Improve survival prediction using principal components of gene expression data

The purpose of many microarray studies is to find the association between gene expression and sample characteristics such as treatment type or sample phenotype. There has been a surge of efforts developing different methods for delineating the association. Aside from the high dimensionality of microarray data, one well recognized challenge is the fact that genes could be complicatedly inter-related, thus making many statistical methods inappropriate to use directly on the expression data. Multivariate methods such as principal component analysis （PCA） and clustering are often used as a part of the effort to capture the gene correlation, and the derived components or clusters are used to describe the association between gene expression and sample phenotype. We propose a method for patient population dichotomization using maximally selected test statistics in combination with the PCA method, which shows favorable results. The proposed method is compared with a currently well-recognized method.     

Reconstruction of Gene Regulatory Networks Based on Two-Stage Bayesian Network Structure Learning Algorithm

In the post-genomic biology era,the reconstruction of gene regulatory networks from microarray gene expression data isvery important to understand the underlying biological system,and it has been a challenging task in bioinformatics.TheBayesian network model has been used in reconstructing the gene regulatory network for its advantages,but how to determinethe network structure and parameters is still important to be explored.This paper proposes a two-stage structure learning algorithmwhich integrates immune evolution algorithm to build a Bayesian network.The new algorithm is evaluated with the use ofboth simulated and yeast cell cycle data.The experimental results indicate that the proposed algorithm can find many of theknown real regulatory relationships from literature and predict the others unknown with high validity and accuracy.     

GWAS 2011: Opportunities and challenges

The wide adoption of genome-wide association study (GWAS) has dramatically changed the landscape of the genetic studies of human diseases.Banking on the study design that employs large and multiple-independent samples,linkage disequilibrium (LD) -based systematic genome-wide interrogation,and vigorous statistical standard for declaring genetic association,GWAS has greatly advanced the genetic studies of human disease by successfully identifying over 4 thousands of genetic susceptibility SNPs or loci for 210 diseases/traits in human.Besides its unrivaled scientific achievements,GWAS has also transformed the communities of human genetics by stimulating unprecedented broad and large-scale collaboration and data sharing across different groups and countries,which has enabled some mega genetic studies where dozens or hundreds of thousands of samples were investigated through mete-analysis,providing enormous statistical power for discovering genetic variants,even the ones with very moderate effect on disease phenotype or physiological trait.While the success of GWAS has been widely recognized,there are many concerns on GWAS that are being passionately debated.In particular,there ate heated discussions on why only a limited proportion,quiet often a small proportion,of genetic heritability can be explained by the GWAS findings,and whether and how the GWAS findings have really advanced the biological investigation and understanding of disease mechanisms.Concerning these shortcomings of GWAS,many have genuinely questioned the perspective of translating the GWAS findings into clinical practice.To provide a platform to discuss the progresses and shortcomings of GWAS,a nature conference,titled “GWAS 2011:Opportunities and Challenges”,was organized through the collaboration between the Nature Genetics and Anhui Medical University,which was held in Hefei,China on May 19-21,2011.     

A platform to standardize,store, and visualize proteomics experimental data

With the development of functional genomics research, large-scale proteomics studies are now widespread, presenting significant challenges for data storage, exchange, and analysis. Here we present the Integrated Proteomics Exploring Database （IPED） as a platform for managing proteomics experimental data （both process and result data）. IPED is based on the schema of the Proteome Experimental Data Repository （PEDRo）, and complies with the General Proteomics Standard （GPS） drafted by the Proteomics Standards Committee of the Human Proteome Organization. In our work, we developed three components for the IPED platform： the IPED client editor, IPED server software, and IPED web interface. The client editor collects experimental data and generates an extensible markup language （XML） data file compliant with PEDRo and GPS; the server software parses the XML data file and loads information into a core database; and the web interface displays experimental results, to provide a convenient graphic representation of data. Given software convenience and data abundance, IPED is a powerful platform for data exchange and presents an important resource for the proteomics community. In its current release, IPED is available at http：//www. biosino.org/iped2.     

