYH7 mutation.

X-Linked Syndrome of Polyendocrinopathy, Immune Dysfunction, and Diarrhea Maps to Xp11.23-Xq13.3

PubMed Central

Bennett, Craig L.; Yoshioka, Ritsuko; Kiyosawa, Hidenori; Barker, David F.; Fain, Pamela R.; Shigeoka, Ann O.; Chance, Phillip F.

2000-01-01

Summary We describe genetic analysis of a large pedigree with an X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID), which frequently results in death during infancy or childhood. Linkage analysis mapped the XPID gene to a 17-cM interval defined by markers DXS8083 and DXS8107 on the X chromosome, at Xp11.23-Xq13.3. The maximum LOD score was 3.99 (recombination fraction0) at DXS1235. Because this interval also harbors the gene for Wiskott-Aldrich syndrome (WAS), we investigated mutations in the WASP gene, as the molecular basis of XPID. Northern blot analysis detected the same relative amount and the same-sized WASP message in patients with XPID and in a control. Analysis of the WASP coding sequence, an alternate promoter, and an untranslated upstream first exon was carried out, and no mutations were found in patients with XPID. A C→T transition within the alternate translation start site cosegregated with the XPID phenotype in this family; however, the same transition site was detected in a normal control male. We conclude that XPID maps to Xp11.23-Xq13.3 and that mutations of WASP are not associated with XPID. PMID:10677306

Morphometric analysis and neuroanatomical mapping of the zebrafish brain.

PubMed

Gupta, Tripti; Marquart, Gregory D; Horstick, Eric J; Tabor, Kathryn M; Pajevic, Sinisa; Burgess, Harold A

2018-06-21

Large-scale genomic studies have recently identified genetic variants causative for major neurodevelopmental disorders, such as intellectual disability and autism. However, determining how underlying developmental processes are affected by these mutations remains a significant challenge in the field. Zebrafish is an established model system in developmental neurogenetics that may be useful in uncovering the mechanisms of these mutations. Here we describe the use of voxel-intensity, deformation field, and volume-based morphometric techniques for the systematic and unbiased analysis of gene knock-down and environmental exposure-induced phenotypes in zebrafish. We first present a computational method for brain segmentation based on transgene expression patterns to create a comprehensive neuroanatomical map. This map allowed us to disclose statistically significant changes in brain microstructure and composition in neurodevelopmental models. We demonstrate the effectiveness of morphometric techniques in measuring changes in the relative size of neuroanatomical subdivisions in atoh7 morphant larvae and in identifying phenotypes in larvae treated with valproic acid, a chemical demonstrated to increase the risk of autism in humans. These tools enable rigorous evaluation of the effects of gene mutations and environmental exposures on neural development, providing an entry point for cellular and molecular analysis of basic developmental processes as well as neurodevelopmental and neurodegenerative disorders. Published by Elsevier Inc.

Joint genotype- and ancestry-based genome-wide association studies in admixed populations.

PubMed

Szulc, Piotr; Bogdan, Malgorzata; Frommlet, Florian; Tang, Hua

2017-09-01

In genome-wide association studies (GWAS) genetic loci that influence complex traits are localized by inspecting associations between genotypes of genetic markers and the values of the trait of interest. On the other hand, admixture mapping, which is performed in case of populations consisting of a recent mix of two ancestral groups, relies on the ancestry information at each locus (locus-specific ancestry). Recently it has been proposed to jointly model genotype and locus-specific ancestry within the framework of single marker tests. Here, we extend this approach for population-based GWAS in the direction of multimarker models. A modified version of the Bayesian information criterion is developed for building a multilocus model that accounts for the differential correlation structure due to linkage disequilibrium (LD) and admixture LD. Simulation studies and a real data example illustrate the advantages of this new approach compared to single-marker analysis or modern model selection strategies based on separately analyzing genotype and ancestry data, as well as to single-marker analysis combining genotypic and ancestry information. Depending on the signal strength, our procedure automatically chooses whether genotypic or locus-specific ancestry markers are added to the model. This results in a good compromise between the power to detect causal mutations and the precision of their localization. The proposed method has been implemented in R and is available at http://www.math.uni.wroc.pl/~mbogdan/admixtures/. © 2017 WILEY PERIODICALS, INC.

Genetic interaction analysis of point mutations enables interrogation of gene function at a residue-level resolution

PubMed Central

Braberg, Hannes; Moehle, Erica A.; Shales, Michael; Guthrie, Christine; Krogan, Nevan J.

2014-01-01

We have achieved a residue-level resolution of genetic interaction mapping – a technique that measures how the function of one gene is affected by the alteration of a second gene – by analyzing point mutations. Here, we describe how to interpret point mutant genetic interactions, and outline key applications for the approach, including interrogation of protein interaction interfaces and active sites, and examination of post-translational modifications. Genetic interaction analysis has proven effective for characterizing cellular processes; however, to date, systematic high-throughput genetic interaction screens have relied on gene deletions or knockdowns, which limits the resolution of gene function analysis and poses problems for multifunctional genes. Our point mutant approach addresses these issues, and further provides a tool for in vivo structure-function analysis that complements traditional biophysical methods. We also discuss the potential for genetic interaction mapping of point mutations in human cells and its application to personalized medicine. PMID:24842270

Identification of new mutations in primary hyperoxaluria type 1 (PH1).

PubMed

von Schnakenburg, C; Rumsby, G

1998-01-01

Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). The AGXT gene, which codes for the 392 amino acid protein, has been mapped to chromosome 2q37.3. In order to identify new mutations in the AGXT gene we studied 79 PH1 patients using single strand conformation polymorphism analysis. In addition to a cluster of new mutations in exon 7 we report five novel mutations in exons 2, 4, 5, 9 and 10. These are T444C, G640A, G690A, 1008-1010delGCG and G1171A. These five new mutations contribute to our knowledge of the AGXT gene. Their possible consequences for PH1 phenotype and enzyme activity are discussed.

A Mutation in the Rett Syndrome Gene, MECP2, Causes X-Linked Mental Retardation and Progressive Spasticity in Males

PubMed Central

Meloni, Ilaria; Bruttini, Mirella; Longo, Ilaria; Mari, Francesca; Rizzolio, Flavio; D’Adamo, Patrizia; Denvriendt, Koenraad; Fryns, Jean-Pierre; Toniolo, Daniela; Renieri, Alessandra

2000-01-01

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders. PMID:10986043

Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer

PubMed Central

Arighi, Cecilia N.; Wu, Cathy H.

2015-01-01

Given the wealth of bioinformatics resources and the growing complexity of biological information, it is valuable to integrate data from disparate sources to gain insight into the role of genes/proteins in health and disease. We have developed a bioinformatics framework that combines literature mining with information from biomedical ontologies and curated databases to create knowledge “maps” of genes/proteins of interest. We applied this approach to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated in cancer. The knowledge map includes post-translational modifications (PTMs), protein-protein interactions, disease-associated mutations, and transcription factors co-activated by beta-catenin and their targets and captures the major processes in which beta-catenin is known to participate. Using the map, we generated testable hypotheses about beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple relation types, we identified proteins that may participate in feedback loops regulating beta-catenin transcriptional activity. By combining multiple network relations with PTM proteoform-specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity. Finally, by overlaying cancer-associated mutation data with sequence features, we observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin mutations can contribute to cancer. The approach described, which captures rich information for molecular species from genes and proteins to PTM proteoforms, is extensible to other proteins and their involvement in disease. PMID:26509276

Structure-functional prediction and analysis of cancer mutation effects in protein kinases.

PubMed

Dixit, Anshuman; Verkhivker, Gennady M

2014-01-01

A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal "low" activity state to the "active" state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes.

Mutational analysis of the TCOF1 gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis.

PubMed

Horiuchi, Katsumi; Ariga, Tadashi; Fujioka, Hirotaka; Kawashima, Kunihiro; Yamamoto, Yuhei; Igawa, Hiroharu; Sugihara, Tsuneki; Sakiyama, Yukio

2005-05-01

Treacher Collins Syndrome (TCS) (OMIM 154500) is a congenital, craniofacial disorder inherited as an autosomal dominant trait. The responsible gene for TCS, TCOF1, was mapped to 5q32-33.1 and identified in 1996. Since then, TCOF1 mutations in patients with TCS have been reported from Europe, North and South America, however, no TCS cases from an Asian country have been molecularly characterized. Here we report mutational analysis for 11 Japanese patients with TCS for the first time, and have identified TCOF1 mutations in 9 of them. The mutations detected were various, but most likely all the mutations are predicted to result in a truncated gene product, known as treacle. One mutation frequently reported was included in our cases, but no missense mutations were detected. These findings are similar to those for the previous studies for TCS in other races. We have speculated about the molecular mechanisms of the mutations in most cases. Collectively, we have defined some of the characteristic molecular features commonly observed in TCS patients, irrespective of racial difference. 2005 Wiley-Liss, Inc.

Social deprivation and population density are not associated with small area risk of amyotrophic lateral sclerosis.

PubMed

Rooney, James P K; Tobin, Katy; Crampsie, Arlene; Vajda, Alice; Heverin, Mark; McLaughlin, Russell; Staines, Anthony; Hardiman, Orla

2015-10-01

Evidence of an association between areal ALS risk and population density has been previously reported. We aim to examine ALS spatial incidence in Ireland using small areas, to compare this analysis with our previous analysis of larger areas and to examine the associations between population density, social deprivation and ALS incidence. Residential area social deprivation has not been previously investigated as a risk factor for ALS. Using the Irish ALS register, we included all cases of ALS diagnosed in Ireland from 1995-2013. 2006 census data was used to calculate age and sex standardised expected cases per small area. Social deprivation was assessed using the pobalHP deprivation index. Bayesian smoothing was used to calculate small area relative risk for ALS, whilst cluster analysis was performed using SaTScan. The effects of population density and social deprivation were tested in two ways: (1) as covariates in the Bayesian spatial model; (2) via post-Bayesian regression. 1701 cases were included. Bayesian smoothed maps of relative risk at small area resolution matched closely to our previous analysis at a larger area resolution. Cluster analysis identified two areas of significant low risk. These areas did not correlate with population density or social deprivation indices. Two areas showing low frequency of ALS have been identified in the Republic of Ireland. These areas do not correlate with population density or residential area social deprivation, indicating that other reasons, such as genetic admixture may account for the observed findings. Copyright © 2015 Elsevier Inc. All rights reserved.

Predicting coastal cliff erosion using a Bayesian probabilistic model

USGS Publications Warehouse

Hapke, Cheryl J.; Plant, Nathaniel G.

2010-01-01

Regional coastal cliff retreat is difficult to model due to the episodic nature of failures and the along-shore variability of retreat events. There is a growing demand, however, for predictive models that can be used to forecast areas vulnerable to coastal erosion hazards. Increasingly, probabilistic models are being employed that require data sets of high temporal density to define the joint probability density function that relates forcing variables (e.g. wave conditions) and initial conditions (e.g. cliff geometry) to erosion events. In this study we use a multi-parameter Bayesian network to investigate correlations between key variables that control and influence variations in cliff retreat processes. The network uses Bayesian statistical methods to estimate event probabilities using existing observations. Within this framework, we forecast the spatial distribution of cliff retreat along two stretches of cliffed coast in Southern California. The input parameters are the height and slope of the cliff, a descriptor of material strength based on the dominant cliff-forming lithology, and the long-term cliff erosion rate that represents prior behavior. The model is forced using predicted wave impact hours. Results demonstrate that the Bayesian approach is well-suited to the forward modeling of coastal cliff retreat, with the correct outcomes forecast in 70–90% of the modeled transects. The model also performs well in identifying specific locations of high cliff erosion, thus providing a foundation for hazard mapping. This approach can be employed to predict cliff erosion at time-scales ranging from storm events to the impacts of sea-level rise at the century-scale.

A full-spectral Bayesian reconstruction approach based on the material decomposition model applied in dual-energy computed tomography.

PubMed

Cai, C; Rodet, T; Legoupil, S; Mohammad-Djafari, A

2013-11-01

Dual-energy computed tomography (DECT) makes it possible to get two fractions of basis materials without segmentation. One is the soft-tissue equivalent water fraction and the other is the hard-matter equivalent bone fraction. Practical DECT measurements are usually obtained with polychromatic x-ray beams. Existing reconstruction approaches based on linear forward models without counting the beam polychromaticity fail to estimate the correct decomposition fractions and result in beam-hardening artifacts (BHA). The existing BHA correction approaches either need to refer to calibration measurements or suffer from the noise amplification caused by the negative-log preprocessing and the ill-conditioned water and bone separation problem. To overcome these problems, statistical DECT reconstruction approaches based on nonlinear forward models counting the beam polychromaticity show great potential for giving accurate fraction images. This work proposes a full-spectral Bayesian reconstruction approach which allows the reconstruction of high quality fraction images from ordinary polychromatic measurements. This approach is based on a Gaussian noise model with unknown variance assigned directly to the projections without taking negative-log. Referring to Bayesian inferences, the decomposition fractions and observation variance are estimated by using the joint maximum a posteriori (MAP) estimation method. Subject to an adaptive prior model assigned to the variance, the joint estimation problem is then simplified into a single estimation problem. It transforms the joint MAP estimation problem into a minimization problem with a nonquadratic cost function. To solve it, the use of a monotone conjugate gradient algorithm with suboptimal descent steps is proposed. The performance of the proposed approach is analyzed with both simulated and experimental data. The results show that the proposed Bayesian approach is robust to noise and materials. It is also necessary to have the accurate spectrum information about the source-detector system. When dealing with experimental data, the spectrum can be predicted by a Monte Carlo simulator. For the materials between water and bone, less than 5% separation errors are observed on the estimated decomposition fractions. The proposed approach is a statistical reconstruction approach based on a nonlinear forward model counting the full beam polychromaticity and applied directly to the projections without taking negative-log. Compared to the approaches based on linear forward models and the BHA correction approaches, it has advantages in noise robustness and reconstruction accuracy.

Spatial Modelling of Soil-Transmitted Helminth Infections in Kenya: A Disease Control Planning Tool

PubMed Central

Pullan, Rachel L.; Gething, Peter W.; Smith, Jennifer L.; Mwandawiro, Charles S.; Sturrock, Hugh J. W.; Gitonga, Caroline W.; Hay, Simon I.; Brooker, Simon

2011-01-01

Background Implementation of control of parasitic diseases requires accurate, contemporary maps that provide intervention recommendations at policy-relevant spatial scales. To guide control of soil transmitted helminths (STHs), maps are required of the combined prevalence of infection, indicating where this prevalence exceeds an intervention threshold of 20%. Here we present a new approach for mapping the observed prevalence of STHs, using the example of Kenya in 2009. Methods and Findings Observed prevalence data for hookworm, Ascaris lumbricoides and Trichuris trichiura were assembled for 106,370 individuals from 945 cross-sectional surveys undertaken between 1974 and 2009. Ecological and climatic covariates were extracted from high-resolution satellite data and matched to survey locations. Bayesian space-time geostatistical models were developed for each species, and were used to interpolate the probability that infection prevalence exceeded the 20% threshold across the country for both 1989 and 2009. Maps for each species were integrated to estimate combined STH prevalence using the law of total probability and incorporating a correction factor to adjust for associations between species. Population census data were combined with risk models and projected to estimate the population at risk and requiring treatment in 2009. In most areas for 2009, there was high certainty that endemicity was below the 20% threshold, with areas of endemicity ≥20% located around the shores of Lake Victoria and on the coast. Comparison of the predicted distributions for 1989 and 2009 show how observed STH prevalence has gradually decreased over time. The model estimated that a total of 2.8 million school-age children live in districts which warrant mass treatment. Conclusions Bayesian space-time geostatistical models can be used to reliably estimate the combined observed prevalence of STH and suggest that a quarter of Kenya's school-aged children live in areas of high prevalence and warrant mass treatment. As control is successful in reducing infection levels, updated models can be used to refine decision making in helminth control. PMID:21347451

National-scale aboveground biomass geostatistical mapping with FIA inventory and GLAS data: Preparation for sparsely sampled lidar assisted forest inventory

NASA Astrophysics Data System (ADS)

Babcock, C. R.; Finley, A. O.; Andersen, H. E.; Moskal, L. M.; Morton, D. C.; Cook, B.; Nelson, R.

2017-12-01

Upcoming satellite lidar missions, such as GEDI and IceSat-2, are designed to collect laser altimetry data from space for narrow bands along orbital tracts. As a result lidar metric sets derived from these sources will not be of complete spatial coverage. This lack of complete coverage, or sparsity, means traditional regression approaches that consider lidar metrics as explanatory variables (without error) cannot be used to generate wall-to-wall maps of forest inventory variables. We implement a coregionalization framework to jointly model sparsely sampled lidar information and point-referenced forest variable measurements to create wall-to-wall maps with full probabilistic uncertainty quantification of all inputs. We inform the model with USFS Forest Inventory and Analysis (FIA) in-situ forest measurements and GLAS lidar data to spatially predict aboveground forest biomass (AGB) across the contiguous US. We cast our model within a Bayesian hierarchical framework to better model complex space-varying correlation structures among the lidar metrics and FIA data, which yields improved prediction and uncertainty assessment. To circumvent computational difficulties that arise when fitting complex geostatistical models to massive datasets, we use a Nearest Neighbor Gaussian process (NNGP) prior. Results indicate that a coregionalization modeling approach to leveraging sampled lidar data to improve AGB estimation is effective. Further, fitting the coregionalization model within a Bayesian mode of inference allows for AGB quantification across scales ranging from individual pixel estimates of AGB density to total AGB for the continental US with uncertainty. The coregionalization framework examined here is directly applicable to future spaceborne lidar acquisitions from GEDI and IceSat-2. Pairing these lidar sources with the extensive FIA forest monitoring plot network using a joint prediction framework, such as the coregionalization model explored here, offers the potential to improve forest AGB accounting certainty and provide maps for post-model fitting analysis of the spatial distribution of AGB.

