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PubMed2005

Data mining for protein-protein interactions in invertebrate model organisms.

Well-annotated genome databases are available for many invertebrate species, notably the fruitfly, Drosophila melanogaster, and the nematode, Caenorhabditis elegans. An adequate interpretation of this information at the biological level requires the exploration of the interactions between the gene products. Knowledge of protein interactions and the components of cell signalling pathways in the fly and worm are particularly valuable as hypotheses can be rapidly tested using the powerful genetic toolkits available. Invertebrates offer additional experimental advantages when attempting to characterise protein-protein interactions (PPIs). Their relatively small genome size compared to mammals helps to reduce missed interactions due to redundancy, and their function can be addressed using forward (mutants) and reverse (RNA interference) genetics. However, the researcher looking for evidence of PPIs for a protein of interest is faced with the challenge of extracting interaction data from sources that are highly varied, such as the results of microarray experiments in the unstructured text of research papers. This challenge is greatly reduced by a range of public databases of curated information, as well as publicly available, enhanced search engines, which can provide either direct experimental evidence for a PPI, or valuable clues for generating new hypotheses.

Animals↗
PubMed2000

SAWTED: structure assignment with text description--enhanced detection of remote homologues with automated SWISS-PROT annotation comparisons.

MOTIVATION: Sequence database search methods often identify putative sub-threshold hits of known function or structure for a given query sequence. It is widespread practice to filter these hits by hand using knowledge of function and other factors; to the expert, some hits may appear more sensible than others. SAWTED (Structure Assignment With Text Description) is an automated solution to this post-filtering problem which will be applicable to large scale genome assignments. RESULTS: A standard document comparison algorithm is applied to text descriptions extracted from SWISS-PROT annotations. The added value of SAWTED in combination with PSI-BLAST has been shown with a benchmark of difficult remote homologues taken from the SCOP structure database. AVAILABILITY: A WAWTED PSI-BLAST Web server is available to perform sensitive searches against the protein structure database (http://www.bmm.icnet.uk/servers/sawted). CONTACT: R.MacCallum@icrf.icnet.uk

Algorithms↗
PubMed2005

The Ashbya Genome Database (AGD)--a tool for the yeast community and genome biologists.

The Ashbya Genome Database (AGD) is a comprehensive online source of information covering genes from the filamentous fungus Ashbya gossypii. The database content is based upon comparative genome annotation between A.gossypii and the closely related budding yeast Saccharomyces cerevisiae taking both sequence similarity and synteny (conserved order and orientation) into account. Release 2 of AGD contains 4718 protein-encoding loci located across seven chromosomes. Information can be retrieved using systematic or standard locus names from A.gossypii as well as budding and fission yeast. Approximately 90% of the genes in the genome of A.gossypii are homologous and syntenic to loci of budding yeast. Therefore, AGD is a useful tool not only for the various yeast communities in general but also for biologists who are interested in evolutionary aspects of genome research and comparative genome annotation. The database provides scientists with a convenient graphical user interface that includes various locus search and genome browsing options, data download and export functionalities and numerous reciprocal links to external databases including SGD, MIPS, GeneDB, KEGG, GermOnline and Swiss-Prot/TrEMBL. AGD is accessible at http://agd.unibas.ch/.

Computer Graphics↗
PubMed2000

An annotated catalog of inverted repeats of Caenorhabditis elegans chromosomes III and X, with observations concerning odd/even biases and conserved motifs.

We have taken a computational approach to the problem of discovering and deciphering the grammar and syntax of gene regulation in eukaryotes. A logical first step is to produce an annotated catalog of all regulatory sites in a given genome. Likely candidates for such sites are direct and indirect repeats, including three subcategories of indirect repeats: inverted (palindromic), everted, and mirror-image repeats. To that end we have produced a searchable database of inverted repeats of chromosomes III and X of Caenorhabditis elegans, the first completely sequenced multicellular eukaryote. Initial results from the use of this catalog are observations concerning odd/even biases in perfect IRs. The potential usefulness of the catalog as a discovery tool for promoters was shown for some of the genes involved with G-protein functions and for heat shock protein 104 (hsp104).

Algorithms↗
PubMed2003

Identification of Drosophila MicroRNA targets.