Incorporating functional annotation information in prioritizing disease associated SNPs from genome wide association studies

With recent advances in genotyping and sequencing technologies,many disease susceptibility loci have been identified.However,much of the genetic heritability remains unexplained and the replication rate between independent studies is still low.Meanwhile,there have been increasing efforts on functional annotations of the entire human genome,such as the Encyclopedia of DNA Elements(ENCODE)project and other similar projects.It has been shown that incorporating these functional annotations to prioritize genome wide association signals may help identify true association signals.However,to our knowledge,the extent of the improvement when functional annotation data are considered has not been studied in the literature.In this article,we propose a statistical framework to estimate the improvement in replication rate with annotation data,and apply it to Crohn’s disease and DNase I hypersensitive sites.The results show that with cell line specific functional annotations,the expected replication rate is improved,but only at modest level.     

QTL Scanning for Rice Yield Using a Whole Genome SNP Array

High-throughput SNP genotyping is widely used for plant genetic studies. Recently, a RICE6K SNP array has been developed based on the Illumina Bead Array platform and Infinium SNP assay technology for genome-wide evaluation of allelic variations and breeding applications. In this study, the RICE6K SNP array was used to genotype a recombinant inbred line （RIL） population derived from the cross between the indica variety, Zhenshan 97, and the japonica variety, Xizang 2. A total of 3324 SNP markers of high quality were identified and were grouped into 1495 recombination bins in the RIL population. A high-density linkage map, consisting of the 1495 bins, was developed, covering 1591.2 cM and with average length ofl.1 cM per bin. Segregation distortions were observed in 24 regions of the 11 chromosomes in the RILs. One half of the distorted regions contained fertility genes that had been previously reported. A total of 23 QTLs were identified for yield. Seven QTLs were firstly detected in this study. The positive alleles from about half of the identified QTLs came from Zhenshan 97 and they had lower phenotypic values than Xizang 2. This indicated that favorable alleles for breeding were dispersed in both parents and pyramiding favorable alleles could develop elite lines. The size of the mapping population for QTL analysis using high throughput SNP genotyping platform is also discussed.     

The Long Road to Understanding the Baculovirus PIO Protein

The baculovirus P 10 protein has always represented a mystery in the field of insect virology. Like the baculovirus polyhedrin protein it is expressed at high levels very late in infection. Homologues of the Autographa californica nucleopolyhedrovirus p10 gene are conserved in all Alphabaculoviruses and in other viruses of lepidopteran hosts yet is completely dispensable for virus replication and transmission. PIO is a microtubule interacting protein whose expression has been associated with the formation of a variety of complex and extensive cytoplasmic and nuclear structures. PIO has been associated with a number of roles during infection ranging from the formation of virus occlusion bodies, to affecting the rate of cellular and/or nuclear lysis during the final stages of the virus replication cycle. In this article we review recent work aimed at understanding the role of this enigmatic protein, putting them into context with recent advances in understanding of protein structure and function. We look back at a number of historical studies and observations, reanalysing their conclusions based on recent data and our own observations. The role of the P 10 protein during baculovirus replication remains elusive, however, novel avenues of investigation have been identified that will, we are sure, eventually lead to an understanding of this protein.     

A functional approach toward xerogel immobilization for encapsulation biocompatibility of Rhizobium toward biosensor

Sol-gel derived silica has tremendous applications as a biocompatible scaffold for the immobilization of cells. The use of xerogel as a matrix in the blueprint of biosensors is an appealing proposition due to several inimitable characteristics of xerogels, primarily because of their high porous nature, amendable pore size, and exceptionally large internal surface area. Morphological （X-Ray Diffraction and Thermogravimmetric Analysis） and optical （Fourier Transform Infrared and UV-Vis absorption） studies of the silica matrices with entrapped Rhizobial （Rz） structure of the biomaterial has been made. Temporal and concentration dependent studies were conducted for impregnated samples; it showed that the response time for the new biosensor for determining the concentration of Rz is less than 20 min. In this work, first time a novel avenue to create a generic approach for the fabrication of biosensor has been created.     