High-resolution gravity model of Venus

NASA Technical Reports Server (NTRS)

Reasenberg, R. D.; Goldberg, Z. M.

1992-01-01

The anomalous gravity field of Venus shows high correlation with surface features revealed by radar. We extract gravity models from the Doppler tracking data from the Pioneer Venus Orbiter by means of a two-step process. In the first step, we solve the nonlinear spacecraft state estimation problem using a Kalman filter-smoother. The Kalman filter has been evaluated through simulations. This evaluation and some unusual features of the filter are discussed. In the second step, we perform a geophysical inversion using a linear Bayesian estimator. To allow an unbiased comparison between gravity and topography, we use a simulation technique to smooth and distort the radar topographic data so as to yield maps having the same characteristics as our gravity maps. The maps presented cover 2/3 of the surface of Venus and display the strong topography-gravity correlation previously reported. The topography-gravity scatter plots show two distinct trends.

Mapping Land Cover Types in Amazon Basin Using 1km JERS-1 Mosaic

NASA Technical Reports Server (NTRS)

Saatchi, Sassan S.; Nelson, Bruce; Podest, Erika; Holt, John

2000-01-01

In this paper, the 100 meter JERS-1 Amazon mosaic image was used in a new classifier to generate a I km resolution land cover map. The inputs to the classifier were 1 km resolution mean backscatter and seven first order texture measures derived from the 100 m data by using a 10 x 10 independent sampling window. The classification approach included two interdependent stages: 1) a supervised maximum a posteriori Bayesian approach to classify the mean backscatter image into 5 general land cover categories of forest, savannah, inundated, white sand, and anthropogenic vegetation classes, and 2) a texture measure decision rule approach to further discriminate subcategory classes based on taxonomic information and biomass levels. Fourteen classes were successfully separated at 1 km scale. The results were verified by examining the accuracy of the approach by comparison with the IBGE and the AVHRR 1 km resolution land cover maps.

Dana-Farber Cancer Institute: Mapping the Function of Rare Oncogenic Variants | Office of Cancer Genomics

Cancer.gov

Although some oncogenes and tumor suppressor genes are recurrently mutated at high frequency, the majority of somatic sequence alterations found in cancers occur at low frequency, and the functional consequences of the majority of these mutated alleles remain unknown. We are developing a scalable systematic approach to interrogate the function of cancer-associated gene variants. Read the abstract

Landslide Susceptibility Mapping of Tegucigalpa, Honduras Using Artificial Neural Network, Bayesian Network and Decision Trees

NASA Astrophysics Data System (ADS)

Garcia Urquia, E. L.; Braun, A.; Yamagishi, H.

2016-12-01

Tegucigalpa, the capital city of Honduras, experiences rainfall-induced landslides on a yearly basis. The high precipitation regime and the rugged topography the city has been built in couple with the lack of a proper urban expansion plan to contribute to the occurrence of landslides during the rainy season. Thousands of inhabitants live at risk of losing their belongings due to the construction of precarious shelters in landslide-prone areas on mountainous terrains and next to the riverbanks. Therefore, the city is in the need for landslide susceptibility and hazard maps to aid in the regulation of future development. Major challenges in the context of highly dynamic urbanizing areas are the overlap of natural and anthropogenic slope destabilizing factors, as well as the availability and accuracy of data. Data-driven multivariate techniques have proven to be powerful in discovering interrelations between factors, identifying important factors in large datasets, capturing non-linear problems and coping with noisy and incomplete data. This analysis focuses on the creation of a landslide susceptibility map using different methods from the field of data mining, Artificial Neural Networks (ANN), Bayesian Networks (BN) and Decision Trees (DT). The input dataset of the study contains geomorphological and hydrological factors derived from a digital elevation model with a 10 m resolution, lithological factors derived from a geological map, and anthropogenic factors, such as information on the development stage of the neighborhoods in Tegucigalpa and road density. Moreover, a landslide inventory map that was developed in 2014 through aerial photo interpretation was used as target variable in the analysis. The analysis covers an area of roughly 100 km2, while 8.95 km2 are occupied by landslides. In a first step, the dataset was explored by assessing and improving the data quality, identifying unimportant variables and finding interrelations. Then, based on a training partition of the dataset, the ANN, BN and DT were optimized for the prediction of landslides. The predictive power and ability to generalize of the resulting models were assessed in a test partition and evaluated using success rate curves, skill scores and by ensuring the spatial plausibility of the prediction.

Mapping of rock types using a joint approach by combining the multivariate statistics, self-organizing map and Bayesian neural networks: an example from IODP 323 site

NASA Astrophysics Data System (ADS)

Karmakar, Mampi; Maiti, Saumen; Singh, Amrita; Ojha, Maheswar; Maity, Bhabani Sankar

2017-07-01

Modeling and classification of the subsurface lithology is very important to understand the evolution of the earth system. However, precise classification and mapping of lithology using a single framework are difficult due to the complexity and the nonlinearity of the problem driven by limited core sample information. Here, we implement a joint approach by combining the unsupervised and the supervised methods in a single framework for better classification and mapping of rock types. In the unsupervised method, we use the principal component analysis (PCA), K-means cluster analysis (K-means), dendrogram analysis, Fuzzy C-means (FCM) cluster analysis and self-organizing map (SOM). In the supervised method, we use the Bayesian neural networks (BNN) optimized by the Hybrid Monte Carlo (HMC) (BNN-HMC) and the scaled conjugate gradient (SCG) (BNN-SCG) techniques. We use P-wave velocity, density, neutron porosity, resistivity and gamma ray logs of the well U1343E of the Integrated Ocean Drilling Program (IODP) Expedition 323 in the Bering Sea slope region. While the SOM algorithm allows us to visualize the clustering results in spatial domain, the combined classification schemes (supervised and unsupervised) uncover the different patterns of lithology such of as clayey-silt, diatom-silt and silty-clay from an un-cored section of the drilled hole. In addition, the BNN approach is capable of estimating uncertainty in the predictive modeling of three types of rocks over the entire lithology section at site U1343. Alternate succession of clayey-silt, diatom-silt and silty-clay may be representative of crustal inhomogeneity in general and thus could be a basis for detail study related to the productivity of methane gas in the oceans worldwide. Moreover, at the 530 m depth down below seafloor (DSF), the transition from Pliocene to Pleistocene could be linked to lithological alternation between the clayey-silt and the diatom-silt. The present results could provide the basis for the detailed study to get deeper insight into the Bering Sea' sediment deposition and sequence.

Observations and Bayesian location methodology of transient acoustic signals (likely blue whales) in the Indian Ocean, using a hydrophone triplet.

PubMed

Le Bras, Ronan J; Kuzma, Heidi; Sucic, Victor; Bokelmann, Götz

2016-05-01

A notable sequence of calls was encountered, spanning several days in January 2003, in the central part of the Indian Ocean on a hydrophone triplet recording acoustic data at a 250 Hz sampling rate. This paper presents signal processing methods applied to the waveform data to detect, group, extract amplitude and bearing estimates for the recorded signals. An approximate location for the source of the sequence of calls is inferred from extracting the features from the waveform. As the source approaches the hydrophone triplet, the source level (SL) of the calls is estimated at 187 ± 6 dB re: 1 μPa-1 m in the 15-60 Hz frequency range. The calls are attributed to a subgroup of blue whales, Balaenoptera musculus, with a characteristic acoustic signature. A Bayesian location method using probabilistic models for bearing and amplitude is demonstrated on the calls sequence. The method is applied to the case of detection at a single triad of hydrophones and results in a probability distribution map for the origin of the calls. It can be extended to detections at multiple triads and because of the Bayesian formulation, additional modeling complexity can be built-in as needed.

Hierarchical Bayesian modeling of spatio-temporal patterns of lung cancer incidence risk in Georgia, USA: 2000-2007

NASA Astrophysics Data System (ADS)

Yin, Ping; Mu, Lan; Madden, Marguerite; Vena, John E.

2014-10-01

Lung cancer is the second most commonly diagnosed cancer in both men and women in Georgia, USA. However, the spatio-temporal patterns of lung cancer risk in Georgia have not been fully studied. Hierarchical Bayesian models are used here to explore the spatio-temporal patterns of lung cancer incidence risk by race and gender in Georgia for the period of 2000-2007. With the census tract level as the spatial scale and the 2-year period aggregation as the temporal scale, we compare a total of seven Bayesian spatio-temporal models including two under a separate modeling framework and five under a joint modeling framework. One joint model outperforms others based on the deviance information criterion. Results show that the northwest region of Georgia has consistently high lung cancer incidence risk for all population groups during the study period. In addition, there are inverse relationships between the socioeconomic status and the lung cancer incidence risk among all Georgian population groups, and the relationships in males are stronger than those in females. By mapping more reliable variations in lung cancer incidence risk at a relatively fine spatio-temporal scale for different Georgian population groups, our study aims to better support healthcare performance assessment, etiological hypothesis generation, and health policy making.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

PubMed

Park, Y W; Han, K; Ahn, S S; Choi, Y S; Chang, J H; Kim, S H; Kang, S-G; Kim, E H; Lee, S-K

2018-04-01

Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1 -mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. Ninety-three patients with World Health Organization grade II gliomas with known IDH1- mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1- mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1 -mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1 -mutant subgroups were evaluated using the least absolute shrinkage and selection operator. Various histogram and texture parameters differed significantly according to IDH1 -mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1 -mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1 -mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. © 2018 by American Journal of Neuroradiology.

Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes.

PubMed

Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Mendez, Vanessa; Vazquez, Pedro Juan; Lozada, Maria Eugenia; Freyre, Katerina; Lathroum, Liselle; Gonzalez-Pons, Maria; Hernandez-Marrero, Jessica; Giardiello, Francis; Rodriguez-Quilichini, Segundo

2013-09-01

Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis.

Applications of next-generation sequencing analysis for the detection of hepatocellular carcinoma-associated hepatitis B virus mutations.

PubMed

Wu, I-Chin; Liu, Wen-Chun; Chang, Ting-Tsung

2018-06-02

Next-generation sequencing (NGS) is a powerful and high-throughput method for the detection of viral mutations. This article provides a brief overview about optimization of NGS analysis for hepatocellular carcinoma (HCC)-associated hepatitis B virus (HBV) mutations, and hepatocarcinogenesis of relevant mutations. For the application of NGS analysis in the genome of HBV, four noteworthy steps were discovered in testing. First, a sample-specific reference sequence was the most effective mapping reference for NGS. Second, elongating the end of reference sequence improved mapping performance at the end of the genome. Third, resetting the origin of mapping reference sequence could probed deletion mutations and variants at a certain location with common mutations. Fourth, using a platform-specific cut-off value to distinguish authentic minority variants from technical artifacts was found to be highly effective. One hundred and sixty-seven HBV single nucleotide variants (SNVs) were found to be studied previously through a systematic literature review, and 12 SNVs were determined to be associated with HCC by meta-analysis. From comprehensive research using a HBV genome-wide NGS analysis, 60 NGS-defined HCC-associated SNVs with their pathogenic frequencies were identified, with 19 reported previously. All the 12 HCC-associated SNVs proved by meta-analysis were confirmed by NGS analysis, except for C1766T and T1768A which were mainly expressed in genotypes A and D, but including the subgroup analysis of A1762T. In the 41 novel NGS-defined HCC-associated SNVs, 31.7% (13/41) had cut-off values of SNV frequency lower than 20%. This showed that NGS could be used to detect HCC-associated SNVs with low SNV frequency. Most SNV II (the minor strains in the majority of non-HCC patients) had either low (< 20%) or high (> 80%) SNV frequencies in HCC patients, a characteristic U-shaped distribution pattern. The cut-off values of SNV frequency for HCC-associated SNVs represent their pathogenic frequencies. The pathogenic frequencies of HCC-associated SNV II also showed a U-shaped distribution. Hepatocarcinogenesis induced by HBV mutated proteins through cellular pathways was reviewed. NGS analysis is useful to discover novel HCC-associated HBV SNVs, especially those with low SNV frequency. The hepatocarcinogenetic mechanisms of novel HCC-associated HBV SNVs defined by NGS analysis deserve further investigation.

Mapping mutational effects along the evolutionary landscape of HIV envelope.

PubMed

Haddox, Hugh K; Dingens, Adam S; Hilton, Sarah K; Overbaugh, Julie; Bloom, Jesse D

2018-03-28

The immediate evolutionary space accessible to HIV is largely determined by how single amino acid mutations affect fitness. These mutational effects can shift as the virus evolves. However, the prevalence of such shifts in mutational effects remains unclear. Here, we quantify the effects on viral growth of all amino acid mutations to two HIV envelope (Env) proteins that differ at [Formula: see text]100 residues. Most mutations similarly affect both Envs, but the amino acid preferences of a minority of sites have clearly shifted. These shifted sites usually prefer a specific amino acid in one Env, but tolerate many amino acids in the other. Surprisingly, shifts are only slightly enriched at sites that have substituted between the Envs-and many occur at residues that do not even contact substitutions. Therefore, long-range epistasis can unpredictably shift Env's mutational tolerance during HIV evolution, although the amino acid preferences of most sites are conserved between moderately diverged viral strains. © 2018, Haddox et al.

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.

PubMed

Janouskova, Hana; El Tekle, Geniver; Bellini, Elisa; Udeshi, Namrata D; Rinaldi, Anna; Ulbricht, Anna; Bernasocchi, Tiziano; Civenni, Gianluca; Losa, Marco; Svinkina, Tanya; Bielski, Craig M; Kryukov, Gregory V; Cascione, Luciano; Napoli, Sara; Enchev, Radoslav I; Mutch, David G; Carney, Michael E; Berchuck, Andrew; Winterhoff, Boris J N; Broaddus, Russell R; Schraml, Peter; Moch, Holger; Bertoni, Francesco; Catapano, Carlo V; Peter, Matthias; Carr, Steven A; Garraway, Levi A; Wild, Peter J; Theurillat, Jean-Philippe P

2017-09-01

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2

PubMed Central

Coady, Michael J.; El Tarazi, Abdulah; Santer, René; Bissonnette, Pierre; Sasseville, Louis J.; Calado, Joaquim; Lussier, Yoann; Dumayne, Christopher; Bichet, Daniel G.

2017-01-01

The renal proximal tubule reabsorbs 90% of the filtered glucose load through the Na+-coupled glucose transporter SGLT2, and specific inhibitors of SGLT2 are now available to patients with diabetes to increase urinary glucose excretion. Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that increased SGLT2 activity in RNA-injected Xenopus oocytes by two orders of magnitude. Significant stimulation of SGLT2 activity also occurred in opossum kidney cells cotransfected with SGLT2 and MAP17. Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type. To confirm the physiologic relevance of the MAP17–SGLT2 interaction, we studied a cohort of 60 individuals with familial renal glucosuria. One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1). In the proximal tubule and in other tissues, MAP17 is known to interact with PDZK1, a scaffolding protein linked to other transporters, including Na+/H+ exchanger 3, and to signaling pathways, such as the A-kinase anchor protein 2/protein kinase A pathway. Thus, these results provide the basis for a more thorough characterization of SGLT2 which would include the possible effects of its inhibition on colocalized renal transporters. PMID:27288013

Hybrid ICA-Bayesian network approach reveals distinct effective connectivity differences in schizophrenia.

PubMed

Kim, D; Burge, J; Lane, T; Pearlson, G D; Kiehl, K A; Calhoun, V D

2008-10-01

We utilized a discrete dynamic Bayesian network (dDBN) approach (Burge, J., Lane, T., Link, H., Qiu, S., Clark, V.P., 2007. Discrete dynamic Bayesian network analysis of fMRI data. Hum Brain Mapp.) to determine differences in brain regions between patients with schizophrenia and healthy controls on a measure of effective connectivity, termed the approximate conditional likelihood score (ACL) (Burge, J., Lane, T., 2005. Learning Class-Discriminative Dynamic Bayesian Networks. Proceedings of the International Conference on Machine Learning, Bonn, Germany, pp. 97-104.). The ACL score represents a class-discriminative measure of effective connectivity by measuring the relative likelihood of the correlation between brain regions in one group versus another. The algorithm is capable of finding non-linear relationships between brain regions because it uses discrete rather than continuous values and attempts to model temporal relationships with a first-order Markov and stationary assumption constraint (Papoulis, A., 1991. Probability, random variables, and stochastic processes. McGraw-Hill, New York.). Since Bayesian networks are overly sensitive to noisy data, we introduced an independent component analysis (ICA) filtering approach that attempted to reduce the noise found in fMRI data by unmixing the raw datasets into a set of independent spatial component maps. Components that represented noise were removed and the remaining components reconstructed into the dimensions of the original fMRI datasets. We applied the dDBN algorithm to a group of 35 patients with schizophrenia and 35 matched healthy controls using an ICA filtered and unfiltered approach. We determined that filtering the data significantly improved the magnitude of the ACL score. Patients showed the greatest ACL scores in several regions, most markedly the cerebellar vermis and hemispheres. Our findings suggest that schizophrenia patients exhibit weaker connectivity than healthy controls in multiple regions, including bilateral temporal, frontal, and cerebellar regions during an auditory paradigm.

