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PubMed2004

Bioinformatics strategies for translating genome-wide expression analyses into clinically useful cancer markers.

The DNA microarray has revolutionized cancer research. Now, scientists can obtain a genome-wide perspective of cancer gene expression. One potential application of this technology is the discovery of novel cancer biomarkers for more accurate diagnosis and prognosis, and potentially for the earlier detection of disease or the monitoring of treatment effectiveness. Because microarray experiments generate a tremendous amount of data and because the number of laboratories generating microarray data is rapidly growing, new bioinformatics strategies that promote the maximum utilization of such data are necessary. Here, we describe a method to validate multiple microarray data sets, a Web-based cancer microarray database for biomarker discovery, and methods for integrating gene ontology annotations with microarray data to improve candidate biomarker selection.

Biomarkers, Tumor↗
PubMed2006

Statistical, computational and visualization methodologies to unveil gene primary structure features.

OBJECTIVES: Gene sequence features such as codon bias, codon context, and codon expansion (e.g. trinucleotide repeats) can be better understood at the genomic scale level by combining statistical methodologies with advanced computer algorithms and data visualization through sophisticated graphical interfaces. This paper presents the ANACONDA system, a bioinformatics application for gene primary structure analysis. METHODS: Codon usage tables using absolute metrics and software for multivariate analysis of codon and amino acid usage are available in public databases. However, they do not provide easy computational and statistical tools to carry out detailed gene primary structure analysis on a genomic scale. We propose the usage of several statistical methods--contingency table analysis, residual analysis, multivariate analysis (cluster analysis)--to analyze the codon bias under various aspects (degree of association, contexts and clustering). RESULTS: The developed solution is a software application that provides a user-guided analysis of codon sequences considering several contexts and codon usage on a genomic scale. The utilization of this tool in our molecular biology laboratory is focused on particular genomes, especially those from Saccharomyces cerevisiae, Candida albicans and Escherichia coli. In order to illustrate the applicability and output layouts of the software these species are herein used as examples. CONCLUSIONS: The statistical tools incorporated in the system are allowing to obtain global views of important sequence features. It is expected that the results obtained will permit identification of general rules that govern codon context and codon usage in any genome. Additionally, identification of genes containing expanded codons that arise as a consequence of erroneous DNA replication events will permit uncovering new genes associated with human disease.

Algorithms↗
PubMed2006

The identification of novel ovarian proteases through the use of genomic and bioinformatic methodologies.

Proteolytic activities are essential for follicular growth, ovulation, as well as for luteal formation and regression. Using suppression subtractive hybridization (SSH), a novel mouse ovary-selective gene (termed protease serine 35, Prss35) was identified. Analysis of the mouse genome database using the Prss35 sequence led to the identification of a homologous protease (protease serine 23, Prss23). PRSS35 possesses general features that are characteristic of serine (Ser) proteases, but is unique in that the canonical Ser that defines this enzyme family is replaced by a threonine (Thr). In contrast, PRSS23 possesses the standard catalytic Ser typical for this family of proteases. As determined by real-time polymerase chain reaction (PCR), the Prss35 mRNA levels increased around the time of ovulation and remained elevated in the developing corpus luteum. Steroid ablation/replacement studies demonstrated progesterone-dependent regulation of Prss35 gene expression prior to follicle rupture. Prss35 gene expression was localized to the theca cells of pre-antral follicles, the theca and granulosa cells of pre-ovulatory and ovulatory follicles, as well as to the developing corpus luteum. In contrast, Prss23 mRNA levels decreased transiently after ovulation induction and again in the postovulatory period. Prss23 gene expression was noted primarily in the granulosa cells of the secondary/early antral follicles. PRSS35 and PRSS23 orthologs in the rat, human, rhesus macaque, chimpanzee, cattle, dog, and chicken were identified and found to be highly homologous to one another (75-99% homology). Collectively, these results suggest that the PRSS35 and PRSS23 genes have been conserved as critical ovarian proteases throughout the course of vertebrate evolution.