Genome editing in Bombyx mori: New opportunities for silkworm functional genomics and the sericulture industry

In recent years, research in life sciences has been remarkably revolutionized owing to the establishment, development and application of genome editing technologies. Genome editing has not only accelerated fundamental research but has also shown promising applications in agricultural breeding and therapy. In particular, the clustered, regularly interspaced, short palindromic repeat (CRISPR) technology has become an indispensable tool in molecular biology owing to its high efficacy and simplicity. Genome editing tools have also been established in silkworm (Bombyx mori), a model organism of Lepidoptera insects with high economic importance. This has remarkably improved the level and scope of silkworm research and could reveal new mechanisms or targets in basic entomology and pest management studies. In this review, we summarize the progress and potential of genome editing in silkworm and its applications in functional genomic studies for generating novel genetic materials.     

Identifying G-protein coupled receptors using weighted Levenshtein distance and the nearest neighbor method

G-protein coupled receptors （GPCRs） are a class of seven-helix transmembrane proteins that have been used in bioinformatics as the targets to facilitate drug discovery for human diseases. Although thousands of GPCR sequences have been collected, the ligand specificity of many GPCRs is still unknown and only one crystal structure of the rhodopsin-like family has been solved. Therefore, identifying GPCR types only from sequence data has become an important research issue. In this study, a novel technique for identifying GPCR types based on the weighted Levenshtein distance between two receptor sequences and the nearest neighbor method （NNM） is introduced, which can deal with receptor sequences with different lengths directly. In our experiments for classifying four classes （acetylcholine, adrenoceptor, dopamine, and serotonin） of the rhodopsin-like family of GPCRs, the error rates from the leave-one-out procedure and the leave-half-out procedure were 0.62% and 1.24%, respectively. These results are prior to those of the covariant discriminant algorithm, the support vector machine method, and the NNM with Euclidean distance.     

The Triassic platform of the Gador-Turon unit (Alpujarride complex, Betic Cordillera, southeast Spain): climate versus tectonic factors controlling platform architecture

A litho-biostratigraphic analysis has been carried out in the Gador-Turon unit of the Sierra de Gador (Alpujarride complex, Betic Cordillera, SE Spain). The Triassic succession of this unit is composed of a lower meta-detrital formation overlain by an upper meta-carbonate formation divided in six members. In the latter, a Ladinian–Carnian-rich fossil association has been found (foraminifers, algae, bivalves, microproblematica, trace fossils). Facies analysis has enabled the recognition of 22 facies of platform origin. This succession accumulated as a subsiding margin-type carbonate platform with homoclinal ramp geometry (Anisian?–Ladinian) evolving into a fault-block-type platform with a steeper-margined geometry (Ladinian–Carnian). Slope deposits of this latter platform show a prism-like geometry with progradational patterns and include syn-sedimentary structures associated with normal faults capped by younger beds. The results of the present research indicate that the architecture of the platform studied has been controlled mainly by climate and oceanic factors during the development of the ramp, and by syn-sedimentary extensional tectonics during the development of the steeper-margined platform. The Ladinian–Carnian tectonic activity was probably also responsible for the siliciclastic input and the shift to a mixed terrigenous-carbonate platform.     

Depositional environment and constraining factors on the facies architecture of the Qom Formation,Central Basin,Iran

In the Central Iran Basin, the mixed carbonate–siliciclastic deposits of the C member of the Qom Formation were deposited on a carbonate platform which is dominated by rhodalgal associations occurring in tropical–subtropical environment. The biogenic rhodalgal association is dominated by bryozoa, coralline red algae, bivalves and echinoids together with smaller amounts of photo-dependent biota including large benthic foraminifera and corals. The abundance of heterozoan association and the bloom of suspension-feeding organisms are the result of an increase in nutrient availability which has profound controlling effect on the biotic system. The low occurrence of symbiont-bearing benthic foraminifera and coral, typical of stable, oligotrophic condition, represents their low tolerance to unstable, nutrient-rich environment. In the investigated Oligocene–Miocene shallow marine carbonate succession, 10 different microfacies were distinguished through depositional texture and biotic components. The rock sequences investigated are referred to an open shelf carbonate platform in which the depositional environments range from outer shelf to inner shelf conditions.     

