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PubMed2002

Visualization techniques for genomic data.

In order to take full advantage of the newly available public human genome sequence data and associated annotations, biologists require visualization tools that can accommodate the high frequency of alternative splicing in human genes and other complexities. In this article, we describe techniques for presenting human genomic sequence data and annotations in an interactive, graphical format, with the aim of providing developers with a guide to what features are most likely to meet biologists' needs. These techniques include: one-dimensional semantic zooming to show sequence data alongside gene structures; moveable, adjustable tiers; visual encoding of translation frame to show how alternative transcript structure affects encoded proteins; and display of protein domains in the context of genomic sequence to show how alternative splicing impacts protein structure and function.

Algorithms↗
PubMed2006

Differential expression of genes related to HFE and iron status in mouse duodenal epithelium.

Iron absorption, distribution, use, and storage are thought to be tightly regulated since altered iron stores may lead to cellular damage and disease. HFE, the hereditary hemochromatosis gene product, is expressed in the crypts of the duodenum, but the molecular mechanism by which it contributes to the inhibition of iron absorption is still unknown. In this study we aimed to identify transcriptional profiles in the duodenal epithelium of Hfe(-/-) mice. We used dedicated microarrays to compare gene expression among the duodenum of Hfe(-/-) mice, induced iron overload mice, and control mice. We found 151 differentially expressed genes and unknown sequences between Hfe(-/-) mice and normal littermates. Gene profiling revealed a gene subset more specific for Hfe inactivation. The functional annotation of upregulated genes highlighted that mucus production and cell maintenance may account for the influence of Hfe on epithelium integrity and luminal iron uptake.

Animals↗
PubMed2001

Engineering chromosomal rearrangements in mice.

The combination of gene-targeting techniques in mouse embryonic stem cells and the Cre/loxP site-specific recombination system has resulted in the emergence of chromosomal-engineering technology in mice. This advance has opened up new opportunities for modelling human diseases that are associated with chromosomal rearrangements. It has also led to the generation of visibly marked deletions and balancer chromosomes in mice, which provide essential reagents for maximizing the efficiency of large-scale mutagenesis efforts and which will accelerate the functional annotation of mammalian genomes, including the human genome.

Animals↗
PubMed2006

Phytophthora functional genomics database (PFGD): functional genomics of phytophthora-plant interactions.

The Phytophthora Functional Genomics Database (PFGD; http://www.pfgd.org), developed by the National Center for Genome Resources in collaboration with The Ohio State University-Ohio Agricultural Research and Development Center (OSU-OARDC), is a publicly accessible information resource for Phytophthora-plant interaction research. PFGD contains transcript, genomic, gene expression and functional assay data for Phytophthora infestans, which causes late blight of potato, and Phytophthora sojae, which affects soybeans. Automated analyses are performed on all sequence data, including consensus sequences derived from clustered and assembled expressed sequence tags. The PFGD search filter interface allows intuitive navigation of transcript and genomic data organized by library and derived queries using modifiers, annotation keywords or sequence names. BLAST services are provided for libraries built from the transcript and genomic sequences. Transcript data visualization tools include Quality Screening, Multiple Sequence Alignment and Features and Annotations viewers. A genomic browser that supports comparative analysis via novel dynamic functional annotation comparisons is also provided. PFGD is integrated with the Solanaceae Genomics Database (SolGD; http://www.solgd.org) to help provide insight into the mechanisms of infection and resistance, specifically as they relate to the genus Phytophthora pathogens and their plant hosts.

Algal Proteins↗
PubMed2006

The crystal structure of Rv0793, a hypothetical monooxygenase from M. tuberculosis.

Mycobacterium tuberculosis infects millions worldwide. The Structural Genomics Consortium for M. tuberculosis has targeted all genes from this bacterium in hopes of discovering and developing new therapeutic agents. Open reading frame Rv0793 from M. tuberculosis was annotated with an unknown function. The 3-dimensional structure of Rv0793 has been solved to 1.6 A resolution. Its structure is very similar to that of Streptomyces coelicolor ActVA-Orf6, a monooxygenase that participates in tailoring of polyketide antibiotics in the absence of a cofactor. It is also similar to the recently solved structure of YgiN, a quinol monooxygenase from Escherichia coli. In addition, the structure of Rv0793 is similar to several structures of other proteins with unknown function. These latter structures have been determined recently as a result of structural genomic projects for various bacterial species. In M. tuberculosis, Rv0793 and its homologs may represent a class of monooygenases acting as reactive oxygen species scavengers that are essential for evading host defenses. Since the most prevalent mode of attack by the host defense on M. tuberculosis is by reactive oxygen species and reactive nitrogen species, Rv0793 may provide a novel target to combat infection by M. tuberculosis.