Amino Acid Sequence↗
PubMed2000

Cloning of Human Myelin Protein Zero-like Genes by Bioinformatics Strategy.

To clone novel myelin protein related genes, two human ESTs, which shared significant similarity with the human myelin protein zero gene, were found by the comparison of homologue between the cDNA coding region sequences of MPZ gene and the EST database of NCBI. An 801 bp EST contig was assembled, which was 100% identical with a 128 kb genomic sequence, mapped to 1q24. A 435 bp open reading frame (ORF) within the 801 bp contig was shown by computer analysis. Two primers designed according to the sequence of the contig, were coupled with the primers(lambdagt10-5 and gt10-5) on the sequences flanking cloning site of the cDNA library vector to amplify the cDNA library sequences by nested PCR. New primers, designed based on novel cDNA sequences, were used for the PCR amplification with lambdagt10-5 and gt10-5 in the same way as above. Finally, the human myelin protein zero like gene isoform I and II (MPZL1a, MPZL1b GenBank AF095727, AF092424) were cloned. Comparison of gene and protein structures between MPZL1 and MPZ revealed that MPZL1 is the second member of MPZ family. Mutation analysis of MPZL1 gene was performed in 24 Charcot-Marie-Tooth disease (CMT) families and 26 nonsyndrome deafness families, but no mutation was found.

Journal Article↗
PubMed2006

Mining ORESTES no-match database: can we still contribute to cancer transcriptome?

The Human Cancer Genome Project generated about 1 million expressed sequence tags by the ORESTES method, principally with the aim of obtaining data from cancer. Of this total, 341,680 showed no similarity with sequences in the public transcript databases, referred to as "no-match". Some of them represent low abundance or difficult to detect human transcripts, but part of these sequences represent genomic contamination or immature mRNA. We performed a bioinformatics pipeline to determine the novelty of ORESTES "no-match" datasets from prostate or breast tissues. We started with 14,908 clusters mapped on the human genome. A total of 2226 clusters originating from more than two libraries or singletons with gaps upon genome alignment were selected. Ninety-four clusters with canonical splice sites representing the most stringent criteria to be considered a gene were subjected to manual inspection regarding genomic hits. Of the manually inspected clusters, 49.6% contained new sequences where 42.2% were probable low-expression alternative forms of the characterized genes and 7.4% unpredicted genes. RT-PCR followed by sequencing was performed to validate the largest spliced sequence from 8 clusters, resulting in the confirmation of five sequences as true human transcript fragments. Some of them were differentially expressed between tumor and normal tissue by an in silico analysis. We can conclude that after clean up of the no-match dataset, we still have about 939 new exons and 165 unpredicted genes that could complete the prostate or breast transcriptome.

Breast Neoplasms↗
PubMed2005

Osteo-Promoter Database (OPD) -- promoter analysis in skeletal cells.

BACKGROUND: Increasing our knowledge about the complex expression of genes in skeletal tissue will provide a better understanding of the physiology of skeletal cells. The study summarizes transcriptional regulation factors interacting and cooperating at promoter regions that regulate gene expression. Specifically, we analyzed A/T rich elements along the promoter sequences. DESCRIPTION: The Osteo-Promoter Database (OPD) is a collection of genes and promoters expressed in skeletal cells. We have compiled a new viewer, OPD, as unique database developed and created as an accessible tool for skeletal promoter sequences. OPD can navigate to identify genes specific to skeletal cDNA databases and promoter analysis sites. OPD offers exclusive access to facilitate a dynamic extraction of promoters' gene-specific analyses in skeletal tissue. The data on promoters included in OPD contains cloned promoters or predicted promoters that were analyzed by bioinformatics tools. OPD offers MAR-analysis, which allocates A/T rich elements along these promoter sequences. CONCLUSION: The analysis leads to a better insight of proteins that bind to DNA, regulate DNA, and function in chromatin remodeling. The OPD is a distinctive tool for understanding the complex function of chromatin remodeling and transcriptional regulation of specific gene expression in skeletal tissue.