Storing,linking, and mining microarray databases using SRS

Background  

SRS (Sequence Retrieval System) has proven to be a valuable platform for storing, linking, and querying biological databases. Due to the availability of a broad range of different scientific databases in SRS, it has become a useful platform to incorporate and mine microarray data to facilitate the analyses of biological questions and non-hypothesis driven quests. Here we report various solutions and tools for integrating and mining annotated expression data in SRS.     

Whole genome genotyping technologies on the BeadArray platform

The ability to simultaneously genotype hundreds of thousands of single-nucleotide polymorphisms (SNPs) in a single assay has recently become feasible due to innovative combinations of assay and array platform multiplexing. In this review, we describe the development of the Infinium whole genome genotyping technology and the BeadArray platform. We discuss the automated use and performance of a series of genotyping BeadChips, including data quality, technology scalability, and flexibility in designing array content. We describe high-density tag SNP-based Bead-Chips and various multi-sample BeadChip configurations with their respective applications. These technologies are enabling large-scale whole genome association studies that have the potential to revolutionize our ability to detect common genetic variants with a significant role in identifying disease-associated loci, proteins, biomarkers, and pharmacogenomic responses.     

Down syndrome, water fluoridation, and maternal age

It has been claimed that there is a positive association between the frequency of Down syndrome and the fluoridation of drinking water. It has also been suggested that this association is most pronounced in young women. Recent congenital malformations data obtained from birth certificates from large U.S. cities have been analyzed. Some cities had fluoridated water supplies, while others had supplies deficient in fluoride. The rates of Down syndrome in the cities with fluoridated and in those with non-fluoridated water supplies were comparable. In addition, there was no indication of any maternal age-specific association.     

High-throughput genotyping of single nucleotide polymorphisms using new biplex invader technology

The feasibility of large-scale genome-wide association studies of complex human disorders depends on the availability of accurate and efficient genotyping methods for single nucleotide polymorphisms (SNPs). We describe a new platform of the invader assay, a biplex assay, where both alleles are interrogated in a single reaction tube. The assay was evaluated on over 50 different SNPs, with over 20 SNPs genotyped in study cohorts of over 1500 individuals. We assessed the usefulness of the new platform in high-throughput genotyping and compared its accuracy to genotyping results obtained by the traditional monoplex invader assay, TaqMan genotyping and sequencing data. We present representative data for two SNPs in different genes (CD36 and protein tyrosine phosphatase 1β) from a study cohort comprising over 1500 individuals with high or low-normal blood pressure. In this high-throughput application, the biplex invader assay is very accurate, with an error rate of <0.3% and a failure rate of 1.64%. The set-up of the assay is highly automated, facilitating the processing of large numbers of samples simultaneously. We present new analysis tools for the assignment of genotypes that further improve genotyping success. The biplex invader assay with its automated set-up and analysis offers a new efficient high-throughput genotyping platform that is suitable for association studies in large study cohorts.     

Evaluation of methods for detecting conversion events in gene clusters

Background

Several platforms for the analysis of genome-wide association data are available. However, these platforms focus on the evaluation of the genotype inherited by affected (i.e. case) individuals, whereas for some conditions (e.g. birth defects) the genotype of the mothers of affected individuals may also contribute to risk. For such conditions, it is critical to evaluate associations with both the maternal and the inherited (i.e. case) genotype. When genotype data are available for case-parent triads, a likelihood-based approach using log-linear modeling can be used to assess both the maternal and inherited genotypes. However, available software packages for log-linear analyses are not well suited to the analysis of typical genome-wide association data (e.g. including missing data).

Results

An integrated platform, Maternal and Inherited Analyses for Genome-wide Association Studies (MI-GWAS) for log-linear analyses of maternal and inherited genetic effects in large, genome-wide datasets, is described. MI-GWAS uses SAS and LEM software in combination to appropriately format data, perform the log-linear analyses and summarize the results. This platform was evaluated using existing genome-wide data and was shown to perform accurately and relatively efficiently.