Aurora-A as a Modifier of Breast Cancer Risk in BRCA 1/2 Mutation Carriers

DTIC Science & Technology

2007-06-01

Dieter Schaefer, Institute of Human Genetics, University of Frankfurt, Frankfurt, Germany; Norbert Arnold, University of Schleswig- Holstein , Campus...Intron 2 Opossum Mouse Rat Cow Dog Intron 1 Figure 3 | The FGFR2 locus. a, Map of the whole FGFR2 gene, viewed relative to common SNPs on HapMap

Modeling the occurrence of Mycobacterium avium subsp. paratuberculosis in bulk raw milk and the impact of management options for exposure mitigation.

PubMed

Boulais, Christophe; Wacker, Ron; Augustin, Jean-Christophe; Cheikh, Mohamed Hedi Ben; Peladan, Fabrice

2011-07-01

Mycobacterium avium subsp. paratuberculosis (MAP) is the causal agent of paratuberculosis (Johne's disease) in cattle and other farm ruminants. The potential role of MAP in Crohn's disease in humans and the contribution of dairy products to human exposure to MAP continue to be the subject of scientific debate. The occurrence of MAP in bulk raw milk from dairy herds was assessed using a stochastic modeling approach. Raw milk samples were collected from bulk tanks in dairy plants and tested for the presence of MAP. Results from this analytical screening were used in a Bayesian network to update the model prediction. Of the 83 raw milk samples tested, 4 were positive for MAP by culture and PCR. We estimated that the level of MAP in bulk tanks ranged from 0 CFU/ml for the 2.5th percentile to 65 CFU/ml for the 97.5th percentile, with 95% credibility intervals of [0, 0] and [16, 326], respectively. The model was used to evaluate the effect of measures aimed at reducing the occurrence of MAP in raw milk. Reducing the prevalence of paratuberculosis has less of an effect on the occurrence of MAP in bulk raw milk than does managing clinically infected animals through good farming practices. Copyright ©, International Association for Food Protection

Mapping malaria risk among children in Côte d'Ivoire using Bayesian geo-statistical models.

PubMed

Raso, Giovanna; Schur, Nadine; Utzinger, Jürg; Koudou, Benjamin G; Tchicaya, Emile S; Rohner, Fabian; N'goran, Eliézer K; Silué, Kigbafori D; Matthys, Barbara; Assi, Serge; Tanner, Marcel; Vounatsou, Penelope

2012-05-09

In Côte d'Ivoire, an estimated 767,000 disability-adjusted life years are due to malaria, placing the country at position number 14 with regard to the global burden of malaria. Risk maps are important to guide control interventions, and hence, the aim of this study was to predict the geographical distribution of malaria infection risk in children aged <16 years in Côte d'Ivoire at high spatial resolution. Using different data sources, a systematic review was carried out to compile and geo-reference survey data on Plasmodium spp. infection prevalence in Côte d'Ivoire, focusing on children aged <16 years. The period from 1988 to 2007 was covered. A suite of Bayesian geo-statistical logistic regression models was fitted to analyse malaria risk. Non-spatial models with and without exchangeable random effect parameters were compared to stationary and non-stationary spatial models. Non-stationarity was modelled assuming that the underlying spatial process is a mixture of separate stationary processes in each ecological zone. The best fitting model based on the deviance information criterion was used to predict Plasmodium spp. infection risk for entire Côte d'Ivoire, including uncertainty. Overall, 235 data points at 170 unique survey locations with malaria prevalence data for individuals aged <16 years were extracted. Most data points (n = 182, 77.4%) were collected between 2000 and 2007. A Bayesian non-stationary regression model showed the best fit with annualized rainfall and maximum land surface temperature identified as significant environmental covariates. This model was used to predict malaria infection risk at non-sampled locations. High-risk areas were mainly found in the north-central and western area, while relatively low-risk areas were located in the north at the country border, in the north-east, in the south-east around Abidjan, and in the central-west between two high prevalence areas. The malaria risk map at high spatial resolution gives an important overview of the geographical distribution of the disease in Côte d'Ivoire. It is a useful tool for the national malaria control programme and can be utilized for spatial targeting of control interventions and rational resource allocation.

Mapping malaria risk among children in Côte d’Ivoire using Bayesian geo-statistical models

PubMed Central

2012-01-01

Background In Côte d’Ivoire, an estimated 767,000 disability-adjusted life years are due to malaria, placing the country at position number 14 with regard to the global burden of malaria. Risk maps are important to guide control interventions, and hence, the aim of this study was to predict the geographical distribution of malaria infection risk in children aged <16 years in Côte d’Ivoire at high spatial resolution. Methods Using different data sources, a systematic review was carried out to compile and geo-reference survey data on Plasmodium spp. infection prevalence in Côte d’Ivoire, focusing on children aged <16 years. The period from 1988 to 2007 was covered. A suite of Bayesian geo-statistical logistic regression models was fitted to analyse malaria risk. Non-spatial models with and without exchangeable random effect parameters were compared to stationary and non-stationary spatial models. Non-stationarity was modelled assuming that the underlying spatial process is a mixture of separate stationary processes in each ecological zone. The best fitting model based on the deviance information criterion was used to predict Plasmodium spp. infection risk for entire Côte d’Ivoire, including uncertainty. Results Overall, 235 data points at 170 unique survey locations with malaria prevalence data for individuals aged <16 years were extracted. Most data points (n = 182, 77.4%) were collected between 2000 and 2007. A Bayesian non-stationary regression model showed the best fit with annualized rainfall and maximum land surface temperature identified as significant environmental covariates. This model was used to predict malaria infection risk at non-sampled locations. High-risk areas were mainly found in the north-central and western area, while relatively low-risk areas were located in the north at the country border, in the north-east, in the south-east around Abidjan, and in the central-west between two high prevalence areas. Conclusion The malaria risk map at high spatial resolution gives an important overview of the geographical distribution of the disease in Côte d’Ivoire. It is a useful tool for the national malaria control programme and can be utilized for spatial targeting of control interventions and rational resource allocation. PMID:22571469

A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2) Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model

PubMed Central

Rupp, Rachel; Senin, Pavel; Sarry, Julien; Allain, Charlotte; Tasca, Christian; Ligat, Laeticia; Portes, David; Woloszyn, Florent; Bouchez, Olivier; Tabouret, Guillaume; Lebastard, Mathieu; Caubet, Cécile

2015-01-01

Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2). The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host’s inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway. PMID:26658352

Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep

PubMed Central

Suárez-Vega, Aroa; Gutiérrez-Gil, Beatriz; Benavides, Julio; Perez, Valentín; Tosser-Klopp, Gwenola; Klopp, Christophe; Keennel, Stephen J.; Arranz, Juan José

2015-01-01

In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412_4415del). The c.4412_4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412_4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approach evidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforward. PMID:25955497

A Point Mutation in Suppressor of Cytokine Signalling 2 (Socs2) Increases the Susceptibility to Inflammation of the Mammary Gland while Associated with Higher Body Weight and Size and Higher Milk Production in a Sheep Model.

PubMed

Rupp, Rachel; Senin, Pavel; Sarry, Julien; Allain, Charlotte; Tasca, Christian; Ligat, Laeticia; Portes, David; Woloszyn, Florent; Bouchez, Olivier; Tabouret, Guillaume; Lebastard, Mathieu; Caubet, Cécile; Foucras, Gilles; Tosser-Klopp, Gwenola

2015-12-01

Mastitis is an infectious disease mainly caused by bacteria invading the mammary gland. Genetic control of susceptibility to mastitis has been widely evidenced in dairy ruminants, but the genetic basis and underlying mechanisms are still largely unknown. We describe the discovery, fine mapping and functional characterization of a genetic variant associated with elevated milk leukocytes count, or SCC, as a proxy for mastitis. After implementing genome-wide association studies, we identified a major QTL associated with SCC on ovine chromosome 3. Fine mapping of the region, using full sequencing with 12X coverage in three animals, provided one strong candidate SNP that mapped to the coding sequence of a highly conserved gene, suppressor of cytokine signalling 2 (Socs2). The frequency of the SNP associated with increased SCC was 21.7% and the Socs2 genotype explained 12% of the variance of the trait. The point mutation induces the p.R96C substitution in the SH2 functional domain of SOCS2 i.e. the binding site of the protein to various ligands, as well-established for the growth hormone receptor GHR. Using surface plasmon resonance we showed that the p.R96C point mutation completely abrogates SOCS2 binding affinity for the phosphopeptide of GHR. Additionally, the size, weight and milk production in p.R96C homozygote sheep, were significantly increased by 24%, 18%, and 4.4%, respectively, when compared to wild type sheep, supporting the view that the point mutation causes a loss of SOCS2 functional activity. Altogether these results provide strong evidence for a causal mutation controlling SCC in sheep and highlight the major role of SOCS2 as a tradeoff between the host's inflammatory response to mammary infections, and body growth and milk production, which are all mediated by the JAK/STAT signaling pathway.

Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep.

PubMed

Suárez-Vega, Aroa; Gutiérrez-Gil, Beatriz; Benavides, Julio; Perez, Valentín; Tosser-Klopp, Gwenola; Klopp, Christophe; Keennel, Stephen J; Arranz, Juan José

2015-01-01

In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412_4415del). The c.4412_4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412_4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approach evidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforward.

FLG mutations in ichthyosis vulgaris and atopic eczema: spectrum of mutations and population genetics.

PubMed

Akiyama, M

2010-03-01

Filaggrin is a key protein involved in skin barrier function. Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris and have been shown to be major predisposing factors for atopic eczema (AE), initially in European populations. Subsequently, FLG mutations were identified in Japanese, Chinese, Taiwanese and Korean populations. It was demonstrated that FLG mutations are closely associated with AE in the Japanese population. Notably, the same FLG mutations identified in the European population were rarely found in Asians. These results exemplify differences in filaggrin population genetics between Europe and Asia. For mutation screening, background information needs to be obtained on prevalent FLG mutations for each geographical population. It is therefore important to establish the global population genetics maps for FLG mutations. Mutations at any site within FLG, even mutations in C-terminal imperfect filaggrin repeats, cause significant reductions in amounts of profilaggrin/filaggrin peptide in patient epidermis as the C-terminal region is essential for proper processing of profilaggrin into filaggrin. Thus, no genotype-phenotype correlation has been observed in patients with FLG mutations. A restoration of the barrier function seems a feasible and promising strategy for treatment and prevention in individuals with filaggrin deficiency.

Transdimensional, hierarchical, Bayesian inversion of ambient seismic noise: Australia

NASA Astrophysics Data System (ADS)

Crowder, E.; Rawlinson, N.; Cornwell, D. G.

2017-12-01

We present models of crustal velocity structure in southeastern Australia using a novel, transdimensional and hierarchical, Bayesian inversion approach. The inversion is applied to long-time ambient noise cross-correlations. The study area of SE Australia is thought to represent the eastern margin of Gondwana. Conflicting tectonic models have been proposed to explain the formation of eastern Gondwana and the enigmatic geological relationships in Bass Strait, which separates Tasmania and the mainland. A geologically complex area of crustal accretion, Bass Strait may contain part of an exotic continental block entrained in colliding crusts. Ambient noise data recorded by an array of 24 seismometers is used to produce a high resolution, 3D shear wave velocity model of Bass Strait. Phase velocity maps in the period range 2-30 s are produced and subsequently inverted for 3D shear wave velocity structure. The transdimensional, hierarchical Bayesian, inversion technique is used. This technique proves far superior to linearised inversion. The inversion model is dynamically parameterised during the process, implicitly controlled by the data, and noise is treated as an inversion unknown. The resulting shear wave velocity model shows three sedimentary basins in Bass Strait constrained by slow shear velocities (2.4-2.9 km/s) at 2-10 km depth. These failed rift basins from the breakup of Australia-Antartica appear to be overlying thinned crust, where typical mantle velocities of 3.8-4.0 km/s occur at depths greater than 20 km. High shear wave velocities ( 3.7-3.8 km/s) in our new model also match well with regions of high magnetic and gravity anomalies. Furthermore, we use both Rayleigh and Love wave phase data to to construct Vsv and Vsh maps. These are used to estimate crustal radial anisotropy in the Bass Strait. We interpret that structures delineated by our velocity models support the presence and extent of the exotic Precambrian micro-continent (the Selwyn Block) that was most likely entrained during crustal accretion.

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

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.

Using Current and Historic Climate Data and Bayesian Belief Networks to Predict Optimum Satellite Image Acquisition Periods for Detecting Cheatgrass on the Snake River Plain, Idaho

NASA Astrophysics Data System (ADS)

Rope, R. C.; Ames, D. P.; Jerry, T. D.; Cherry, S. J.

2005-12-01

Invasive plant species, such as Bromus tectorum (cheatgrass), cost the United States over $36 billion per year and have encroached upon over 100 million acres while impacting range site productivity, disturbing wildlife habitat, altering the wildland fire regime and frequencies, and reducing biodiversity. Because of these adverse impacts, federal, tribal, state, and county land managers are faced with the challenge of prevention, early detection, management, and monitoring of invasive plants. Often these managers rely on the analysis of remotely sensed imagery as part of their management plan. However, it's difficult to predict specific phenological events that allow for the spectral discrimination of invasive species using only remotely sensed imagery. To address this issue tools are being developed to model and view optimal periods to collect high spatial and/or spectral resolution remotely sensed data for refined detection and mapping of invasive species and for use as a decision support tool for land managers. These tools involve the integration of historic and current climate data (cumulative growing days and precipitation) satellite imagery (MODIS) and Bayesian Belief Networks, and a web ArcIMS application to distribute the information. The general approach is to issue an initial forecast early in the year based on the previous years' data. As the year progresses, air temperature, precipitation and newly acquired low resolution MODIS satellite imagery will be used to update the prediction. Updating will be accomplished using a Bayesian Belief Network model that indicates the probabilistic relationships between prior years' conditions and those of the current year. These tools have specific application in providing a means for which land managers can efficiently and effectively detect, map, and monitor invasive plant species, specifically cheatgrass, in western rangelands. This information can then be integrated into management studies and plans to help land managers more accurately and completely determine areas infested with cheatgrass to aid in their eradication practices and future management plans.

Spatial cluster detection using dynamic programming.

PubMed

Sverchkov, Yuriy; Jiang, Xia; Cooper, Gregory F

2012-03-25

The task of spatial cluster detection involves finding spatial regions where some property deviates from the norm or the expected value. In a probabilistic setting this task can be expressed as finding a region where some event is significantly more likely than usual. Spatial cluster detection is of interest in fields such as biosurveillance, mining of astronomical data, military surveillance, and analysis of fMRI images. In almost all such applications we are interested both in the question of whether a cluster exists in the data, and if it exists, we are interested in finding the most accurate characterization of the cluster. We present a general dynamic programming algorithm for grid-based spatial cluster detection. The algorithm can be used for both Bayesian maximum a-posteriori (MAP) estimation of the most likely spatial distribution of clusters and Bayesian model averaging over a large space of spatial cluster distributions to compute the posterior probability of an unusual spatial clustering. The algorithm is explained and evaluated in the context of a biosurveillance application, specifically the detection and identification of Influenza outbreaks based on emergency department visits. A relatively simple underlying model is constructed for the purpose of evaluating the algorithm, and the algorithm is evaluated using the model and semi-synthetic test data. When compared to baseline methods, tests indicate that the new algorithm can improve MAP estimates under certain conditions: the greedy algorithm we compared our method to was found to be more sensitive to smaller outbreaks, while as the size of the outbreaks increases, in terms of area affected and proportion of individuals affected, our method overtakes the greedy algorithm in spatial precision and recall. The new algorithm performs on-par with baseline methods in the task of Bayesian model averaging. We conclude that the dynamic programming algorithm performs on-par with other available methods for spatial cluster detection and point to its low computational cost and extendability as advantages in favor of further research and use of the algorithm.

Spatial cluster detection using dynamic programming

PubMed Central

2012-01-01

Background The task of spatial cluster detection involves finding spatial regions where some property deviates from the norm or the expected value. In a probabilistic setting this task can be expressed as finding a region where some event is significantly more likely than usual. Spatial cluster detection is of interest in fields such as biosurveillance, mining of astronomical data, military surveillance, and analysis of fMRI images. In almost all such applications we are interested both in the question of whether a cluster exists in the data, and if it exists, we are interested in finding the most accurate characterization of the cluster. Methods We present a general dynamic programming algorithm for grid-based spatial cluster detection. The algorithm can be used for both Bayesian maximum a-posteriori (MAP) estimation of the most likely spatial distribution of clusters and Bayesian model averaging over a large space of spatial cluster distributions to compute the posterior probability of an unusual spatial clustering. The algorithm is explained and evaluated in the context of a biosurveillance application, specifically the detection and identification of Influenza outbreaks based on emergency department visits. A relatively simple underlying model is constructed for the purpose of evaluating the algorithm, and the algorithm is evaluated using the model and semi-synthetic test data. Results When compared to baseline methods, tests indicate that the new algorithm can improve MAP estimates under certain conditions: the greedy algorithm we compared our method to was found to be more sensitive to smaller outbreaks, while as the size of the outbreaks increases, in terms of area affected and proportion of individuals affected, our method overtakes the greedy algorithm in spatial precision and recall. The new algorithm performs on-par with baseline methods in the task of Bayesian model averaging. Conclusions We conclude that the dynamic programming algorithm performs on-par with other available methods for spatial cluster detection and point to its low computational cost and extendability as advantages in favor of further research and use of the algorithm. PMID:22443103

Mapping Flagellar Genes in Chlamydomonas Using Restriction Fragment Length Polymorphisms

PubMed Central

Ranum, LPW.; Thompson, M. D.; Schloss, J. A.; Lefebvre, P. A.; Silflow, C. D.