Bone and Bones↗
PubMed2005

Molecular cloning and primary functional analysis of a novel human testis-specific gene.

In this study, a new data mining tool called Digital Differential Display (DDD) from the NCBI was used to predict testis-specific expressed genes from the expressed sequence tag (EST) database. DDD (digital differential display) was performed between nine testis libraries and seventy libraries derived from other tissues. We identified a new contig of ESTs (HS. 326528) which was from testis libraries. To validate the use of bioinformatic approaches in gene discovery, the ESTs (HS. 326528), which were predicted to be testis-specific, were chosen for further study. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis of matched sets of cDNAs from testis and other tissues indicated that the ESTs were specifically expressed in testis. This result was further validated by multi-tissue Northern blot. The full-length cDNA encompassing the entire open reading frame was cloned and, in view of its apparent specificity to testis, the gene was termed homo sapiens spermatogenesis-related gene 8---SRG8 (GenBank accession number: AY489187). The gene whose full cDNA length is 1 044 bp containing 3 exons and 2 introns is located in human chromosome 15q26.2, the cDNA encodes a novel protein of 105 amino acides with a theoretical molecular weight of 11.7 kD and isoelectric point of 10.09 which shares no significant homology with any known proteins in database. Real time PCR analysis of testis of different developmental periods revealed that SRG8 gene is significantly expressed in adult testis. The green fluorescent protein produced by pEGFP-C3/SRG8 was detected in the nucleus of HeLa cells after 24 h post-transfection. Cell cycle analysis showed that SRG8 can accelerate HeLa cells to traverse the S-phase and enter the G2-phase compared with the control without transfection of SRG8, which suggested that this gene plays an important role in the development of testis. The discovery of SRG8 showed that DDD combined with experiments is a feasible, time-saving strategy to identify new candidate genes for testis-specific development

Adult↗
PubMed2006

Structural bioinformatics of DNA: a web-based tool for the analysis of molecular dynamics results and structure prediction.

UNLABELLED: We report here the release of a web-based tool (MDDNA) to study and model the fine structural details of DNA on the basis of data extracted from a set of molecular dynamics (MD) trajectories of DNA sequences involving all the unique tetranucleotides. The dynamic web interface can be employed to analyze the first neighbor sequence context effects on the 10 unique dinucleotide steps of DNA. Functionality is included to build all atom models of any user-defined sequence based on the MD results. The backend of this interface is a relational database storing the conformational details of DNA obtained in 39 different MD simulation trajectories comprising all the 136 unique tetranucleotide steps. Examples of the use of this data to predict DNA structures are included. AVAILABILITY: http://humphry.chem.wesleyan.edu:8080/MDDNA. SUPPLEMENTARY INFORMATION: Supplementary data including color figures are available at Bioinformatics online.

Base Sequence↗
PubMed2005

Novel biological networks modulated by complement.

The almost complete deciphering of the human genome has paved the way for the application of new technology platforms in understanding the contribution of complex biological pathways to human pathophysiology and disease. In the post-genomic era, the concept of systems biology has gained significant momentum and biomedical research is now being conducted on an integrated and cross-disciplinary platform that pulls together its resources from diverse fields such as computational biology, bioinformatics, functional genomics, structural biology, and proteomics. In this perspective, the identity of established biologic systems is being re-examined in the light of novel findings that suggest novel associations between otherwise unrelated pathways and individual proteins. Complement exemplifies such a system that, transcending its innate immune identity, has forged functional associations with multiple pathways and networks in modulating basic biologic processes. In the present article, we provide a global overview of these unusual system associations of complement with the aid of a powerful and high-throughput bioinformatics platform. Using a novel approach called systems literature analysis that allows the rapid extraction of text-based associations between genes and pathways from the ever expanding scientific article database, we have selected a broad range of biologic processes modulated by complement proteins and have constructed an integrated map of complement-mediated networks that incorporates well over 85 diverse biologic pathways. Expanding the complement cascade beyond its approximately 35 designated components, we discuss protein-protein interactions involving novel ligands and associations with signaling cascades and cellular networks that affect both inflammatory and non-inflammatory processes. This integrated consideration of complement within a unified 'systems biology' framework underscores the concept that innate immunity goes well beyond the protection of 'self' extending links to critical developmental, homeostatic, and metabolic processes.