Amino Acid Sequence↗
PubMed2002

Gene networks: how to put the function in genomics.

An increasingly popular model of regulation is to represent networks of genes as if they directly affect each other. Although such gene networks are phenomenological because they do not explicitly represent the proteins and metabolites that mediate cell interactions, they are a logical way of describing phenomena observed with transcription profiling, such as those that occur with popular microarray technology. The ability to create gene networks from experimental data and use them to reason about their dynamics and design principles will increase our understanding of cellular function. We propose that gene networks are also a good way to describe function unequivocally, and that they could be used for genome functional annotation. Here, we review some of the concepts and methods associated with gene networks, with emphasis on their construction based on experimental data.

Animals↗
PubMed2003

A structural perspective on genome evolution.

Protein translations of over 100 complete genomes are now available. About half of these sequences can be provided with structural annotation, thereby enabling some profound insights into protein and pathway evolution. Whereas the major domain structure families are common to all kingdoms of life, these are combined in different ways in multidomain proteins to give various domain architectures that are specific to kingdoms or individual genomes, and contribute to the diverse phenotypes observed. These data argue for more targets in structural genomics initiatives and particularly for the selection of different domain architectures to gain better insights into protein functions.

Evolution, Molecular↗
PubMed1995

[Mutagenesis study of pharmacological receptors: approach to their structure-function relationships].

Recent cDNA cloning of pharmacological receptors revealed their primary structures, and the following functional studies with those cloned receptors enabled us to discover the existence of various receptor subtypes. Each receptor has three characteristics properties: 1) ligand binding, 2) effector coupling and 3) desensitization. Delineation of precise domains of a receptors involved in these functions is now an important matter. The molecular mapping of receptors would give us not only a rationale for designing selective drugs, but also new insight about the genotype-phenotype relationships of a certain kinds of hereditary diseases caused by a mutation of receptor genes. A mutagenesis study is a powerful approach for elucidating the structure-function relationships of pharmacological receptors. In contrast to a peptide, a protein is impossible to engineer in vitro. However, modulation of a specific codon in a given cDNA could bring about a substitution of a corresponding amino acid in the protein expressed in vivo. In this article, the popular strategies for generating artificially mutated receptors are discussed. This review will focus on three types of mutant receptors: 1) point mutation, 2) chimeric and 3) truncated receptors. The annotated bibliographies will also come in handy when devising experimental protocols.

Animals↗
PubMed2003

Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation.

UNLABELLED: The genomic response to BMP was investigated by ectopic expression of activated BMP type I receptors in C2C12 myoblast using cDNA microarrays. Novel BMP receptor target genes with possible roles in inhibition of myoblast differentiation and stimulation of osteoblast differentiation were identified. INTRODUCTION: Bone morphogenetic proteins (BMPs) have an important role in controlling mesenchymal cell fate and mediate these effects by regulating gene expression. BMPs signal through three distinct specific BMP type I receptors (also termed activin receptor-like kinases) and their downstream nuclear effectors, termed Smads. The critical target genes by which activated BMP receptors mediate change cell fate are poorly characterized. MATERIALS AND METHODS: We performed transcriptional profiling of C2C12 myoblasts differentiation into osteoblast-like cells by ectopic expression of three distinct constitutively active (ca)BMP type I receptors using adenoviral gene transfer. Cells were harvested 48 h after infection, which allowed detection of both early and late response genes. Expression analysis was performed using the mouse GEM1 microarray, which is comprised of approximately 8700 unique sequences. Hybridizations were performed in duplicate with a reverse fluor labeling. Genes were considered to be significantly regulated if the p value for differential expression was less than 0.01 and inverted expression ratios per duplicate successful reciprocal hybridizations differed by less than 25%. RESULTS AND CONCLUSIONS: Each of the three caBMP type I receptors stimulated equal levels of R-Smad phosphorylation and alkaline phosphatase activity, an early marker for osteoblast differentiation. Interestingly, all three type I receptors induced identical transcriptional profiles; 97 genes were significantly upregulated and 103 genes were downregulated. Many extracellular matrix genes were upregulated, muscle-related genes downregulated, and transcription factors/signaling components modulated. In addition to 41 expressed sequence tags without known function and a number of known BMP target genes, including PPAR-gamma and fibromodulin, a large number of novel BMP target genes with an annotated function were identified, including transcription factors HesR1, ITF-2, and ICSBP, apoptosis mediators DRP-1 death kinase and ZIP kinase, IkappaB alpha, Edg-2, ZO-1, and E3 ligase Dactylin. These target genes, some of them unexpected, offer new insights into how BMPs elicit biological effects, in particular into the mechanism of inhibition of myoblast differentiation and stimulation of osteoblast differentiation.