1988-01-01

To correlate cloned nuclear DNA sequences with previously characterized mutations in Chlamydomonas and, to gain insight into the organization of its nuclear genome, we have begun to map molecular markers using restriction fragment length polymorphisms (RFLPs). A Chlamydomonas reinhardtii strain (CC-29) containing phenotypic markers on nine of the 19 linkage groups was crossed to the interfertile species Chlamydomonas smithii. DNA from each member of 22 randomly selected tetrads was analyzed for the segregation of RFLPs associated with cloned genes detected by hybridization with radioactive DNA probes. The current set of markers allows the detection of linkage to new molecular markers over approximately 54% of the existing genetic map. This study focused on mapping cloned flagellar genes and genes whose transcripts accumulate after deflagellation. Twelve different molecular clones have been assigned to seven linkage groups. The α-1 tubulin gene maps to linkage group III and is linked to the genomic sequence homologous to pcf6-100, a cDNA clone whose corresponding transcript accumulates after deflagellation. The α-2 tubulin gene maps to linkage group IV. The two β-tubulin genes are linked, with the β-1 gene being approximately 12 cM more distal from the centromere than the β-2 gene. A clone corresponding to a 73-kD dynein protein maps to the opposite arm of the same linkage group. The gene corresponding to the cDNA clone pcf6-187, whose mRNA accumulates after deflagellation, maps very close to the tightly linked pf-26 and pf-1 mutations on linkage group V. PMID:2906025

Ewes carrying the Booroola and Vacaria prolificacy alleles respond differently to ovulation induction with equine chorionic gonadotrophin.

PubMed

Moraes, J C F; Souza, C J H

2017-09-21

The magnitude of ovulation rate (OR) after hormonal induction in sheep should be considered when prolific genotypes are used. We investigated for the first time the effect of the Vacaria allele and its combined effect with the Booroola prolificacy mutation on OR after hormonal treatment during breeding and anoestrous season. A hundred forty-nine Ile de France crossbred ewes, raised in natural pastures in South Brazil, were used to evaluate the OR after treatment with progestagen (MAP) followed or not by equine chorionic gonadotrophin (eCG) treatment (MAP + eCG). During the breeding season, 96% MAP-treated ewes ovulated in comparison to 97% of MAP + eCG-treated females. The double heterozygous carriers (BNVN) presented the higher OR, followed by the single Vacaria (NNVN) and Booroola (BNNN) heterozygous females and least the wild-type (NNNN) ewes. During anoestrus, 96% eCG-treated ewes ovulated, in contrast to 6% treated with MAP alone. The OR of the gonadotrophin-treated females was higher in BNVN and BNNN than NNVN and NNNN ewes. An additive effect in the OR of the two mutations was observed since OR in double heterozygous ewes was similar to the sum of the effects of the alleles of the single heterozygous carrier ewes.

Immunohistochemical comparative analysis of GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 expression in WHO 2016 classified neuroepithelial tumours and their prognostic value.

PubMed

Schwab, David Emanuel; Lepski, Guilherme; Borchers, Christian; Trautmann, Katrin; Paulsen, Frank; Schittenhelm, Jens

2018-01-01

Immunohistochemistry is routinely used in differential diagnosis of tumours of the central nervous system (CNS). The latest 2016 WHO 2016 revision now includes molecular data such as IDH mutation and 1p/19q codeletion thus restructuring glioma classification. Direct comparative information between commonly used immunohistochemical markers for glial tumours GFAP, MAP - 2, NOGO - A, OLIG - 2 and WT - 1 concerning quality and quantity of expression and their relation to the new molecular markers are lacking. We therefore compared the immunohistochemical staining results of all five antibodies in 34 oligodendrogliomas, 106 ependymomas and 423 astrocytic tumours. GFAP expression was reduced in cases with higher WHO grade, oligodendroglial differentiation and in IDH wildtype diffuse astrocytomas. By contrast MAP - 2 expression was significantly increased in diffuse astrocytomas with IDH mutation, while NOGO - A expression was not associated with any molecular marker. WT - 1 expression was significantly decreased in tumours with IDH mutation and ATRX loss. OLIG - 2 was increased in IDH-mutant grade II astrocytomas and in cases with higher proliferation rate. In univariate survival analysis high WT - 1 expression was significantly associated with worse outcome in diffuse astrocytic tumours (log rank p < 0.0001; n = 211; median time: 280 days vs 562 days). None of the markers was prognostic in multivariate survival analysis. Among the evaluated markers MAP - 2, OLIG - 2 and WT - 1 showed the best potential to separate between glioma entities and can be recommended for a standardized immunohistochemical panel. Copyright © 2017 Elsevier GmbH. All rights reserved.

Evaluation of performance of bacterial culture of feces and serum ELISA across stages of Johne's disease in cattle using a Bayesian latent class model.

PubMed

Espejo, L A; Zagmutt, F J; Groenendaal, H; Muñoz-Zanzi, C; Wells, S J

2015-11-01

The objective of this study was to evaluate the performance of bacterial culture of feces and serum ELISA to correctly identify cows with Mycobacterium avium ssp. paratuberculosis (MAP) at heavy, light, and non-fecal-shedding levels. A total of 29,785 parallel test results from bacterial culture of feces and serum ELISA were collected from 17 dairy herds in Minnesota, Pennsylvania, and Colorado. Samples were obtained from adult cows from dairy herds enrolled for up to 10 yr in the National Johne's Disease Demonstration Herd Project. A Bayesian latent class model was fitted to estimate the probabilities that bacterial culture of feces (using 72-h sedimentation or 30-min centrifugation methods) and serum ELISA results correctly identified cows as high positive, low positive, or negative given that cows were heavy, light, and non-shedders, respectively. The model assumed that no gold standard test was available and conditional independency existed between diagnostic tests. The estimated conditional probabilities that bacterial culture of feces correctly identified heavy shedders, light shedders, and non-shedders were 70.9, 32.0, and 98.5%, respectively. The same values for the serum ELISA were 60.6, 18.7, and 99.5%, respectively. Differences in diagnostic test performance were observed among states. These results improve the interpretation of results from bacterial culture of feces and serum ELISA for detection of MAP and MAP antibody (respectively), which can support on-farm infection control decisions and can be used to evaluate disease-testing strategies, taking into account the accuracy of these tests. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A statistical assessment of seismic models of the U.S. continental crust using Bayesian inversion of ambient noise surface wave dispersion data

NASA Astrophysics Data System (ADS)

Olugboji, T. M.; Lekic, V.; McDonough, W.

2017-07-01

We present a new approach for evaluating existing crustal models using ambient noise data sets and its associated uncertainties. We use a transdimensional hierarchical Bayesian inversion approach to invert ambient noise surface wave phase dispersion maps for Love and Rayleigh waves using measurements obtained from Ekström (2014). Spatiospectral analysis shows that our results are comparable to a linear least squares inverse approach (except at higher harmonic degrees), but the procedure has additional advantages: (1) it yields an autoadaptive parameterization that follows Earth structure without making restricting assumptions on model resolution (regularization or damping) and data errors; (2) it can recover non-Gaussian phase velocity probability distributions while quantifying the sources of uncertainties in the data measurements and modeling procedure; and (3) it enables statistical assessments of different crustal models (e.g., CRUST1.0, LITHO1.0, and NACr14) using variable resolution residual and standard deviation maps estimated from the ensemble. These assessments show that in the stable old crust of the Archean, the misfits are statistically negligible, requiring no significant update to crustal models from the ambient noise data set. In other regions of the U.S., significant updates to regionalization and crustal structure are expected especially in the shallow sedimentary basins and the tectonically active regions, where the differences between model predictions and data are statistically significant.

A Bayesian analysis of redshifted 21-cm H I signal and foregrounds: simulations for LOFAR

NASA Astrophysics Data System (ADS)

Ghosh, Abhik; Koopmans, Léon V. E.; Chapman, E.; Jelić, V.

2015-09-01

Observations of the epoch of reionization (EoR) using the 21-cm hyperfine emission of neutral hydrogen (H I) promise to open an entirely new window on the formation of the first stars, galaxies and accreting black holes. In order to characterize the weak 21-cm signal, we need to develop imaging techniques that can reconstruct the extended emission very precisely. Here, we present an inversion technique for LOw Frequency ARray (LOFAR) baselines at the North Celestial Pole (NCP), based on a Bayesian formalism with optimal spatial regularization, which is used to reconstruct the diffuse foreground map directly from the simulated visibility data. We notice that the spatial regularization de-noises the images to a large extent, allowing one to recover the 21-cm power spectrum over a considerable k⊥-k∥ space in the range 0.03 Mpc-1 < k⊥ < 0.19 Mpc-1 and 0.14 Mpc-1 < k∥ < 0.35 Mpc-1 without subtracting the noise power spectrum. We find that, in combination with using generalized morphological component analysis (GMCA), a non-parametric foreground removal technique, we can mostly recover the spherical average power spectrum within 2σ statistical fluctuations for an input Gaussian random root-mean-square noise level of 60 mK in the maps after 600 h of integration over a 10-MHz bandwidth.

Implementation of bayesian model averaging on the weather data forecasting applications utilizing open weather map

NASA Astrophysics Data System (ADS)

Rahmat, R. F.; Nasution, F. R.; Seniman; Syahputra, M. F.; Sitompul, O. S.

2018-02-01

Weather is condition of air in a certain region at a relatively short period of time, measured with various parameters such as; temperature, air preasure, wind velocity, humidity and another phenomenons in the atmosphere. In fact, extreme weather due to global warming would lead to drought, flood, hurricane and other forms of weather occasion, which directly affects social andeconomic activities. Hence, a forecasting technique is to predict weather with distinctive output, particullary mapping process based on GIS with information about current weather status in certain cordinates of each region with capability to forecast for seven days afterward. Data used in this research are retrieved in real time from the server openweathermap and BMKG. In order to obtain a low error rate and high accuracy of forecasting, the authors use Bayesian Model Averaging (BMA) method. The result shows that the BMA method has good accuracy. Forecasting error value is calculated by mean square error shows (MSE). The error value emerges at minumum temperature rated at 0.28 and maximum temperature rated at 0.15. Meanwhile, the error value of minimum humidity rates at 0.38 and the error value of maximum humidity rates at 0.04. Afterall, the forecasting error rate of wind speed is at 0.076. The lower the forecasting error rate, the more optimized the accuracy is.

Bayesian Non-Stationary Index Gauge Modeling of Gridded Precipitation Extremes

NASA Astrophysics Data System (ADS)

Verdin, A.; Bracken, C.; Caldwell, J.; Balaji, R.; Funk, C. C.

2017-12-01

We propose a Bayesian non-stationary model to generate watershed scale gridded estimates of extreme precipitation return levels. The Climate Hazards Group Infrared Precipitation with Stations (CHIRPS) dataset is used to obtain gridded seasonal precipitation extremes over the Taylor Park watershed in Colorado for the period 1981-2016. For each year, grid cells within the Taylor Park watershed are aggregated to a representative "index gauge," which is input to the model. Precipitation-frequency curves for the index gauge are estimated for each year, using climate variables with significant teleconnections as proxies. Such proxies enable short-term forecasting of extremes for the upcoming season. Disaggregation ratios of the index gauge to the grid cells within the watershed are computed for each year and preserved to translate the index gauge precipitation-frequency curve to gridded precipitation-frequency maps for select return periods. Gridded precipitation-frequency maps are of the same spatial resolution as CHIRPS (0.05° x 0.05°). We verify that the disaggregation method preserves spatial coherency of extremes in the Taylor Park watershed. Validation of the index gauge extreme precipitation-frequency method consists of ensuring extreme value statistics are preserved on a grid cell basis. To this end, a non-stationary extreme precipitation-frequency analysis is performed on each grid cell individually, and the resulting frequency curves are compared to those produced by the index gauge disaggregation method.

Co-occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11.

PubMed

Yagasaki, Hideaki; Nakane, Takaya; Hasebe, Youhei; Watanabe, Atsushi; Kise, Hiroaki; Toda, Takako; Koizumi, Keiichi; Hoshiai, Minako; Sugita, Kanji

2015-12-01

Most cases of Noonan syndrome (NS) result from mutations in one of the RAS-MAPK signaling genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 (MAP2K1), and CBL. Cardiovascular diseases of varying severity, such as pulmonary stenosis and hypertrophic cardiomyopathy (HCM), are common in NS patients. RAF1 mutations are most frequent in NS with HCM, while PTPN11 mutations are also well known. Thr73Ile is a gain-of-function mutation of PTPN11, which has been highly associated with juvenile myelomonocytic leukemia and NS/myeloproliferative disease (MPD), but has not previously been reported in HCM. Here, we report a Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio-ventricular septal defect, and rapidly progressive HCM. No other HCM-related mutations were detected in PTPN11, RAF1, KRAS, BRAF, and SHOC2. This patient provides additional information regarding the genotype-phenotype correlation for PTPN11 T73I mutation in NS. © 2015 Wiley Periodicals, Inc.

Developing a spatial-statistical model and map of historical malaria prevalence in Botswana using a staged variable selection procedure

PubMed Central

Craig, Marlies H; Sharp, Brian L; Mabaso, Musawenkosi LH; Kleinschmidt, Immo

2007-01-01

Background Several malaria risk maps have been developed in recent years, many from the prevalence of infection data collated by the MARA (Mapping Malaria Risk in Africa) project, and using various environmental data sets as predictors. Variable selection is a major obstacle due to analytical problems caused by over-fitting, confounding and non-independence in the data. Testing and comparing every combination of explanatory variables in a Bayesian spatial framework remains unfeasible for most researchers. The aim of this study was to develop a malaria risk map using a systematic and practicable variable selection process for spatial analysis and mapping of historical malaria risk in Botswana. Results Of 50 potential explanatory variables from eight environmental data themes, 42 were significantly associated with malaria prevalence in univariate logistic regression and were ranked by the Akaike Information Criterion. Those correlated with higher-ranking relatives of the same environmental theme, were temporarily excluded. The remaining 14 candidates were ranked by selection frequency after running automated step-wise selection procedures on 1000 bootstrap samples drawn from the data. A non-spatial multiple-variable model was developed through step-wise inclusion in order of selection frequency. Previously excluded variables were then re-evaluated for inclusion, using further step-wise bootstrap procedures, resulting in the exclusion of another variable. Finally a Bayesian geo-statistical model using Markov Chain Monte Carlo simulation was fitted to the data, resulting in a final model of three predictor variables, namely summer rainfall, mean annual temperature and altitude. Each was independently and significantly associated with malaria prevalence after allowing for spatial correlation. This model was used to predict malaria prevalence at unobserved locations, producing a smooth risk map for the whole country. Conclusion We have produced a highly plausible and parsimonious model of historical malaria risk for Botswana from point-referenced data from a 1961/2 prevalence survey of malaria infection in 1–14 year old children. After starting with a list of 50 potential variables we ended with three highly plausible predictors, by applying a systematic and repeatable staged variable selection procedure that included a spatial analysis, which has application for other environmentally determined infectious diseases. All this was accomplished using general-purpose statistical software. PMID:17892584

Minimal entropy approximation for cellular automata

NASA Astrophysics Data System (ADS)

Fukś, Henryk

2014-02-01

We present a method for the construction of approximate orbits of measures under the action of cellular automata which is complementary to the local structure theory. The local structure theory is based on the idea of Bayesian extension, that is, construction of a probability measure consistent with given block probabilities and maximizing entropy. If instead of maximizing entropy one minimizes it, one can develop another method for the construction of approximate orbits, at the heart of which is the iteration of finite-dimensional maps, called minimal entropy maps. We present numerical evidence that the minimal entropy approximation sometimes outperforms the local structure theory in characterizing the properties of cellular automata. The density response curve for elementary CA rule 26 is used to illustrate this claim.

Physical mapping of a pollen modifier locus controlling self-incompatibility in apricot and synteny analysis within the Rosaceae.

PubMed

Zuriaga, Elena; Molina, Laura; Badenes, María Luisa; Romero, Carlos

2012-06-01

S-locus products (S-RNase and F-box proteins) are essential for the gametophytic self-incompatibility (GSI) specific recognition in Prunus. However, accumulated genetic evidence suggests that other S-locus unlinked factors are also required for GSI. For instance, GSI breakdown was associated with a pollen-part mutation unlinked to the S-locus in the apricot (Prunus armeniaca L.) cv. 'Canino'. Fine-mapping of this mutated modifier gene (M-locus) and the synteny analysis of the M-locus within the Rosaceae are here reported. A segregation distortion loci mapping strategy, based on a selectively genotyped population, was used to map the M-locus. In addition, a bacterial artificial chromosome (BAC) contig was constructed for this region using overlapping oligonucleotides probes, and BAC-end sequences (BES) were blasted against Rosaceae genomes to perform micro-synteny analysis. The M-locus was mapped to the distal part of chr.3 flanked by two SSR markers within an interval of 1.8 cM corresponding to ~364 Kb in the peach (Prunus persica L. Batsch) genome. In the integrated genetic-physical map of this region, BES were mapped against the peach scaffold_3 and BACs were anchored to the apricot map. Micro-syntenic blocks were detected in apple (Malus × domestica Borkh.) LG17/9 and strawberry (Fragaria vesca L.) FG6 chromosomes. The M-locus fine-scale mapping provides a solid basis for self-compatibility marker-assisted selection and for positional cloning of the underlying gene, a necessary goal to elucidate the pollen rejection mechanism in Prunus. In a wider context, the syntenic regions identified in peach, apple and strawberry might be useful to interpret GSI evolution in Rosaceae.