Complement System Proteins↗
PubMed2006

Kinetoplastid PPEF phosphatases: dual acylated proteins expressed in the endomembrane system of Leishmania.

Bioinformatic analyses have been used to identify potential downstream targets of the essential enzyme N-myristoyl transferase in the TriTryp species, Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. These database searches predict approximately 60 putative N-myristoylated proteins with high confidence, including both previously characterised and novel molecules. One of the latter is an N-myristoylated protein phosphatase which has high sequence similarity to the Protein Phosphatase with EF-Hand (PPEF) proteins identified in sensory cells of higher eukaryotes. In L. major and T. brucei, the PPEF-like phosphatases are encoded by single-copy genes and are constitutively expressed in all parasite life cycle stages. The N-terminus of LmPPEF is a substrate for N-myristoyl transferase and is also palmitoylated in vivo. The wild type protein has been localised to the endocytic system by immunofluorescence. The catalytic and fused C-terminal domains of the kinetoplastid and other eukaryotic PPEFs share high sequence similarity, but unlike their higher eukaryotic relatives, the C-terminal parasite EF-hand domains are degenerate and do not bind calcium.

Acyltransferases↗
PubMed2005

Design issues in toxicogenomics using DNA microarray experiment.

The methods of toxicogenomics might be classified into omics study (e.g., genomics, proteomics, and metabolomics) and population study focusing on risk assessment and gene-environment interaction. In omics study, microarray is the most popular approach. Genes falling into several categories (e.g., xenobiotics metabolism, cell cycle control, DNA repair etc.) can be selected up to 20,000 according to a priori hypothesis. The appropriate type of samples and species should be selected in advance. Multiple doses and varied exposure durations are suggested to identify those genes clearly linked to toxic response. Microarray experiments can be affected by numerous nuisance variables including experimental designs, sample extraction, type of scanners, etc. The number of slides might be determined from the magnitude and variance of expression change, false-positive rate, and desired power. Instead, pooling samples is an alternative. Online databases on chemicals with known exposure-disease outcomes and genetic information can aid the interpretation of the normalized results. Gene function can be inferred from microarray data analyzed by bioinformatics methods such as cluster analysis. The population study often adopts hospital-based or nested case-control design. Biases in subject selection and exposure assessment should be minimized, and confounding bias should also be controlled for in stratified or multiple regression analysis. Optimal sample sizes are dependent on the statistical test for gene-to-environment or gene-to-gene interaction. The design issues addressed in this mini-review are crucial in conducting toxicogenomics study. In addition, integrative approach of exposure assessment, epidemiology, and clinical trial is required.

Computational Biology↗
PubMed2006

Piecing together a ciliome.

Cilia are slender microtubule-based appendages that emanate from the surfaces of a large proportion of eukaryotic cells. The motile and non-motile forms of cilia represent bona fide organelles comprising distinct repertoires of proteins that serve specific roles in locomotion or fluid movement, and sense chemical or physical extracellular cues. Owing in part to the growing number of genes associated with ciliary disorders, such as polycystic kidney disease and Bardet-Biedl syndrome, there has been a recent profusion of studies aimed at unveiling the protein makeup of cilia. The approaches used are complementary, involving several different organisms and spanning the fields of bioinformatics, genomics and proteomics. Here we review these studies and assess the various data sets to help define a comprehensive ciliary proteome, or 'ciliome'. We have compiled a cilia protein database that includes known cilia-associated proteins and numerous putative ciliary proteins including RAB-like small GTPases, which might be implicated in vesicular trafficking, and the microtubule-binding protein MIP-T3, some of which might be associated with ciliopathies.