Conclusions

The MI-GWAS platform provides a valuable tool for the analysis of association of a phenotype or condition with maternal and inherited genotypes using genome-wide data from case-parent triads. The source code for this platform is freely available at http://www.sph.uth.tmc.edu/sbrr/mi-gwas.htm.     

New dasycladalean algae from the Middle Norian (Upper Triassic) of northern Italy (Mt. Pramaggiore, Carnic Prealps)

In the Eastern Southern Alps of northern Italy (Carnic Prealps, Friuli region), the shallow-water carbonate platform deposits of the Dolomia Principale Fm. (Norian–Rhaetian, Upper Triassic) show best-preserved platform to basin facies transition. The palaeontological study of an algal-rich level recovered from the platform margin facies (Mt. Pramaggiore) has displayed a very interesting association of Dasycladales. Two new genera (Bystrickyella and Elliottporella) and four new species (Bystrickyella ottii, Elliottporella morelloae, Palaeodasycladus lorigae and Holosporella conradii) have been described. These new data suggest that the Norian represents a period of turnover in the evolutionary history of the green algae community. This stage, placed between two extinctions, end-Ladinian and end-Norian, is here interpreted as a re-organization period of the evolutionary schemes of Dasycladales. The new lineages originated in the Norian developed further and characterized the Early Jurassic scenery. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Reverse-Phase Protein Array: Technology,Application, Data Processing,and Integration

Reverse-phase protein array (RPPA) is a high-throughput antibody-based targeted proteomics platform that can quantify hundreds of proteins in thousands of samples derived from tissue or cell lysates, serum, plasma, or other body fluids. Protein samples are robotically arrayed as microspots on nitrocellulose-coated glass slides. Each slide is probed with a specific antibody that can detect levels of total protein expression or post-translational modifications, such as phosphorylation as a measure of protein activity. Here we describe workflow protocols and software tools that we have developed and optimized for RPPA in a core facility setting that includes sample preparation, microarray mapping and printing of protein samples, antibody labeling, slide scanning, image analysis, data normalization and quality control, data reporting, statistical analysis, and management of data. Our RPPA platform currently analyzes ∼240 validated antibodies that primarily detect proteins in signaling pathways and cellular processes that are important in cancer biology. This is a robust technology that has proven to be of value for both validation and discovery proteomic research and integration with other omics data sets.     

Paleocene reefs on the Maiella Platform Margin, Italy: An example of the effects of the cretaceous/tertiary boundary events on reefs and carbonate platforms

Summary Reef facies, reef types and their biotic associations in the Maiella platform margin (central Italy) provide qualitative evidence for a significant reef decline across the Cretaceous/Tertiary (K/T) boundary, and indicate two phases of reef recovery during the Paleocene. Rudists dominated the reef community until the latest Cretaceous. A significant sea-level fall around the time of the K/T boundary is documented by a truncation surface associated with emersion. During sea-level highstands in the Danian to Early Thanetian and, more extensively, during the Late Thanetian, coral-algal patch-reefs grew along the platform margin and top. Already in the Danian to Early Thanetian, the reef communities were more diverse and the constructional types more evolved than previously known from this time. Differences between the Danian to Early Thanetian coral association, the Late Thanetian association, and Late Cretaceous coral faunas may have ecological or evolutionary causes. Repeated emergence produced a complex diagenetic history in the Danian to Lower Thanetian limestones. All Paleocene reefs were displaced by gravitative redeposition. Coral-algal reefs are less important in the Early to mid Eocene, when alveolinid foraminifera dominated on the Maiella shelf. Reefs on the Maiella platform diversified and attained large sizes in the Late Eocene to Early Oligocene, as known from other Mediterranean platforms. The external controls on the Late Cretaceous to Oligocene evolution and demise of reef communities that are most easily demonstrated with our data are sealevel fluctuations and climate change. We propose that the change in reef biota and reef types across the K/T boundary and during the Early Tertiary were important causes of the parallel changes in platform growth style.