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females

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

Pegoraro, E.; Wessel, H.B.; Schwartz, L.

1994-06-01

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carries who show preferential inactivation ofmore » the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here the authors study X-inactivation patterns of 13 female dystrophinopathy patients - 10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. They show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in the assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, the results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. The results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients. 58 refs., 7 figs., 2 tabs.« less

The Impact of Mutation and Gene Conversion on the Local Diversification of Antigen Genes in African Trypanosomes

PubMed Central

Gjini, Erida; Haydon, Daniel T.; Barry, J. David; Cobbold, Christina A.

2012-01-01

Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair. PMID:22735079

Penetrance estimates for BRCA1, BRCA2 (also applied to Lynch syndrome) based on presymptomatic testing: a new unbiased method to assess risk?

PubMed

Evans, D Gareth; Woodward, Emma; Harkness, Elaine F; Howell, Anthony; Plaskocinska, Inga; Maher, Eamonn R; Tischkowitz, Marc D; Lalloo, Fiona

2018-02-26

The identification of BRCA1 , BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive. We assessed the penetrance of BRCA1 , BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1 / BRCA2. RESULTS: Using results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1 , 60% (95% CI 49% to 71%) for BRCA2 , 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2 . There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1. CONCLUSION: We describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Quantitative characterization of all single amino acid variants of a viral capsid-based drug delivery vehicle.

PubMed

Hartman, Emily C; Jakobson, Christopher M; Favor, Andrew H; Lobba, Marco J; Álvarez-Benedicto, Ester; Francis, Matthew B; Tullman-Ercek, Danielle

2018-04-11

Self-assembling proteins are critical to biological systems and industrial technologies, but predicting how mutations affect self-assembly remains a significant challenge. Here, we report a technique, termed SyMAPS (Systematic Mutation and Assembled Particle Selection), that can be used to characterize the assembly competency of all single amino acid variants of a self-assembling viral structural protein. SyMAPS studies on the MS2 bacteriophage coat protein revealed a high-resolution fitness landscape that challenges some conventional assumptions of protein engineering. An additional round of selection identified a previously unknown variant (CP[T71H]) that is stable at neutral pH but less tolerant to acidic conditions than the wild-type coat protein. The capsids formed by this variant could be more amenable to disassembly in late endosomes or early lysosomes-a feature that is advantageous for delivery applications. In addition to providing a mutability blueprint for virus-like particles, SyMAPS can be readily applied to other self-assembling proteins.

Dana-Farber Cancer Institute: Mapping the Function of Rare Oncogenic Variants | Office of Cancer Genomics

Cancer.gov

Although some oncogenes and tumor suppressor genes are recurrently mutated at high frequency, the majority of somatic sequence alterations found in cancers occur at low frequency, and the functional consequences of the majority of these mutated alleles remain unknown. We are developing a scalable systematic approach to interrogate the function of cancer-associated gene variants. Read the abstract: Kim et al., 2016

Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency.

PubMed

Breitfeld, Jana; Martens, Susanne; Klammt, Jürgen; Schlicke, Marina; Pfäffle, Roland; Krause, Kerstin; Weidle, Kerstin; Schleinitz, Dorit; Stumvoll, Michael; Führer, Dagmar; Kovacs, Peter; Tönjes, Anke

2013-12-01

The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.

Genetic analyses of bone morphogenetic protein 2, 4 and 7 in congenital combined pituitary hormone deficiency

PubMed Central

2013-01-01

Background The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. Methods We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. Results Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. Conclusions A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD. PMID:24289245

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.

PubMed

Stephen, Joshi; Vilboux, Thierry; Haberman, Yael; Pri-Chen, Hadass; Pode-Shakked, Ben; Mazaheri, Sina; Marek-Yagel, Dina; Barel, Ortal; Di Segni, Ayelet; Eyal, Eran; Hout-Siloni, Goni; Lahad, Avishay; Shalem, Tzippora; Rechavi, Gideon; Malicdan, May Christine V; Weiss, Batia; Gahl, William A; Anikster, Yair

2016-08-01

Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia.

PubMed

Cai, Xiaodong; Chen, Xin; Wu, Song; Liu, Wenlan; Zhang, Xiejun; Zhang, Doudou; He, Sijie; Wang, Bo; Zhang, Mali; Zhang, Yuan; Li, Zongyang; Luo, Kun; Cai, Zhiming; Li, Weiping

2016-05-12

Dystonia is a neurological movement disorder that is clinically and genetically heterogeneous. Herein, we report the identification a novel homozygous missense mutation, c.156 C > A in VPS16, co-segregating with disease status in a Chinese consanguineous family with adolescent-onset primary dystonia by whole exome sequencing and homozygosity mapping. To assess the biological role of c.156 C > A homozygous mutation of VPS16, we generated mice with targeted mutation site of Vps16 through CRISPR-Cas9 genome-editing approach. Vps16 c.156 C > A homozygous mutant mice exhibited significantly impaired motor function, suggesting that VPS16 is a new causative gene for adolescent-onset primary dystonia.

Structure-Functional Prediction and Analysis of Cancer Mutation Effects in Protein Kinases

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2014-01-01

A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal “low” activity state to the “active” state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes. PMID:24817905

Detection and sequence/structure mapping of biophysical constraints to protein variation in saturated mutational libraries and protein sequence alignments with a dedicated server.

PubMed

Abriata, Luciano A; Bovigny, Christophe; Dal Peraro, Matteo

2016-06-17

Protein variability can now be studied by measuring high-resolution tolerance-to-substitution maps and fitness landscapes in saturated mutational libraries. But these rich and expensive datasets are typically interpreted coarsely, restricting detailed analyses to positions of extremely high or low variability or dubbed important beforehand based on existing knowledge about active sites, interaction surfaces, (de)stabilizing mutations, etc. Our new webserver PsychoProt (freely available without registration at http://psychoprot.epfl.ch or at http://lucianoabriata.altervista.org/psychoprot/index.html ) helps to detect, quantify, and sequence/structure map the biophysical and biochemical traits that shape amino acid preferences throughout a protein as determined by deep-sequencing of saturated mutational libraries or from large alignments of naturally occurring variants. We exemplify how PsychoProt helps to (i) unveil protein structure-function relationships from experiments and from alignments that are consistent with structures according to coevolution analysis, (ii) recall global information about structural and functional features and identify hitherto unknown constraints to variation in alignments, and (iii) point at different sources of variation among related experimental datasets or between experimental and alignment-based data. Remarkably, metabolic costs of the amino acids pose strong constraints to variability at protein surfaces in nature but not in the laboratory. This and other differences call for caution when extrapolating results from in vitro experiments to natural scenarios in, for example, studies of protein evolution. We show through examples how PsychoProt can be a useful tool for the broad communities of structural biology and molecular evolution, particularly for studies about protein modeling, evolution and design.

Mapping and Sequencing of the Canine NRAMP1 Gene and Identification of Mutations in Leishmaniasis-Susceptible Dogs

PubMed Central

Altet, Laura; Francino, Olga; Solano-Gallego, Laia; Renier, Corinne; Sánchez, Armand

2002-01-01

The NRAMP1 gene (Slc11a1) encodes an ion transporter protein involved in the control of intraphagosomal replication of parasites and in macrophage activation. It has been described in mice as the determinant of natural resistance or susceptibility to infection with antigenically unrelated pathogens, including Leishmania. Our aims were to sequence and map the canine Slc11a1 gene and to identify mutations that may be associated with resistance or susceptibility to Leishmania infection. The canine Slc11a1 gene has been mapped to dog chromosome CFA37 and covers 9 kb, including a 700-bp promoter region, 15 exons, and a polymorphic microsatellite in intron 1. It encodes a 547-amino-acid protein that has over 87% identity with the Slc11a1 proteins of different mammalian species. A case-control study with 33 resistant and 84 susceptible dogs showed an association between allele 145 of the microsatellite and susceptible dogs. Sequence variant analysis was performed by direct sequencing of the cDNA and the promoter region of four unrelated beagles experimentally infected with Leishmania infantum to search for possible functional mutations. Two of the dogs were classified as susceptible and the other two were classified as resistant based on their immune responses. Two important mutations were found in susceptible dogs: a G-rich region in the promoter that was common to both animals and a complete deletion of exon 11, which encodes the consensus transport motif of the protein, in the unique susceptible dog that needed an additional and prolonged treatment to avoid continuous relapses. A study with a larger dog population would be required to prove the association of these sequence variants with disease susceptibility. PMID:12010961

Multiple café au lait spots in familial patients with MAP2K2 mutation.

PubMed

Takenouchi, Toshiki; Shimizu, Atsushi; Torii, Chiharu; Kosaki, Rika; Takahashi, Takao; Saya, Hideyuki; Kosaki, Kenjiro

2014-02-01

Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated. © 2013 Wiley Periodicals, Inc.

Kin-Driver: a database of driver mutations in protein kinases.

PubMed

Simonetti, Franco L; Tornador, Cristian; Nabau-Moretó, Nuria; Molina-Vila, Miguel A; Marino-Buslje, Cristina

2014-01-01

Somatic mutations in protein kinases (PKs) are frequent driver events in many human tumors, while germ-line mutations are associated with hereditary diseases. Here we present Kin-driver, the first database that compiles driver mutations in PKs with experimental evidence demonstrating their functional role. Kin-driver is a manual expert-curated database that pays special attention to activating mutations (AMs) and can serve as a validation set to develop new generation tools focused on the prediction of gain-of-function driver mutations. It also offers an easy and intuitive environment to facilitate the visualization and analysis of mutations in PKs. Because all mutations are mapped onto a multiple sequence alignment, analogue positions between kinases can be identified and tentative new mutations can be proposed for studying by transferring annotation. Finally, our database can also be of use to clinical and translational laboratories, helping them to identify uncommon AMs that can correlate with response to new antitumor drugs. The website was developed using PHP and JavaScript, which are supported by all major browsers; the database was built using MySQL server. Kin-driver is available at: http://kin-driver.leloir.org.ar/ © The Author(s) 2014. Published by Oxford University Press.

Towards linked open gene mutations data

PubMed Central

2012-01-01

Background With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. Methods A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. Results We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. Conclusions This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development. The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on mutation data and other biological databases may support data retrieval which is presently not possible. Moreover, reasoning on integrated variation data may support discoveries towards personalized medicine. PMID:22536974

Towards linked open gene mutations data.

PubMed

Zappa, Achille; Splendiani, Andrea; Romano, Paolo

2012-03-28

With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development.The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on mutation data and other biological databases may support data retrieval which is presently not possible. Moreover, reasoning on integrated variation data may support discoveries towards personalized medicine.

The insulin-like growth factor 2 (IGF2) gene intron3-g.3072G>A polymorphism is not the only Sus scrofa chromosome 2p mutation affecting meat production and carcass traits in pigs: evidence from the effects of a cathepsin D (CTSD) gene polymorphism.

PubMed

Fontanesi, L; Speroni, C; Buttazzoni, L; Scotti, E; Dall'Olio, S; Nanni Costa, L; Davoli, R; Russo, V

2010-07-01

The objective of this study was to evaluate the effects of mutations in 2 genes [IGF2 and cathepsin D (CTSD)] that map on the telomeric end of the p arm of SSC2. In this region, an imprinted QTL affecting muscle mass and fat deposition was reported, and the IGF2 intron3-g.3072G>A substitution was identified as the causative mutation. In the same chromosome region, we assigned, by linkage mapping, the CTSD gene, a lysosomal proteinase, for which we previously identified an SNP in the 3'-untranslated region (AM933484, g.70G>A). We have already shown strong effects of this CTSD mutation on several production traits in Italian Large White pigs, suggesting a possible independent role of this marker in fatness and meat deposition in pigs. To evaluate this hypothesis, after having refined the map position of the CTSD gene by radiation hybrid mapping, we analyzed the IGF2 and the CTSD polymorphisms in 270 Italian Large White and 311 Italian Duroc pigs, for which EBV and random residuals from fixed models were calculated for several traits. Different association analyses were carried out to distinguish the effects of the 2 close markers. In the Italian Large White pigs, the results for IGF2 were highly significant for all traits when using either EBV or random residuals (e.g., using EBV: lean cuts, P = 2.2 x 10(-18); ADG, P = 2.6 x 10(-16); backfat thickness, P = 2.2 x 10(-9); feed:gain ratio, P = 2.3 x 10(-9); ham weight, P = 1.5 x 10(-6)). No effect was observed for meat quality traits. The IGF2 intron3-g.3072G>A mutation did not show any association in the Italian Duroc pigs, probably because of the small variability at this polymorphic site for this breed. However, a significant association was evident for the CTSD marker (P < 0.001) with EBV of all carcass and production traits in Italian Duroc pigs (lean content, ADG, backfat thickness, feed:gain ratio) after excluding possible confounding effects of the IGF2 mutation. The effects of the CTSD g.70G>A mutation were also confirmed in a subset of Italian Large White animals carrying the homozygous genotype IGF2 intron3-g.3072GG, and by haplotype analysis between the markers of the 2 considered genes in the complete data set. Overall, these results indicate that the IGF2 intron3-g.3072G>A mutation is not the only polymorphism affecting fatness and muscle deposition on SSC2p. Therefore, the CTSD g.70G>A polymorphism could be used to increase selection efficiency in marker-assisted selection programs that already use the IGF2 mutation. However, for practical applications, because the CTSD gene should not be imprinted (we obtained this information from expression analysis in adult skeletal muscle), the different modes of inheritance of the 2 genes have to be considered.

Novel mutations of MYO7A and USH1G in Israeli Arab families with Usher syndrome type 1.

PubMed

Rizel, Leah; Safieh, Christine; Shalev, Stavit A; Mezer, Eedy; Jabaly-Habib, Haneen; Ben-Neriah, Ziva; Chervinsky, Elena; Briscoe, Daniel; Ben-Yosef, Tamar

2011-01-01

This study investigated the genetic basis for Usher syndrome type 1 (USH1) in four consanguineous Israeli Arab families. Haplotype analysis for all known USH1 loci was performed in each family. In families for which haplotype analysis was inconclusive, we performed genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array. For mutation analysis, specific primers were used to PCR amplify the coding exons of the MYO7A, USH1C, and USH1G genes including intron-exon boundaries. Mutation screening was performed with direct sequencing. A combination of haplotype analysis and genome-wide homozygosity mapping indicated linkage to the USH1B locus in two families, USH1C in one family and USH1G in another family. Sequence analysis of the relevant genes (MYO7A, USH1C, and USH1G) led to the identification of pathogenic mutations in all families. Two of the identified mutations are novel (c.1135-1147dup in MYO7A and c.206-207insC in USH1G). USH1 is a genetically heterogenous condition. Of the five USH1 genes identified to date, USH1C and USH1G are the rarest contributors to USH1 etiology worldwide. It is therefore interesting that two of the four Israeli Arab families reported here have mutations in these two genes. This finding further demonstrates the unique genetic structure of the Israeli population in general, and the Israeli Arab population in particular, which due to high rates of consanguinity segregates many rare autosomal recessive genetic conditions.

An initiator codon mutation in SDE2 causes recessive embryonic lethality in Holstein cattle.

PubMed

Fritz, Sébastien; Hoze, Chris; Rebours, Emmanuelle; Barbat, Anne; Bizard, Méline; Chamberlain, Amanda; Escouflaire, Clémentine; Vander Jagt, Christy; Boussaha, Mekki; Grohs, Cécile; Allais-Bonnet, Aurélie; Philippe, Maëlle; Vallée, Amélie; Amigues, Yves; Hayes, Benjamin J; Boichard, Didier; Capitan, Aurélien

2018-04-18

Researching depletions in homozygous genotypes for specific haplotypes among the large cohorts of animals genotyped for genomic selection is a very efficient strategy to map recessive lethal mutations. In this study, by analyzing real or imputed Illumina BovineSNP50 (Illumina Inc., San Diego, CA) genotypes from more than 250,000 Holstein animals, we identified a new locus called HH6 showing significant negative effects on conception rate and nonreturn rate at 56 d in at-risk versus control mating. We fine-mapped this locus in a 1.1-Mb interval and analyzed genome sequence data from 12 carrier and 284 noncarrier Holstein bulls. We report the identification of a strong candidate mutation in the gene encoding SDE2 telomere maintenance homolog (SDE2), a protein essential for genomic stability in eukaryotes. This A-to-G transition changes the initiator ATG (methionine) codon to ACG because the gene is transcribed on the reverse strand. Using RNA sequencing and quantitative reverse-transcription PCR, we demonstrated that this mutation does not significantly affect SDE2 splicing and expression level in heterozygous carriers compared with control animals. Initiation of translation at the closest in-frame methionine codon would truncate the SDE2 precursor by 83 amino acids, including the cleavage site necessary for its activation. Finally, no homozygote for the G allele was observed in a large population of nearly 29,000 individuals genotyped for the mutation. The low frequency (1.3%) of the derived allele in the French population and the availability of a diagnostic test on the Illumina EuroG10K SNP chip routinely used for genomic evaluation will enable rapid and efficient selection against this deleterious mutation. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

PubMed

Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

2013-03-01

Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

The Plasmodium falciparum chloroquine resistance transporter is associated with the ex vivo P. falciparum African parasite response to pyronaridine.