Animals↗
PubMed2025

Investigating the miRNA-mRNA interactome of human trabecular meshwork cells treated with TGF-β1 provides insights into the pathogenesis of pseudoexfoliation glaucoma.

Pseudoexfoliation glaucoma is a severe form of secondary open angle glaucoma and is associated with activation of the TGF-β pathway by TGF-β1. MicroRNAs (miRNAs) are small non-coding RNA species that are involved in regulation of mRNA expression and translation. To investigate what glaucomatous changes occur in the trabecular meshwork and how these changes may be regulated by miRNAs, we performed a bioinformatics analysis resulting in a miRNA-mRNA interactome. Primary human trabecular meshwork cells originating from normal donors were treated with TGF-β1 at 5 ng/mL for 24h; total RNA was extracted followed by RNA-Seq and miRNA-Seq. For both mRNA and miRNA species, differential expression was determined using a bioinformatics pipeline consisting of FastQC, STAR, FeatureCounts, edgeR (for miRNA) and DESeq2 (for mRNA). Putative mRNA-miRNA interactions between differentially expressed mRNA and miRNA species were determined using interaction databases miRWalk, miRTarBase, TarBase and TargetScan. To classify mRNA species by function and pathway, gene enrichment was performed using Enrichr. The resulting miRNA-mRNA interactome consisted of 1202 interactions. Some highly connected microRNAs were hsa-let-7e-5p, hsa-miR-20a-5p, hsa-miR-122-5p, and hsa-miR-29c-3p. Most differentially expressed genes were indicated to be regulated by miRNAs. The sub-interactomes of genes involved in specific pseudoexfoliation glaucoma related enrichment terms such as oxidative stress, unfolded protein response, signal molecules and ECM remodelling were determined. This is the first study to present a genome-wide microRNA-mRNA regulatory network for human trabecular meshwork cells treated with TGF-β1 and may serve to generate unbiased hypotheses about regulatory functions and mRNA targets of miRNAs in pseudoexfoliation glaucoma and may help to develop miRNA-based therapeutics.

Humans↗
PubMed2001

Bioinformatics issues for automating the annotation of genomic sequences.

The rapid explosion in the amount of biological data being generated worldwide is surpassing efforts to manage analysis of the data. As part of an ongoing project to automate and manage bioinformatics analysis, the authors have designed and implemented a simple automated annotation system, which is described in this paper. The system is applied to existing GenBank/DDBJ/EMBL entries and compared with existing annotations to illustrate not only potential errors but also that they are generally not up-to-date, as a result of new versions of analysis tools and updates of genomic repositories. We highlight the important Bioinformatics issues of storage and management of information to ensure data and results are kept up-to-date in light of new information becoming available. Surprisingly, from just four database entries, a significant number of new features were found. We describe the results as well as identify important issues that need to be addressed in order to automate the re-analysis/re-annotation of genomic sequences within a reasonable timeframe.

Computational Biology↗
PubMed2006

Constructing a semantically enriched biomedical service space: a paradigm with bioinformatics resources.

Biomedical applications are becoming increasingly reliant on resource integration and information exchange within global solution frameworks that offer seamless connectivity and data sharing in distributed environments. Resource autonomy and data heterogeneity are the most important impediments towards this potential. Aiming to overcome these limitations, we propose an implementation of the service-oriented model towards the construction of an open, semantically enriched biomedical service space that enables advanced service registration, selection and access capabilities, as well as service interoperability. The proposed system is realised by defining service annotation ontologies and applying software agent technology as the means for service registration, matchmaking and interfacing in a Grid environment. The applicability of the envisioned biomedical service space is illustrated on a set of bioinformatics resources, addressing computational identification of protein-coding genes.

Computational Biology↗
PubMed2005

Bioinformatic and enzymatic characterization of the MAPEG superfamily.