Animals↗
PubMed2003

Characterization of a novel plasmid from extremely halophilic Archaea: nucleotide sequence and function analysis.

We determined the complete nucleotide sequence of the 16341 bp plasmid pHH205 of the extremely halophilic archaeon Halobacterium salinarum J7. The plasmid has a G+C content of 61.1%. A number of direct and inverted repeat sequences were found in pHH205, while no insertion sequences were found. Thirty-eight large open reading frames (ORFs) were identified in both strands, and most of them had no significant similarities to known proteins. A putative protein encoded by ORF31 showed 20-41% homology to some hypothetical proteins, which are annotated in several archaeal genome databases as predicted nucleic acid-binding proteins containing PIN domain. Sequence analysis using the GC skew procedure predicted a possible origin of replication. A 4.8 kb PvuII-SnaBI fragment containing both this region and ORF31 was shown to be able to restore replicate of pWL102, a replicon-deficient plasmid in Haloferax volcanii and in H. salinarum R1. Several methods failed to completely cure H. salinarum J7 of pHH205, suggesting that the plasmid probably played an important role in the growth and metabolism of the host. Our work describes a novel haloarchaeal replicon, which may be useful in the construction of cloning and shuttle vectors.

Archaeal Proteins↗
PubMed2026

Proinsulin regulators identified with CRISPR screen and in vivo mouse QTL mapping.

Altered proinsulin levels in β-cells and bloodstream are hallmarks of diabetes and other diseases, but our knowledge about the proinsulin regulators remains limited. Here we perform a genome-wide CRISPR screen to identify 84 proinsulin regulators that alter intracellular proinsulin/insulin ratio in a mouse β-cell line. The proinsulin regulators are distinct from the insulin regulators from a previous orthogonal CRISPR screen. Functional annotation of the proinsulin regulators highlights Golgi as the primary organelle for proinsulin storage and regulation. Trafficking towards the Golgi increases the intra-cellular proinsulin/insulin ratio, while trafficking away from the Golgi, including exocytosis and Golgi-to-ER retrograde transport, decreases the intracellular proinsulin levels. We also map mouse quantitative trait loci (QTLs) associated with plasma proinsulin levels and use the CRISPR screen results to pinpoint the causal genes within the QTL loci. Interestingly, protein disulfide isomerase Pdia6 is the strongest hit from both CRISPR screen and the in vivo QTL mapping. Knocking down Pdia6 significantly reduce proinsulin accumulation in Golgi and secretory granules. Intriguingly, Pdia6-depletion in both human and mouse β-cells does not affect the folding status of proinsulin but causes significantly impaired proinsulin production through a UPR-independent mechanism. Taken together, our genetic profiles provide mechanistic insights into the regulation of proinsulin/insulin homeostasis.

Animals↗
PubMed2002

Structural diversity and transcription of class III peroxidases from Arabidopsis thaliana.

Understanding peroxidase function in plants is complicated by the lack of substrate specificity, the high number of genes, their diversity in structure and our limited knowledge of peroxidase gene transcription and translation. In the present study we sequenced expressed sequence tags (ESTs) encoding novel heme-containing class III peroxidases from Arabidopsis thaliana and annotated 73 full-length genes identified in the genome. In total, transcripts of 58 of these genes have now been observed. The expression of individual peroxidase genes was assessed in organ-specific EST libraries and compared to the expression of 33 peroxidase genes which we analyzed in whole plants 3, 6, 15, 35 and 59 days after sowing. Expression was assessed in root, rosette leaf, stem, cauline leaf, flower bud and cell culture tissues using the gene-specific and highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR). We predicted that 71 genes could yield stable proteins folded similarly to horseradish peroxidase (HRP). The putative mature peroxidases derived from these genes showed 28-94% amino acid sequence identity and were all targeted to the endoplasmic reticulum by N-terminal signal peptides. In 20 peroxidases these signal peptides were followed by various N-terminal extensions of unknown function which are not present in HRP. Ten peroxidases showed a C-terminal extension indicating vacuolar targeting. We found that the majority of peroxidase genes were expressed in root. In total, class III peroxidases accounted for an impressive 2.2% of root ESTs. Rather few peroxidases showed organ specificity. Most importantly, genes expressed constitutively in all organs and genes with a preference for root represented structurally diverse peroxidases (< 70% sequence identity). Furthermore, genes appearing in tandem showed distinct expression profiles. The alignment of 73 Arabidopsis peroxidase sequences provides an easy access to the identification of orthologous peroxidases in other plant species and will provide a common platform for combining knowledge of peroxidase structure and function relationships obtained in various species.