PubMed

Madamet, Marylin; Briolant, Sébastien; Amalvict, Rémy; Benoit, Nicolas; Bouchiba, Housem; Cren, Julien; Pradines, Bruno

2016-02-09

The pyronaridine-artesunate combination is one of the most recent oral artemisinin-based therapeutic combinations (ACTs) recommended for the treatment of uncomplicated P. falciparum malaria. The emergence of P. falciparum resistance to artemisinin has recently developed in Southeast Asia. Little data are available on the association between pyronaridine susceptibility and polymorphisms in genes involved in antimalarial drug resistance. The objective of the present study was to investigate the association between ex vivo responses to pyronaridine and the K76T mutation in the pfcrt gene in P. falciparum isolates. The assessment of ex vivo susceptibility to pyronaridine was performed on 296 P. falciparum isolates using a standard 42-h 3H-hypoxanthine uptake inhibition method. The K76T mutation was also investigated. The pyronaridine IC50 (inhibitory concentration 50 %) ranged from 0.55 to 80.0 nM. Ex vivo responses to pyronaridine were significantly associated with the K76T mutation (p-value = 0.020). The reduced susceptibility to pyronaridine, defined as IC50 > 60 nM, was significantly associated with the K76T mutation (p-value = 0.004). Using a Bayesian mixture modelling approach, the pyronaridine IC50 were classified into three components: component A (IC50 median 15.9 nM), component B (IC50 median 34.2 nM) and component C (IC50 median 63.3 nM). The K76T mutation was represented in 46.3% of the isolates in component A, 47.2% of the isolates in component B and 73.3% of the isolates in component C (p-value = 0.021). These results showed the ex vivo reduced susceptibility to pyronaridine, i.e., IC50 > 60 nM, associated with the K76T mutation.

An optimal strategy for functional mapping of dynamic trait loci.

PubMed

Jin, Tianbo; Li, Jiahan; Guo, Ying; Zhou, Xiaojing; Yang, Runqing; Wu, Rongling

2010-02-01

As an emerging powerful approach for mapping quantitative trait loci (QTLs) responsible for dynamic traits, functional mapping models the time-dependent mean vector with biologically meaningful equations and are likely to generate biologically relevant and interpretable results. Given the autocorrelation nature of a dynamic trait, functional mapping needs the implementation of the models for the structure of the covariance matrix. In this article, we have provided a comprehensive set of approaches for modelling the covariance structure and incorporated each of these approaches into the framework of functional mapping. The Bayesian information criterion (BIC) values are used as a model selection criterion to choose the optimal combination of the submodels for the mean vector and covariance structure. In an example for leaf age growth from a rice molecular genetic project, the best submodel combination was found between the Gaussian model for the correlation structure, power equation of order 1 for the variance and the power curve for the mean vector. Under this combination, several significant QTLs for leaf age growth trajectories were detected on different chromosomes. Our model can be well used to study the genetic architecture of dynamic traits of agricultural values.

A new high resolution permafrost map of Iceland from Earth Observation data

NASA Astrophysics Data System (ADS)

Barnie, Talfan; Conway, Susan; Balme, Matt; Graham, Alastair

2017-04-01

High resolution maps of permafrost are required for ongoing monitoring of environmental change and the resulting hazards to ecosystems, people and infrastructure. However, permafrost maps are difficult to construct - direct observations require maintaining networks of sensors and boreholes in harsh environments and are thus limited in extent in space and time, and indirect observations require models or assumptions relating the measurements (e.g. weather station air temperature, basal snow temperature) to ground temperature. Operationally produced Land Surface Temperature maps from Earth Observation data can be used to make spatially contiguous estimates of mean annual skin temperature, which has been used a proxy for the presence of permafrost. However these maps are subject to biases due to (i) selective sampling during the day due to limited satellite overpass times, (ii) selective sampling over the year due to seasonally varying cloud cover, (iii) selective sampling of LST only during clearsky conditions, (iv) errors in cloud masking (v) errors in temperature emissivity separation (vi) smoothing over spatial variability. In this study we attempt to compensate for some of these problems using a bayesian modelling approach and high resolution topography-based downscaling.

Manifold absolute pressure estimation using neural network with hybrid training algorithm

PubMed Central

Selamat, Hazlina; Alimin, Ahmad Jais; Haniff, Mohamad Fadzli

2017-01-01

In a modern small gasoline engine fuel injection system, the load of the engine is estimated based on the measurement of the manifold absolute pressure (MAP) sensor, which took place in the intake manifold. This paper present a more economical approach on estimating the MAP by using only the measurements of the throttle position and engine speed, resulting in lower implementation cost. The estimation was done via two-stage multilayer feed-forward neural network by combining Levenberg-Marquardt (LM) algorithm, Bayesian Regularization (BR) algorithm and Particle Swarm Optimization (PSO) algorithm. Based on the results found in 20 runs, the second variant of the hybrid algorithm yields a better network performance than the first variant of hybrid algorithm, LM, LM with BR and PSO by estimating the MAP closely to the simulated MAP values. By using a valid experimental training data, the estimator network that trained with the second variant of the hybrid algorithm showed the best performance among other algorithms when used in an actual retrofit fuel injection system (RFIS). The performance of the estimator was also validated in steady-state and transient condition by showing a closer MAP estimation to the actual value. PMID:29190779

Mental maps and travel behaviour: meanings and models

NASA Astrophysics Data System (ADS)

Hannes, Els; Kusumastuti, Diana; Espinosa, Maikel León; Janssens, Davy; Vanhoof, Koen; Wets, Geert

2012-04-01

In this paper, the " mental map" concept is positioned with regard to individual travel behaviour to start with. Based on Ogden and Richards' triangle of meaning (The meaning of meaning: a study of the influence of language upon thought and of the science of symbolism. International library of psychology, philosophy and scientific method. Routledge and Kegan Paul, London, 1966) distinct thoughts, referents and symbols originating from different scientific disciplines are identified and explained in order to clear up the notion's fuzziness. Next, the use of this concept in two major areas of research relevant to travel demand modelling is indicated and discussed in detail: spatial cognition and decision-making. The relevance of these constructs to understand and model individual travel behaviour is explained and current research efforts to implement these concepts in travel demand models are addressed. Furthermore, these mental map notions are specified in two types of computational models, i.e. a Bayesian Inference Network (BIN) and a Fuzzy Cognitive Map (FCM). Both models are explained, and a numerical and a real-life example are provided. Both approaches yield a detailed quantitative representation of the mental map of decision-making problems in travel behaviour.

On the structure of Bayesian network for Indonesian text document paraphrase identification

NASA Astrophysics Data System (ADS)

Prayogo, Ario Harry; Syahrul Mubarok, Mohamad; Adiwijaya

2018-03-01

Paraphrase identification is an important process within natural language processing. The idea is to automatically recognize phrases that have different forms but contain same meanings. For examples if we input query “causing fire hazard”, then the computer has to recognize this query that this query has same meaning as “the cause of fire hazard. Paraphrasing is an activity that reveals the meaning of an expression, writing, or speech using different words or forms, especially to achieve greater clarity. In this research we will focus on classifying two Indonesian sentences whether it is a paraphrase to each other or not. There are four steps in this research, first is preprocessing, second is feature extraction, third is classifier building, and the last is performance evaluation. Preprocessing consists of tokenization, non-alphanumerical removal, and stemming. After preprocessing we will conduct feature extraction in order to build new features from given dataset. There are two kinds of features in the research, syntactic features and semantic features. Syntactic features consist of normalized levenshtein distance feature, term-frequency based cosine similarity feature, and LCS (Longest Common Subsequence) feature. Semantic features consist of Wu and Palmer feature and Shortest Path Feature. We use Bayesian Networks as the method of training the classifier. Parameter estimation that we use is called MAP (Maximum A Posteriori). For structure learning of Bayesian Networks DAG (Directed Acyclic Graph), we use BDeu (Bayesian Dirichlet equivalent uniform) scoring function and for finding DAG with the best BDeu score, we use K2 algorithm. In evaluation step we perform cross-validation. The average result that we get from testing the classifier as follows: Precision 75.2%, Recall 76.5%, F1-Measure 75.8% and Accuracy 75.6%.

Wavelet extractor: A Bayesian well-tie and wavelet extraction program

NASA Astrophysics Data System (ADS)

Gunning, James; Glinsky, Michael E.

2006-06-01

We introduce a new open-source toolkit for the well-tie or wavelet extraction problem of estimating seismic wavelets from seismic data, time-to-depth information, and well-log suites. The wavelet extraction model is formulated as a Bayesian inverse problem, and the software will simultaneously estimate wavelet coefficients, other parameters associated with uncertainty in the time-to-depth mapping, positioning errors in the seismic imaging, and useful amplitude-variation-with-offset (AVO) related parameters in multi-stack extractions. It is capable of multi-well, multi-stack extractions, and uses continuous seismic data-cube interpolation to cope with the problem of arbitrary well paths. Velocity constraints in the form of checkshot data, interpreted markers, and sonic logs are integrated in a natural way. The Bayesian formulation allows computation of full posterior uncertainties of the model parameters, and the important problem of the uncertain wavelet span is addressed uses a multi-model posterior developed from Bayesian model selection theory. The wavelet extraction tool is distributed as part of the Delivery seismic inversion toolkit. A simple log and seismic viewing tool is included in the distribution. The code is written in Java, and thus platform independent, but the Seismic Unix (SU) data model makes the inversion particularly suited to Unix/Linux environments. It is a natural companion piece of software to Delivery, having the capacity to produce maximum likelihood wavelet and noise estimates, but will also be of significant utility to practitioners wanting to produce wavelet estimates for other inversion codes or purposes. The generation of full parameter uncertainties is a crucial function for workers wishing to investigate questions of wavelet stability before proceeding to more advanced inversion studies.

Quantum Bayesian networks with application to games displaying Parrondo's paradox

NASA Astrophysics Data System (ADS)

Pejic, Michael

Bayesian networks and their accompanying graphical models are widely used for prediction and analysis across many disciplines. We will reformulate these in terms of linear maps. This reformulation will suggest a natural extension, which we will show is equivalent to standard textbook quantum mechanics. Therefore, this extension will be termed quantum. However, the term quantum should not be taken to imply this extension is necessarily only of utility in situations traditionally thought of as in the domain of quantum mechanics. In principle, it may be employed in any modelling situation, say forecasting the weather or the stock market---it is up to experiment to determine if this extension is useful in practice. Even restricting to the domain of quantum mechanics, with this new formulation the advantages of Bayesian networks can be maintained for models incorporating quantum and mixed classical-quantum behavior. The use of these will be illustrated by various basic examples. Parrondo's paradox refers to the situation where two, multi-round games with a fixed winning criteria, both with probability greater than one-half for one player to win, are combined. Using a possibly biased coin to determine the rule to employ for each round, paradoxically, the previously losing player now wins the combined game with probabilitygreater than one-half. Using the extended Bayesian networks, we will formulate and analyze classical observed, classical hidden, and quantum versions of a game that displays this paradox, finding bounds for the discrepancy from naive expectations for the occurrence of the paradox. A quantum paradox inspired by Parrondo's paradox will also be analyzed. We will prove a bound for the discrepancy from naive expectations for this paradox as well. Games involving quantum walks that achieve this bound will be presented.

Genomic selection and complex trait prediction using a fast EM algorithm applied to genome-wide markers

PubMed Central

2010-01-01

Background The information provided by dense genome-wide markers using high throughput technology is of considerable potential in human disease studies and livestock breeding programs. Genome-wide association studies relate individual single nucleotide polymorphisms (SNP) from dense SNP panels to individual measurements of complex traits, with the underlying assumption being that any association is caused by linkage disequilibrium (LD) between SNP and quantitative trait loci (QTL) affecting the trait. Often SNP are in genomic regions of no trait variation. Whole genome Bayesian models are an effective way of incorporating this and other important prior information into modelling. However a full Bayesian analysis is often not feasible due to the large computational time involved. Results This article proposes an expectation-maximization (EM) algorithm called emBayesB which allows only a proportion of SNP to be in LD with QTL and incorporates prior information about the distribution of SNP effects. The posterior probability of being in LD with at least one QTL is calculated for each SNP along with estimates of the hyperparameters for the mixture prior. A simulated example of genomic selection from an international workshop is used to demonstrate the features of the EM algorithm. The accuracy of prediction is comparable to a full Bayesian analysis but the EM algorithm is considerably faster. The EM algorithm was accurate in locating QTL which explained more than 1% of the total genetic variation. A computational algorithm for very large SNP panels is described. Conclusions emBayesB is a fast and accurate EM algorithm for implementing genomic selection and predicting complex traits by mapping QTL in genome-wide dense SNP marker data. Its accuracy is similar to Bayesian methods but it takes only a fraction of the time. PMID:20969788

Parallelized Bayesian inversion for three-dimensional dental X-ray imaging.

PubMed

Kolehmainen, Ville; Vanne, Antti; Siltanen, Samuli; Järvenpää, Seppo; Kaipio, Jari P; Lassas, Matti; Kalke, Martti

2006-02-01

Diagnostic and operational tasks based on dental radiology often require three-dimensional (3-D) information that is not available in a single X-ray projection image. Comprehensive 3-D information about tissues can be obtained by computerized tomography (CT) imaging. However, in dental imaging a conventional CT scan may not be available or practical because of high radiation dose, low-resolution or the cost of the CT scanner equipment. In this paper, we consider a novel type of 3-D imaging modality for dental radiology. We consider situations in which projection images of the teeth are taken from a few sparsely distributed projection directions using the dentist's regular (digital) X-ray equipment and the 3-D X-ray attenuation function is reconstructed. A complication in these experiments is that the reconstruction of the 3-D structure based on a few projection images becomes an ill-posed inverse problem. Bayesian inversion is a well suited framework for reconstruction from such incomplete data. In Bayesian inversion, the ill-posed reconstruction problem is formulated in a well-posed probabilistic form in which a priori information is used to compensate for the incomplete information of the projection data. In this paper we propose a Bayesian method for 3-D reconstruction in dental radiology. The method is partially based on Kolehmainen et al. 2003. The prior model for dental structures consist of a weighted l1 and total variation (TV)-prior together with the positivity prior. The inverse problem is stated as finding the maximum a posteriori (MAP) estimate. To make the 3-D reconstruction computationally feasible, a parallelized version of an optimization algorithm is implemented for a Beowulf cluster computer. The method is tested with projection data from dental specimens and patient data. Tomosynthetic reconstructions are given as reference for the proposed method.

Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22.

PubMed

Cohen, Rony; Basel-Vanagaite, Lina; Goldberg-Stern, Hadassah; Halevy, Ayelet; Shuper, Avinoam; Feingold-Zadok, Michal; Behar, Doron M; Straussberg, Rachel

2014-11-01

To characterize a new subset of early myoclonic encephalopathy usually associated with metabolic etiologies with a new genetic entity. We describe two siblings with early myoclonic encephalopathy born to consanguineous parents of Arab Muslim origin from Israel. We used homozygosity mapping and candidate gene sequencing to reveal the genetic basis of the myoclonic syndrome. We found a rare missense mutation in the gene encoding one of the two mitochondrial glutamate/H symporters, SLC25A22. The phenotype of early myoclonic encephalopathy was first linked to the same mutation in 2005 in patients of the same ethnicity as our family. Owing to the devastating nature of this encephalopathy, we focus attention on its clinical history, epileptic semiology, distinct electroencephalography features, and genetic basis. We provide the evidence that an integrated diagnostic strategy combining homozygosity mapping with candidate gene sequencing is efficient in consanguineous families with highly heterogeneous autosomal recessive diseases. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

A novel autosomal-recessive mutation, whitish chalk-like teeth, resembling amelogenesis imperfecta, maps to rat chromosome 14 corresponding to human 4q21.

PubMed

Masuyama, Taku; Miyajima, Katsuhiro; Ohshima, Hayato; Osawa, Masaru; Yokoi, Norihide; Oikawa, Toshihiro; Taniguchi, Kazuyuki

2005-12-01

A rat mutant, whitish chalk-like teeth (wct), with white, chalk-like abnormal incisors, was discovered and morphologically and genetically characterized. The mutant rats showed tooth enamel defects that were similar to those of human amelogenesis imperfecta. The wct mutation was found to disturb the morphological transition of ameloblasts from secretory to maturation stages and to induce cyst formation. This mutation also disturbs the transfer of iron into the enamel, resulting in the whitish chalk-like incisors. A genetic linkage study indicated that the wct locus maps to a specific interval of rat chromosome 14 between D14Got13 and D14Wox2. Interestingly, the human chromosomal region orthologous to wct, a 5.5-Mb interval in human chromosome 4q21, is a critical region for the locus of human amelogenesis imperfecta AIH2. These results strongly suggest that this wct mutant is a useful model for the identification of genes responsible for amelogenesis imperfecta and molecular mechanisms of tooth development.

Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.

PubMed

Bi, Hongyan; Gao, Yunying; Yao, Sheng; Dong, Mingrui; Headley, Alexander Peter; Yuan, Yun

2007-10-01

Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long chain base subunit 1 (SPTLC1). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families.

Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

PubMed Central

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M.; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Almeida, Estrella Guarino; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J.; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw JW; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-01-01

Many individuals with multiple or large colorectal adenomas, or early-onset colorectal cancer (CRC), have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple adenoma and/or CRC cases, but in no controls. The susceptibility variants appear to have high penetrance. POLD1 is also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proof-reading (exonuclease) domain of DNA polymerases ε and δ, and are predicted to impair correction of mispaired bases inserted during DNA replication. In agreement with this prediction, mutation carriers’ tumours were microsatellite-stable, but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently-described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE exonuclease domain mutations. PMID:23263490

Homozygous nonsense mutation in SGCA is a common cause of limb-girdle muscular dystrophy in Assiut, Egypt.