The membrane associated proteins in eicosanoid and glutathione metabolism (MAPEG) superfamily includes structurally related membrane proteins with diverse functions of widespread origin. A total of 136 proteins belonging to the MAPEG superfamily were found in database and genome screenings. The members were found in prokaryotes and eukaryotes, but not in any archaeal organism. Multiple sequence alignments and calculations of evolutionary trees revealed a clear subdivision of the eukaryotic MAPEG members, corresponding to the six families of microsomal glutathione transferases (MGST) 1, 2 and 3, leukotriene C4 synthase (LTC4), 5-lipoxygenase activating protein (FLAP), and prostaglandin E synthase. Prokaryotes contain at least two distinct potential ancestral subfamilies, of which one is unique, whereas the other most closely resembles enzymes that belong to the MGST2/FLAP/LTC4 synthase families. The insect members are most similar to MGST1/prostaglandin E synthase. With the new data available, we observe that fish enzymes are present in all six families, showing an early origin for MAPEG family differentiation. Thus, the evolutionary origins and relationships of the MAPEG superfamily can be defined, including distinct sequence patterns characteristic for each of the subfamilies. We have further investigated and functionally characterized representative gene products from Escherichia coli, Synechocystis sp., Arabidopsis thaliana and Drosophila melanogaster, and the fish liver enzyme, purified from pike (Esox lucius). Protein overexpression and enzyme activity analysis demonstrated that all proteins catalyzed the conjugation of 1-chloro-2,4-dinitrobenzene with reduced glutathione. The E. coli protein displayed glutathione transferase activity of 0.11 micromol.min(-1).mg(-1) in the membrane fraction from bacteria overexpressing the protein. Partial purification of the Synechocystis sp. protein yielded an enzyme of the expected molecular mass and an N-terminal amino acid sequence that was at least 50% pure, with a specific activity towards 1-chloro-2,4-dinitrobenzene of 11 micromol.min(-1).mg(-1). Yeast microsomes expressing the Arabidopsis enzyme showed an activity of 0.02 micromol.min(-1).mg(-1), whereas the Drosophila enzyme expressed in E. coli was highly active at 3.6 micromol.min(-1).mg(-1). The purified pike enzyme is the most active MGST described so far with a specific activity of 285 micromol.min(-1).mg(-1). Drosophila and pike enzymes also displayed glutathione peroxidase activity towards cumene hydroperoxide (0.4 and 2.2 micromol.min(-1).mg(-1), respectively). Glutathione transferase activity can thus be regarded as a common denominator for a majority of MAPEG members throughout the kingdoms of life whereas glutathione peroxidase activity occurs in representatives from the MGST1, 2 and 3 and PGES subfamilies.

Animals↗
PubMed2005

SNPHunter: a bioinformatic software for single nucleotide polymorphism data acquisition and management.

BACKGROUND: Single nucleotide polymorphisms (SNPs) provide an important tool in pinpointing susceptibility genes for complex diseases and in unveiling human molecular evolution. Selection and retrieval of an optimal SNP set from publicly available databases have emerged as the foremost bottlenecks in designing large-scale linkage disequilibrium studies, particularly in case-control settings. RESULTS: We describe the architectural structure and implementations of a novel software program, SNPHunter, which allows for both ad hoc-mode and batch-mode SNP search, automatic SNP filtering, and retrieval of SNP data, including physical position, function class, flanking sequences at user-defined lengths, and heterozygosity from NCBI dbSNP. The SNP data extracted from dbSNP via SNPHunter can be exported and saved in plain text format for further down-stream analyses. As an illustration, we applied SNPHunter for selecting SNPs for 10 major candidate genes for type 2 diabetes, including CAPN10, FABP4, IL6, NOS3, PPARG, TNF, UCP2, CRP, ESR1, and AR. CONCLUSION: SNPHunter constitutes an efficient and user-friendly tool for SNP screening, selection, and acquisition. The executable and user's manual are available at http://www.hsph.harvard.edu/ppg/software.htm

Algorithms↗