Amino Acid Sequence↗
PubMed2026

Mitochondrial genome characteristics and phylogenetic analysis of Ramaria longispora.

This study, for the first time, assembled and annotated the complete mitochondrial genome of R.&#xa0;longispora using high-throughput sequencing technology. The genome is a circular molecule with a total length of 157,712&#x2009;bp and a GC content of 31.55%. It encodes 71 genes, including 15 core protein-coding genes (PCGs), 25 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, 5 free-stranding open reading frames (ORFs), and 24 intronic ORFs. Among these, most free-stranding ORFs have unknown functions but include a DNA polymerase gene, while the intronic ORFs primarily encode LAGLIDADG and GIY-YIG endonucleases. The mitochondrial genome contains 39 introns. Phylogenetic analyses based on 15 core PCGs using Bayesian inference (BI) and maximum likelihood (ML) methods revealed that this R. longispora is most closely related to Ramaria flavescens and Ramaria ichnusensis. This study provides foundational data for mitochondrial genome research in the Ramaria genus and offers important references for taxonomic and evolutionary studies of this group.

Mitochondrial genome↗
PubMed2005

PSORTdb: a protein subcellular localization database for bacteria.

Information about bacterial subcellular localization (SCL) is important for protein function prediction and identification of suitable drug/vaccine/diagnostic targets. PSORTdb (http://db.psort.org/) is a web-accessible database of SCL for bacteria that contains both information determined through laboratory experimentation and computational predictions. The dataset of experimentally verified information (approximately 2000 proteins) was manually curated by us and represents the largest dataset of its kind. Earlier versions have been used for training SCL predictors, and its incorporation now into this new PSORTdb resource, with its associated additional annotation information and dataset version control, should aid researchers in future development of improved SCL predictors. The second component of this database contains computational analyses of proteins deduced from the most recent NCBI dataset of completely sequenced genomes. Analyses are currently calculated using PSORTb, the most precise automated SCL predictor for bacterial proteins. Both datasets can be accessed through the web using a very flexible text search engine, a data browser, or using BLAST, and the entire database or search results may be downloaded in various formats. Features such as GO ontologies and multiple accession numbers are incorporated to facilitate integration with other bioinformatics resources. PSORTdb is freely available under GNU General Public License.

Bacterial Proteins↗
PubMed2006

Assessing protein similarity with Gene Ontology and its use in subnuclear localization prediction.

BACKGROUND: The accomplishment of the various genome sequencing projects resulted in accumulation of massive amount of gene sequence information. This calls for a large-scale computational method for predicting protein localization from sequence. The protein localization can provide valuable information about its molecular function, as well as the biological pathway in which it participates. The prediction of localization of a protein at subnuclear level is a challenging task. In our previous work we proposed an SVM-based system using protein sequence information for this prediction task. In this work, we assess protein similarity with Gene Ontology (GO) and then improve the performance of the system by adding a module of nearest neighbor classifier using a similarity measure derived from the GO annotation terms for protein sequences. RESULTS: The performance of the new system proposed here was compared with our previous system using a set of proteins resided within 6 localizations collected from the Nuclear Protein Database (NPD). The overall MCC (accuracy) is elevated from 0.284 (50.0%) to 0.519 (66.5%) for single-localization proteins in leave-one-out cross-validation; and from 0.420 (65.2%) to 0.541 (65.2%) for an independent set of multi-localization proteins. The new system is available at http://array.bioengr.uic.edu/subnuclear.htm. CONCLUSION: The prediction of protein subnuclear localizations can be largely influenced by various definitions of similarity for a pair of proteins based on different similarity measures of GO terms. Using the sum of similarity scores over the matched GO term pairs for two proteins as the similarity definition produced the best predictive outcome. Substantial improvement in predicting protein subnuclear localizations has been achieved by combining Gene Ontology with sequence information.