PubMed

Reddy, Hemakumar M; Hamed, Sherifa A; Lek, Monkol; Mitsuhashi, Satomi; Estrella, Elicia; Jones, Michael D; Mahoney, Lane J; Duncan, Anna R; Cho, Kyung-Ah; Macarthur, Daniel G; Kunkel, Louis M; Kang, Peter B

2016-10-01

The genetic causes of limb-girdle muscular dystrophy (LGMD) have been studied in numerous countries, but such investigations have been limited in Egypt. A cohort of 30 families with suspected LGMD from Assiut, Egypt, was studied using immunohistochemistry, homozygosity mapping, Sanger sequencing, and whole exome sequencing. Six families were confirmed to have pathogenic mutations, 4 in SGCA and 2 in DMD. Of these, 3 families harbored a single nonsense mutation in SGCA, suggesting that this may be a common mutation in Assiut, Egypt, originating from a founder effect. The Assiut region in Egypt appears to share at least several of the common LGMD genes found in other parts of the world. It is notable that 4 of the 6 mutations were ascertained by means of whole exome sequencing, even though it was the last approach adopted. This illustrates the power of this technique for identifying causative mutations for muscular dystrophies. Muscle Nerve 54: 690-695, 2016. © 2016 Wiley Periodicals, Inc.

Identification of the Bovine Arachnomelia Mutation by Massively Parallel Sequencing Implicates Sulfite Oxidase (SUOX) in Bone Development

PubMed Central

Drögemüller, Cord; Tetens, Jens; Sigurdsson, Snaevar; Gentile, Arcangelo; Testoni, Stefania; Lindblad-Toh, Kerstin; Leeb, Tosso

2010-01-01

Arachnomelia is a monogenic recessive defect of skeletal development in cattle. The causative mutation was previously mapped to a ∼7 Mb interval on chromosome 5. Here we show that array-based sequence capture and massively parallel sequencing technology, combined with the typical family structure in livestock populations, facilitates the identification of the causative mutation. We re-sequenced the entire critical interval in a healthy partially inbred cow carrying one copy of the critical chromosome segment in its ancestral state and one copy of the same segment with the arachnomelia mutation, and we detected a single heterozygous position. The genetic makeup of several partially inbred cattle provides extremely strong support for the causality of this mutation. The mutation represents a single base insertion leading to a premature stop codon in the coding sequence of the SUOX gene and is perfectly associated with the arachnomelia phenotype. Our findings suggest an important role for sulfite oxidase in bone development. PMID:20865119

The dominant alopecia phenotypes Bareskin, Rex-denuded, and Reduced Coat 2 are caused by mutations in gasdermin 3.

PubMed

Runkel, F; Marquardt, A; Stoeger, C; Kochmann, E; Simon, D; Kohnke, B; Korthaus, D; Wattler, F; Fuchs, H; Hrabé de Angelis, M; Stumm, G; Nehls, M; Wattler, S; Franz, T; Augustin, M

2004-11-01

Reduced Coat 2 (Rco2) is an ENU-induced mutation affecting hair follicle morphogenesis by an abnormal and protracted catagen. We describe chromosomal mapping and molecular identification of the autosomal dominant Rco2 mutation. The Rco2 critical region on mouse chromosome 11 encompasses the alopecia loci, Bareskin (Bsk), Rex-denuded (Re(den)), Recombination induced mutation 3 (Rim3), and Defolliculated (Dfl). Recently, the gasdermin (Gsdm) gene was described as predominantly expressed in skin and gastric tissues. We provide evidence for a murine-specific gene cluster consisting of Gsdm and two closely related genes which we designate as Gsdm2 and Gsdm3. We show that Gsdm3 reflects a mutation hotspot and that Gsdm3 mutations cause alopecia in Rco2, Re(den), and Bsk mice. We infer a role of Gsdm3 during the catagen to telogen transition at the end of hair follicle morphogenesis and the formation of hair follicle-associated sebaceous glands.

Combining Multiple Types of Intelligence to Generate Probability Maps of Moving Targets

DTIC Science & Technology

2013-09-01

normalization coefficient k similar to Demspter-Shafer’s combination rule. d. Mass Mean This rule of combination is the most straightforward one... coefficient , we can state that without normalizing, the updated distribution is: fupdate t   qk k t M 1 qk n k t M        (3.3) 36...Lawrence, KS. Chen, Z. (2003). Bayesian filtering: From Kalman filters to particle filters and beyond. Technical report, McMaster University. Dempster

Cat-Map: putting cataract on the map

PubMed Central

Bennett, Thomas M.; Hejtmancik, J. Fielding

2010-01-01

Lens opacities, or cataract(s), may be inherited as a classic Mendelian disorder usually with early-onset or, more commonly, acquired with age as a multi-factorial or complex trait. Many genetic forms of cataract have been described in mice and other animal models. Considerable progress has been made in mapping and identifying the genes and mutations responsible for inherited forms of cataract, and genetic determinants of age-related cataract are beginning to be discovered. To provide a convenient and accurate summary of current information focused on the increasing genetic complexity of Mendelian and age-related cataract we have created an online chromosome map and reference database for cataract in humans and mice (Cat-Map). PMID:21042563

Learning Probabilistic Features for Robotic Navigation Using Laser Sensors

PubMed Central

Aznar, Fidel; Pujol, Francisco A.; Pujol, Mar; Rizo, Ramón; Pujol, María-José

2014-01-01

SLAM is a popular task used by robots and autonomous vehicles to build a map of an unknown environment and, at the same time, to determine their location within the map. This paper describes a SLAM-based, probabilistic robotic system able to learn the essential features of different parts of its environment. Some previous SLAM implementations had computational complexities ranging from O(Nlog(N)) to O(N 2), where N is the number of map features. Unlike these methods, our approach reduces the computational complexity to O(N) by using a model to fuse the information from the sensors after applying the Bayesian paradigm. Once the training process is completed, the robot identifies and locates those areas that potentially match the sections that have been previously learned. After the training, the robot navigates and extracts a three-dimensional map of the environment using a single laser sensor. Thus, it perceives different sections of its world. In addition, in order to make our system able to be used in a low-cost robot, low-complexity algorithms that can be easily implemented on embedded processors or microcontrollers are used. PMID:25415377

Learning probabilistic features for robotic navigation using laser sensors.

PubMed

Aznar, Fidel; Pujol, Francisco A; Pujol, Mar; Rizo, Ramón; Pujol, María-José

2014-01-01

SLAM is a popular task used by robots and autonomous vehicles to build a map of an unknown environment and, at the same time, to determine their location within the map. This paper describes a SLAM-based, probabilistic robotic system able to learn the essential features of different parts of its environment. Some previous SLAM implementations had computational complexities ranging from O(Nlog(N)) to O(N(2)), where N is the number of map features. Unlike these methods, our approach reduces the computational complexity to O(N) by using a model to fuse the information from the sensors after applying the Bayesian paradigm. Once the training process is completed, the robot identifies and locates those areas that potentially match the sections that have been previously learned. After the training, the robot navigates and extracts a three-dimensional map of the environment using a single laser sensor. Thus, it perceives different sections of its world. In addition, in order to make our system able to be used in a low-cost robot, low-complexity algorithms that can be easily implemented on embedded processors or microcontrollers are used.

Mapping-by-sequencing of Ligon-lintless-1 (Li 1 ) reveals a cluster of neighboring genes with correlated expression in developing fibers of Upland cotton (Gossypium hirsutum L.).

PubMed

Thyssen, Gregory N; Fang, David D; Turley, Rickie B; Florane, Christopher; Li, Ping; Naoumkina, Marina

2015-09-01

Mapping-by-sequencing and SNP marker analysis were used to fine map the Ligon-lintless-1 ( Li 1 ) short fiber mutation in tetraploid cotton to a 255-kb region that contains 16 annotated proteins. The Ligon-lintless-1 (Li 1 ) mutant of cotton (Gossypium hirsutum L.) has been studied as a model for cotton fiber development since its identification in 1929; however, the causative mutation has not been identified yet. Here we report the fine genetic mapping of the mutation to a 255-kb region that contains only 16 annotated genes in the reference Gossypium raimondii genome. We took advantage of the incompletely dominant dwarf vegetative phenotype to identify 100 mutants (Li 1 /Li 1 ) and 100 wild-type (li 1 /li 1 ) homozygotes from a mapping population of 2567 F2 plants, which we bulked and deep sequenced. Since only homozygotes were sequenced, we were able to use a high stringency in SNP calling to rapidly narrow down the region harboring the Li 1 locus, and designed subgenome-specific SNP markers to test the population. We characterized the expression of all sixteen genes in the region by RNA sequencing of elongating fibers and by RT-qPCR at seven time points spanning fiber development. One of the most highly expressed genes found in this interval in wild-type fiber cells is 40-fold under-expressed at the day of anthesis (DOA) in the mutant fiber cells.  This gene is a major facilitator superfamily protein, part of the large family of proteins that includes auxin and sugar transporters. Interestingly, nearly all genes in this region were most highly expressed at DOA and showed a high degree of co-expression. Further characterization is required to determine if transport of hormones or carbohydrates is involved in both the dwarf and lintless phenotypes of Li 1 plants.

Land cover mapping of the National Park Service northwest Alaska management area using Landsat multispectral and thematic mapper satellite data

USGS Publications Warehouse

Markon, C.J.; Wesser, Sara

1998-01-01

A land cover map of the National Park Service northwest Alaska management area was produced using digitally processed Landsat data. These and other environmental data were incorporated into a geographic information system to provide baseline information about the nature and extent of resources present in this northwest Alaskan environment.This report details the methodology, depicts vegetation profiles of the surrounding landscape, and describes the different vegetation types mapped. Portions of nine Landsat satellite (multispectral scanner and thematic mapper) scenes were used to produce a land cover map of the Cape Krusenstern National Monument and Noatak National Preserve and to update an existing land cover map of Kobuk Valley National Park Valley National Park. A Bayesian multivariate classifier was applied to the multispectral data sets, followed by the application of ancillary data (elevation, slope, aspect, soils, watersheds, and geology) to enhance the spectral separation of classes into more meaningful vegetation types. The resulting land cover map contains six major land cover categories (forest, shrub, herbaceous, sparse/barren, water, other) and 19 subclasses encompassing 7 million hectares. General narratives of the distribution of the subclasses throughout the project area are given along with vegetation profiles showing common relationships between topographic gradients and vegetation communities.

Occupancy mapping and surface reconstruction using local Gaussian processes with Kinect sensors.

PubMed

Kim, Soohwan; Kim, Jonghyuk

2013-10-01

Although RGB-D sensors have been successfully applied to visual SLAM and surface reconstruction, most of the applications aim at visualization. In this paper, we propose a noble method of building continuous occupancy maps and reconstructing surfaces in a single framework for both navigation and visualization. Particularly, we apply a Bayesian nonparametric approach, Gaussian process classification, to occupancy mapping. However, it suffers from high-computational complexity of O(n(3))+O(n(2)m), where n and m are the numbers of training and test data, respectively, limiting its use for large-scale mapping with huge training data, which is common with high-resolution RGB-D sensors. Therefore, we partition both training and test data with a coarse-to-fine clustering method and apply Gaussian processes to each local clusters. In addition, we consider Gaussian processes as implicit functions, and thus extract iso-surfaces from the scalar fields, continuous occupancy maps, using marching cubes. By doing that, we are able to build two types of map representations within a single framework of Gaussian processes. Experimental results with 2-D simulated data show that the accuracy of our approximated method is comparable to previous work, while the computational time is dramatically reduced. We also demonstrate our method with 3-D real data to show its feasibility in large-scale environments.

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

PubMed

Palles, Claire; Cazier, Jean-Baptiste; Howarth, Kimberley M; Domingo, Enric; Jones, Angela M; Broderick, Peter; Kemp, Zoe; Spain, Sarah L; Guarino, Estrella; Guarino Almeida, Estrella; Salguero, Israel; Sherborne, Amy; Chubb, Daniel; Carvajal-Carmona, Luis G; Ma, Yusanne; Kaur, Kulvinder; Dobbins, Sara; Barclay, Ella; Gorman, Maggie; Martin, Lynn; Kovac, Michal B; Humphray, Sean; Lucassen, Anneke; Holmes, Christopher C; Bentley, David; Donnelly, Peter; Taylor, Jenny; Petridis, Christos; Roylance, Rebecca; Sawyer, Elinor J; Kerr, David J; Clark, Susan; Grimes, Jonathan; Kearsey, Stephen E; Thomas, Huw J W; McVean, Gilean; Houlston, Richard S; Tomlinson, Ian

2013-02-01

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.

Evaluation of spatio-temporal Bayesian models for the spread of infectious diseases in oil palm.

PubMed

Denis, Marie; Cochard, Benoît; Syahputra, Indra; de Franqueville, Hubert; Tisné, Sébastien

2018-02-01

In the field of epidemiology, studies are often focused on mapping diseases in relation to time and space. Hierarchical modeling is a common flexible and effective tool for modeling problems related to disease spread. In the context of oil palm plantations infected by the fungal pathogen Ganoderma boninense, we propose and compare two spatio-temporal hierarchical Bayesian models addressing the lack of information on propagation modes and transmission vectors. We investigate two alternative process models to study the unobserved mechanism driving the infection process. The models help gain insight into the spatio-temporal dynamic of the infection by identifying a genetic component in the disease spread and by highlighting a spatial component acting at the end of the experiment. In this challenging context, we propose models that provide assumptions on the unobserved mechanism driving the infection process while making short-term predictions using ready-to-use software. Copyright © 2018 Elsevier Ltd. All rights reserved.

Assessment of a Bayesian Belief Network-GIS framework as a practical tool to support marine planning.

PubMed

Stelzenmüller, V; Lee, J; Garnacho, E; Rogers, S I

2010-10-01

For the UK continental shelf we developed a Bayesian Belief Network-GIS framework to visualise relationships between cumulative human pressures, sensitive marine landscapes and landscape vulnerability, to assess the consequences of potential marine planning objectives, and to map uncertainty-related changes in management measures. Results revealed that the spatial assessment of footprints and intensities of human activities had more influence on landscape vulnerabilities than the type of landscape sensitivity measure used. We addressed questions regarding consequences of potential planning targets, and necessary management measures with spatially-explicit assessment of their consequences. We conclude that the BN-GIS framework is a practical tool allowing for the visualisation of relationships, the spatial assessment of uncertainty related to spatial management scenarios, the engagement of different stakeholder views, and enables a quick update of new spatial data and relationships. Ultimately, such BN-GIS based tools can support the decision-making process used in adaptive marine management. Copyright © 2010 Elsevier Ltd. All rights reserved.

Bayesian multivariate hierarchical transformation models for ROC analysis.

PubMed

O'Malley, A James; Zou, Kelly H

2006-02-15

A Bayesian multivariate hierarchical transformation model (BMHTM) is developed for receiver operating characteristic (ROC) curve analysis based on clustered continuous diagnostic outcome data with covariates. Two special features of this model are that it incorporates non-linear monotone transformations of the outcomes and that multiple correlated outcomes may be analysed. The mean, variance, and transformation components are all modelled parametrically, enabling a wide range of inferences. The general framework is illustrated by focusing on two problems: (1) analysis of the diagnostic accuracy of a covariate-dependent univariate test outcome requiring a Box-Cox transformation within each cluster to map the test outcomes to a common family of distributions; (2) development of an optimal composite diagnostic test using multivariate clustered outcome data. In the second problem, the composite test is estimated using discriminant function analysis and compared to the test derived from logistic regression analysis where the gold standard is a binary outcome. The proposed methodology is illustrated on prostate cancer biopsy data from a multi-centre clinical trial.

Bayesian multivariate hierarchical transformation models for ROC analysis

PubMed Central

O'Malley, A. James; Zou, Kelly H.

2006-01-01

SUMMARY A Bayesian multivariate hierarchical transformation model (BMHTM) is developed for receiver operating characteristic (ROC) curve analysis based on clustered continuous diagnostic outcome data with covariates. Two special features of this model are that it incorporates non-linear monotone transformations of the outcomes and that multiple correlated outcomes may be analysed. The mean, variance, and transformation components are all modelled parametrically, enabling a wide range of inferences. The general framework is illustrated by focusing on two problems: (1) analysis of the diagnostic accuracy of a covariate-dependent univariate test outcome requiring a Box–Cox transformation within each cluster to map the test outcomes to a common family of distributions; (2) development of an optimal composite diagnostic test using multivariate clustered outcome data. In the second problem, the composite test is estimated using discriminant function analysis and compared to the test derived from logistic regression analysis where the gold standard is a binary outcome. The proposed methodology is illustrated on prostate cancer biopsy data from a multi-centre clinical trial. PMID:16217836

Logarithmic Laplacian Prior Based Bayesian Inverse Synthetic Aperture Radar Imaging.

PubMed

Zhang, Shuanghui; Liu, Yongxiang; Li, Xiang; Bi, Guoan

2016-04-28

This paper presents a novel Inverse Synthetic Aperture Radar Imaging (ISAR) algorithm based on a new sparse prior, known as the logarithmic Laplacian prior. The newly proposed logarithmic Laplacian prior has a narrower main lobe with higher tail values than the Laplacian prior, which helps to achieve performance improvement on sparse representation. The logarithmic Laplacian prior is used for ISAR imaging within the Bayesian framework to achieve better focused radar image. In the proposed method of ISAR imaging, the phase errors are jointly estimated based on the minimum entropy criterion to accomplish autofocusing. The maximum a posterior (MAP) estimation and the maximum likelihood estimation (MLE) are utilized to estimate the model parameters to avoid manually tuning process. Additionally, the fast Fourier Transform (FFT) and Hadamard product are used to minimize the required computational efficiency. Experimental results based on both simulated and measured data validate that the proposed algorithm outperforms the traditional sparse ISAR imaging algorithms in terms of resolution improvement and noise suppression.

Spatio-temporal Bayesian model selection for disease mapping

PubMed Central

Carroll, R; Lawson, AB; Faes, C; Kirby, RS; Aregay, M; Watjou, K

2016-01-01

Spatio-temporal analysis of small area health data often involves choosing a fixed set of predictors prior to the final model fit. In this paper, we propose a spatio-temporal approach of Bayesian model selection to implement model selection for certain areas of the study region as well as certain years in the study time line. Here, we examine the usefulness of this approach by way of a large-scale simulation study accompanied by a case study. Our results suggest that a special case of the model selection methods, a mixture model allowing a weight parameter to indicate if the appropriate linear predictor is spatial, spatio-temporal, or a mixture of the two, offers the best option to fitting these spatio-temporal models. In addition, the case study illustrates the effectiveness of this mixture model within the model selection setting by easily accommodating lifestyle, socio-economic, and physical environmental variables to select a predominantly spatio-temporal linear predictor. PMID:28070156

Assembly of the mitochondrial membrane system. XVIII. Genetic loci on mitochondrial DNA involved in cytochrome b biosynthesis.

PubMed

Tzagoloff, A; Foury, F; Akai, A

1976-11-24

1. Fourteen cytoplasmic mutants of Saccharomyces cerevisiae with a specific deficiency of cytochrome b have been studied. The mutations have been shown to occur in two separate genetic loci, COB 1 and COB 2. These loci can be distinguished by mit- X mit- crosses. Pairwise crosses of cytochrome b mutants belonging to different loci yield 4-6% wild type recombinants corresponding to recombinational frequencies of 8-12%. In intra-locus crosses, the recombinational frequencies range from 1% to less than 0.01%. The two loci can also be distinguished by mit- X rho- crosses. Twenty rho- testers have been isolated of which ten preferentially restore mutations in COB 1 and ten others in COB 2. 2. The COB 1 and COB 2 loci have been localized on mitochondrial DNA between the two antibiotic resistance loci OLI 1 and OLI 2 in the order OLI 2-COB 2-COB 1-OLI 1. The results of mit- X mit- and mit- X rho- crosses have also been used to map the cytochrome b mutations relative to each other. The maps obtained by the two independent methods are in good agreement. 3. Mutations in COB 1 have been found to be linked to the OLI1 locus in some but not in other strains of S. cervisiae. This evidence suggests that there may be a spacer region between the two loci whose length varies from strain to strain. 4. Two mutations in COB 2 have been found to cause a loss of a mitochondrial translation product corresponding to the cytochrome b apoprotein. Instead of the wild type protein the mutants have a new low-molecular weight product which is probably a fragment of cytochrome b. The fact that the mutations revert suggests that they are nonsense mutations in the structural gene of cytochrome b.

Multi-angle backscatter classification and sub-bottom profiling for improved seafloor characterization

NASA Astrophysics Data System (ADS)

Alevizos, Evangelos; Snellen, Mirjam; Simons, Dick; Siemes, Kerstin; Greinert, Jens

2018-06-01

This study applies three classification methods exploiting the angular dependence of acoustic seafloor backscatter along with high resolution sub-bottom profiling for seafloor sediment characterization in the Eckernförde Bay, Baltic Sea Germany. This area is well suited for acoustic backscatter studies due to its shallowness, its smooth bathymetry and the presence of a wide range of sediment types. Backscatter data were acquired using a Seabeam1180 (180 kHz) multibeam echosounder and sub-bottom profiler data were recorded using a SES-2000 parametric sonar transmitting 6 and 12 kHz. The high density of seafloor soundings allowed extracting backscatter layers for five beam angles over a large part of the surveyed area. A Bayesian probability method was employed for sediment classification based on the backscatter variability at a single incidence angle, whereas Maximum Likelihood Classification (MLC) and Principal Components Analysis (PCA) were applied to the multi-angle layers. The Bayesian approach was used for identifying the optimum number of acoustic classes because cluster validation is carried out prior to class assignment and class outputs are ordinal categorical values. The method is based on the principle that backscatter values from a single incidence angle express a normal distribution for a particular sediment type. The resulting Bayesian classes were well correlated to median grain sizes and the percentage of coarse material. The MLC method uses angular response information from five layers of training areas extracted from the Bayesian classification map. The subsequent PCA analysis is based on the transformation of these five layers into two principal components that comprise most of the data variability. These principal components were clustered in five classes after running an external cluster validation test. In general both methods MLC and PCA, separated the various sediment types effectively, showing good agreement (kappa >0.7) with the Bayesian approach which also correlates well with ground truth data (r2 > 0.7). In addition, sub-bottom data were used in conjunction with the Bayesian classification results to characterize acoustic classes with respect to their geological and stratigraphic interpretation. The joined interpretation of seafloor and sub-seafloor data sets proved to be an efficient approach for a better understanding of seafloor backscatter patchiness and to discriminate acoustically similar classes in different geological/bathymetric settings.

Atrial Natriuretic Peptide Frameshift Mutation in Familial Atrial Fibrillation

PubMed Central

Hodgson-Zingman, Denice M.; Karst, Margaret L.; Zingman, Leonid V.; Heublein, Denise M.; Darbar, Dawood; Herron, Kathleen J.; Ballew, Jeffrey D.; de Andrade, Mariza; Burnett, John C.; Olson, Timothy M.

2008-01-01

Summary Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide–cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability. PMID:18614783

Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.

PubMed

Corton, Marta; Avila-Fernandez, Almudena; Vallespín, Elena; López-Molina, María Isabel; Almoguera, Berta; Martín-Garrido, Esther; Tatu, Sorina D; Khan, M Imran; Blanco-Kelly, Fiona; Riveiro-Alvarez, Rosa; Brión, María; García-Sandoval, Blanca; Cremers, Frans P M; Carracedo, Angel; Ayuso, Carmen

2014-01-01

We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype. Case series. A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls. High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography. Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings. Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy showed fundus features of pigmentary retinopathy with atrophic macular lesions. This work reveals a higher frequency of LCA5 mutations in a Spanish LCA cohort than in other populations. This study established gene-specific frequencies and the underlying phenotype of LCA5 mutations in the Spanish population. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Genetics Home Reference: pilomatricoma

MedlinePlus

... F, Palacios J. beta-catenin expression in pilomatrixomas. Relationship with beta-catenin gene mutations and comparison with ... for Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & ...

Performance impact of mutation operators of a subpopulation-based genetic algorithm for multi-robot task allocation problems.

PubMed

Liu, Chun; Kroll, Andreas

2016-01-01

Multi-robot task allocation determines the task sequence and distribution for a group of robots in multi-robot systems, which is one of constrained combinatorial optimization problems and more complex in case of cooperative tasks because they introduce additional spatial and temporal constraints. To solve multi-robot task allocation problems with cooperative tasks efficiently, a subpopulation-based genetic algorithm, a crossover-free genetic algorithm employing mutation operators and elitism selection in each subpopulation, is developed in this paper. Moreover, the impact of mutation operators (swap, insertion, inversion, displacement, and their various combinations) is analyzed when solving several industrial plant inspection problems. The experimental results show that: (1) the proposed genetic algorithm can obtain better solutions than the tested binary tournament genetic algorithm with partially mapped crossover; (2) inversion mutation performs better than other tested mutation operators when solving problems without cooperative tasks, and the swap-inversion combination performs better than other tested mutation operators/combinations when solving problems with cooperative tasks. As it is difficult to produce all desired effects with a single mutation operator, using multiple mutation operators (including both inversion and swap) is suggested when solving similar combinatorial optimization problems.

Spatial Bayesian belief networks as a planning decision tool for mapping ecosystem services trade-offs on forested landscapes.

PubMed

Gonzalez-Redin, Julen; Luque, Sandra; Poggio, Laura; Smith, Ron; Gimona, Alessandro

2016-01-01

An integrated methodology, based on linking Bayesian belief networks (BBN) with GIS, is proposed for combining available evidence to help forest managers evaluate implications and trade-offs between forest production and conservation measures to preserve biodiversity in forested habitats. A Bayesian belief network is a probabilistic graphical model that represents variables and their dependencies through specifying probabilistic relationships. In spatially explicit decision problems where it is difficult to choose appropriate combinations of interventions, the proposed integration of a BBN with GIS helped to facilitate shared understanding of the human-landscape relationships, while fostering collective management that can be incorporated into landscape planning processes. Trades-offs become more and more relevant in these landscape contexts where the participation of many and varied stakeholder groups is indispensable. With these challenges in mind, our integrated approach incorporates GIS-based data with expert knowledge to consider two different land use interests - biodiversity value for conservation and timber production potential - with the focus on a complex mountain landscape in the French Alps. The spatial models produced provided different alternatives of suitable sites that can be used by policy makers in order to support conservation priorities while addressing management options. The approach provided provide a common reasoning language among different experts from different backgrounds while helped to identify spatially explicit conflictive areas. Copyright © 2015 Elsevier Inc. All rights reserved.

Cholinergic stimulation enhances Bayesian belief updating in the deployment of spatial attention.

PubMed

Vossel, Simone; Bauer, Markus; Mathys, Christoph; Adams, Rick A; Dolan, Raymond J; Stephan, Klaas E; Friston, Karl J

2014-11-19

The exact mechanisms whereby the cholinergic neurotransmitter system contributes to attentional processing remain poorly understood. Here, we applied computational modeling to psychophysical data (obtained from a spatial attention task) under a psychopharmacological challenge with the cholinesterase inhibitor galantamine (Reminyl). This allowed us to characterize the cholinergic modulation of selective attention formally, in terms of hierarchical Bayesian inference. In a placebo-controlled, within-subject, crossover design, 16 healthy human subjects performed a modified version of Posner's location-cueing task in which the proportion of validly and invalidly cued targets (percentage of cue validity, % CV) changed over time. Saccadic response speeds were used to estimate the parameters of a hierarchical Bayesian model to test whether cholinergic stimulation affected the trial-wise updating of probabilistic beliefs that underlie the allocation of attention or whether galantamine changed the mapping from those beliefs to subsequent eye movements. Behaviorally, galantamine led to a greater influence of probabilistic context (% CV) on response speed than placebo. Crucially, computational modeling suggested this effect was due to an increase in the rate of belief updating about cue validity (as opposed to the increased sensitivity of behavioral responses to those beliefs). We discuss these findings with respect to cholinergic effects on hierarchical cortical processing and in relation to the encoding of expected uncertainty or precision. Copyright © 2014 the authors 0270-6474/14/3415735-08$15.00/0.

Bayesian data fusion for spatial prediction of categorical variables in environmental sciences

NASA Astrophysics Data System (ADS)

Gengler, Sarah; Bogaert, Patrick

2014-12-01

First developed to predict continuous variables, Bayesian Maximum Entropy (BME) has become a complete framework in the context of space-time prediction since it has been extended to predict categorical variables and mixed random fields. This method proposes solutions to combine several sources of data whatever the nature of the information. However, the various attempts that were made for adapting the BME methodology to categorical variables and mixed random fields faced some limitations, as a high computational burden. The main objective of this paper is to overcome this limitation by generalizing the Bayesian Data Fusion (BDF) theoretical framework to categorical variables, which is somehow a simplification of the BME method through the convenient conditional independence hypothesis. The BDF methodology for categorical variables is first described and then applied to a practical case study: the estimation of soil drainage classes using a soil map and point observations in the sandy area of Flanders around the city of Mechelen (Belgium). The BDF approach is compared to BME along with more classical approaches, as Indicator CoKringing (ICK) and logistic regression. Estimators are compared using various indicators, namely the Percentage of Correctly Classified locations (PCC) and the Average Highest Probability (AHP). Although BDF methodology for categorical variables is somehow a simplification of BME approach, both methods lead to similar results and have strong advantages compared to ICK and logistic regression.

A Poisson nonnegative matrix factorization method with parameter subspace clustering constraint for endmember extraction in hyperspectral imagery

NASA Astrophysics Data System (ADS)

Sun, Weiwei; Ma, Jun; Yang, Gang; Du, Bo; Zhang, Liangpei

2017-06-01

A new Bayesian method named Poisson Nonnegative Matrix Factorization with Parameter Subspace Clustering Constraint (PNMF-PSCC) has been presented to extract endmembers from Hyperspectral Imagery (HSI). First, the method integrates the liner spectral mixture model with the Bayesian framework and it formulates endmember extraction into a Bayesian inference problem. Second, the Parameter Subspace Clustering Constraint (PSCC) is incorporated into the statistical program to consider the clustering of all pixels in the parameter subspace. The PSCC could enlarge differences among ground objects and helps finding endmembers with smaller spectrum divergences. Meanwhile, the PNMF-PSCC method utilizes the Poisson distribution as the prior knowledge of spectral signals to better explain the quantum nature of light in imaging spectrometer. Third, the optimization problem of PNMF-PSCC is formulated into maximizing the joint density via the Maximum A Posterior (MAP) estimator. The program is finally solved by iteratively optimizing two sub-problems via the Alternating Direction Method of Multipliers (ADMM) framework and the FURTHESTSUM initialization scheme. Five state-of-the art methods are implemented to make comparisons with the performance of PNMF-PSCC on both the synthetic and real HSI datasets. Experimental results show that the PNMF-PSCC outperforms all the five methods in Spectral Angle Distance (SAD) and Root-Mean-Square-Error (RMSE), and especially it could identify good endmembers for ground objects with smaller spectrum divergences.

Evolution of the cerebellum as a neuronal machine for Bayesian state estimation

NASA Astrophysics Data System (ADS)

Paulin, M. G.

2005-09-01

The cerebellum evolved in association with the electric sense and vestibular sense of the earliest vertebrates. Accurate information provided by these sensory systems would have been essential for precise control of orienting behavior in predation. A simple model shows that individual spikes in electrosensory primary afferent neurons can be interpreted as measurements of prey location. Using this result, I construct a computational neural model in which the spatial distribution of spikes in a secondary electrosensory map forms a Monte Carlo approximation to the Bayesian posterior distribution of prey locations given the sense data. The neural circuit that emerges naturally to perform this task resembles the cerebellar-like hindbrain electrosensory filtering circuitry of sharks and other electrosensory vertebrates. The optimal filtering mechanism can be extended to handle dynamical targets observed from a dynamical platform; that is, to construct an optimal dynamical state estimator using spiking neurons. This may provide a generic model of cerebellar computation. Vertebrate motion-sensing neurons have specific fractional-order dynamical characteristics that allow Bayesian state estimators to be implemented elegantly and efficiently, using simple operations with asynchronous pulses, i.e. spikes. The computational neural models described in this paper represent a novel kind of particle filter, using spikes as particles. The models are specific and make testable predictions about computational mechanisms in cerebellar circuitry, while providing a plausible explanation of cerebellar contributions to aspects of motor control, perception and cognition.

Evolution of the human immunodeficiency virus envelope gene is dominated by purifying selection.

PubMed

Edwards, C T T; Holmes, E C; Pybus, O G; Wilson, D J; Viscidi, R P; Abrams, E J; Phillips, R E; Drummond, A J

2006-11-01

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of low-frequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation.

The mutation-drift balance in spatially structured populations.

PubMed

Schneider, David M; Martins, Ayana B; de Aguiar, Marcus A M

2016-08-07

In finite populations the action of neutral mutations is balanced by genetic drift, leading to a stationary distribution of alleles that displays a transition between two different behaviors. For small mutation rates most individuals will carry the same allele at equilibrium, whereas for high mutation rates of the alleles will be randomly distributed with frequencies close to one half for a biallelic gene. For well-mixed haploid populations the mutation threshold is μc=1/2N, where N is the population size. In this paper we study how spatial structure affects this mutation threshold. Specifically, we study the stationary allele distribution for populations placed on regular networks where connected nodes represent potential mating partners. We show that the mutation threshold is sensitive to spatial structure only if the number of potential mates is very small. In this limit, the mutation threshold decreases substantially, increasing the diversity of the population at considerably low mutation rates. Defining kc as the degree of the network for which the mutation threshold drops to half of its value in well-mixed populations we show that kc grows slowly as a function of the population size, following a power law. Our calculations and simulations are based on the Moran model and on a mapping between the Moran model with mutations and the voter model with opinion makers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hereditary cancer genes are highly susceptible to splicing mutations

PubMed Central

Soemedi, Rachel; Maguire, Samantha; Murray, Michael F.; Monaghan, Sean F.

2018-01-01

Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5′ and 3′ splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID:29505604

Two extraordinarily severe cases of Treacher Collins syndrome.

PubMed

Bauer, Mislen; Saldarriaga, Wilmar; Wolfe, S Anthony; Beckwith, J Bruce; Frias, Jaime L; Cohen, M Michael

2013-03-01

Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well-known variability in the expression in affected families with Treacher Collins syndrome (∼40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (∼60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [2008] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past. Copyright © 2013 Wiley Periodicals, Inc.