Algorithms↗
PubMed2003

Annotation pattern of ESTs from Spodoptera frugiperda Sf9 cells and analysis of the ribosomal protein genes reveal insect-specific features and unexpectedly low codon usage bias.

MOTIVATION: A whole set of Expressed Sequence Tags (ESTs) from the Sf9 cell line of Spodoptera frugiperda is presented here for the first time. By this way we want to identify both conserved and specific genes of this pest species. We also expect from this analysis to find a class of protein sequences providing a tool to explore genomic features and phylogeny of Lepidoptera. RESULTS: The ESTs display both housekeeping as well as developmentally regulated genes, and a high percentage of sequences with unknown function. Among the identified ORFs, almost all ribosomal proteins (RPs) were found with high EST redundancy and hence sequence accuracy. The codon usage found among RP genes is in average surprisingly much less biased in Lepidoptera than in other organisms. Other Spodoptera genes also displayed a low bias, suggesting a general genome expression feature in this Lepidoptera. We also found that the L35A and L36 RP sequences, respectively, display 40 and 10 amino-acid insertions, both being present only in insects. Sequence analysis suggests that they are probably not subjected to a strong selective pressure and may be good phylogenetic markers for Lepidoptera. Most interestingly, the Lepidoptera sequences of 9 RP genes displayed a specific signature different from the canonical one. We conclude that the RP family allows valuable comparative genomics and phylogeny of Lepidoptera. AVAILABILITY: All EST sequence data are available from the private 'Spodo-Base' upon request.

Abstracting and Indexing↗
PubMed2004

Trends between gene content and genome size in prokaryotic species with larger genomes.

Although the evolution process and ecological benefits of symbiotic species with small genomes are well understood, these issues remain poorly elucidated for free-living species with large genomes. We have compared 115 completed prokaryotic genomes by using the Clusters of Orthologous Groups database to determine whether there are changes with genome size in the proportion of the genome attributable to particular cellular processes, because this may reflect both cellular and ecological strategies associated with genome expansion. We found that large genomes are disproportionately enriched in regulation and secondary metabolism genes and depleted in protein translation, DNA replication, cell division, and nucleotide metabolism genes compared to medium- and small-sized genomes. Furthermore, large genomes do not accumulate noncoding DNA or hypothetical ORFs, because the portion of the genome devoted to these functions remained constant with genome size. Traits other than genome size or strain-specific processes are reflected by the dispersion around the mean for cell functions that showed no correlation with genome size. For example, Archaea had significantly more genes in energy production, coenzyme metabolism, and the poorly characterized category, and fewer in cell membrane biogenesis and carbohydrate metabolism than Bacteria. The trends we noted with genome size by using Clusters of Orthologous Groups were confirmed by our independent analysis with The Institute for Genomic Research's Comprehensive Microbial Resource and Kyoto Encyclopedia of Genes and Genomes' Orthology annotation databases. These trends suggest that larger genome-sized species may dominate in environments where resources are scarce but diverse and where there is little penalty for slow growth, such as soil.

Animals↗
PubMed2004

Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling.

Resistance to anticancer drugs such as the widely used antimetabolite 5-fluorouracil (FU) is one of the most important obstacles to cancer chemotherapy. Using GeneChip arrays, we compared the expression profile of different stages of FU resistance in colon cancer cells after in vitro selection of low-, intermediate- and high-resistance phenotypes. Drug resistance was associated with significant changes in expression of 330 genes, mainly during early or intermediate stage. Functional annotation revealed a majority of genes involved in signal transduction, cell adhesion and cytoskeleton with subsequent alterations in apoptotic response, cell cycle control, drug transport, fluoropyrimidine metabolism and DNA repair. A set of 33 genes distinguished all resistant subclones from sensitive progenitor cells. In the early stage, downregulation of collagens and keratins, together with upregulation of profilin 2 and ICAM-2, suggested cytoskeletal changes and cell adhesion remodeling. Interestingly, 6 members of the S100 calcium-binding protein family were suppressed. Acquisition of the intermediate-resistance phenotype included upregulation of the well-known drug resistance gene ABCC6 (ATP-binding cassette subfamily C member 6). The very small number of genes affected during transition to high resistance included the primary FU target thymidylate synthase. Although limited to an in vitro model, our data suggest that resistance to FU cannot be explained by known mechanisms alone and substantially involves a wide molecular repertoire. This study emphasizes the understanding of resistance as a time-depending process: the cell is particularly challenged at the beginning of this process, while acquisition of the high-resistance phenotype seems to be less demanding.

Antimetabolites, Antineoplastic↗