MicroRNAs (miRNAs) are short RNA molecules that regulate gene expression by binding to target messenger RNAs and by controlling protein production or causing RNA cleavage. To date, functions have been assigned to only a few of the hundreds of identified miRNAs, in part because of the difficulty in identifying their targets. The short length of miRNAs and the fact that their complementarity to target sequences is imperfect mean that target identification in animal genomes is not possible by standard sequence comparison methods. Here we screen conserved 3' UTR sequences from the Drosophila melanogaster genome for potential miRNA targets. The screening procedure combines a sequence search with an evaluation of the predicted miRNA-target heteroduplex structures and energies. We show that this approach successfully identifies the five previously validated let-7, lin-4, and bantam targets from a large database and predict new targets for Drosophila miRNAs. Our target predictions reveal striking clusters of functionally related targets among the top predictions for specific miRNAs. These include Notch target genes for miR-7, proapoptotic genes for the miR-2 family, and enzymes from a metabolic pathway for miR-277. We experimentally verified three predicted targets each for miR-7 and the miR-2 family, doubling the number of validated targets for animal miRNAs. Statistical analysis indicates that the best single predicted target sites are at the border of significance; thus, target predictions should be considered as tentative until experimentally validated. We identify features shared by all validated targets that can be used to evaluate target predictions for animal miRNAs. Our initial evaluation and experimental validation of target predictions suggest functions for two miRNAs. For others, the screen suggests plausible functions, such as a role for miR-277 as a metabolic switch controlling amino acid catabolism. Cross-genome comparison proved essential, as it allows reduction of the sequence search space. Improvements in genome annotation and increased availability of cDNA sequences from other genomes will allow more sensitive screens. An increase in the number of confirmed targets is expected to reveal general structural features that can be used to improve their detection. While the screen is likely to miss some targets, our study shows that valid targets can be identified from sequence alone.

3' Untranslated Regions↗
PubMed1997

Sequencing and functional annotation of the Bacillus subtilis genes in the 200 kb rrnB-dnaB region.

The 200 kb region of the Bacillus subtilis chromosome spanning from 255 to 275 degrees on the genetic map was sequenced. The strategy applied, based on use of yeast artificial chromosomes and multiplex Long Accurate PCR, proved to be very efficient for sequencing a large bacterial chromosome area. A total of 193 genes of this part of the chromosome was classified by level of knowledge and biological category of their functions. Five levels of gene function understanding are defined. These are: (i) experimental evidence is available of gene product or biological function; (ii) strong homology exists for the putative gene product with proteins from other organisms; (iii) some indication of the function can be derived from homologies with known proteins; (iv) the gene product can be clustered with hypothetical proteins; (v) no indication on the gene function exists. The percentage of detected genes in each category was: 20, 28, 20, 15 and 17, respectively. In the sequenced region, a high percentage of genes are implicated in transport and metabolic linking of glycolysis and the citric acid cycle. A functional connection of several genes from this region and the genes close to 140 degrees in the chromosome was also observed.

Bacillus subtilis↗
PubMed2000

Genomic exploration of the hemiascomycetous yeasts: 3. Methods and strategies used for sequence analysis and annotation.

The primary analysis of the sequences for our Hemiascomycete random sequence tag (RST) project was performed using a combination of classical methods for sequence comparison and contig assembly, and of specifically written scripts and computer visualization routines. Comparisons were performed first against DNA and protein sequences from Saccharomyces cerevisiae, then against protein sequences from other completely sequenced organisms and, finally, against protein sequences from all other organisms. Blast alignments were individually inspected to help recognize genes within our random genomic sequences despite the fact that only parts of them were available. For each yeast species, validated alignments were used to infer the proper genetic code, to determine codon usage preferences and to calculate their degree of sequence divergence with S. cerevisiae. The quality of each genomic library was monitored from contig analysis of the DNA sequences. Annotated sequences were submitted to the EMBL database, and the general annotation tables produced served as a basis for our comparative description of the evolution, redundancy and function of the Hemiascomycete genomes described in other articles of this issue.

Amino Acid Sequence↗
PubMed2005

Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis.

In the current investigation, we constructed recombinants of expression of HCV genotype 1b, 2a, and 4d whole core proteins and established a human hepatoma (Huh-7) cell line which expressed different core proteins constitutively. In the Affymetrix human gene chip, the HG-U133 A and B were employed for identification of variant core protein gene expression in the Huh-7 cell line. In data analysis, we applied a threshold that eliminated all genes that were not increased or decreased by at least a 3-fold change in a comparison between transfected cells and control cells. All of these genes were annotated by using NetAffx analysis through the Affymetrix website and categorized on the basis of their biological processes. The microarray analysis result suggested that the gene expression profiles caused by three kinds of core proteins were mainly shown in metabolism, signal transduction, protease activity, immune responses, etc. and that some pathogenesis/oncogenesis, apoptosis, or anti-apoptosis gene expression were up/down-regulated simultaneously in the Huh-7 cell line. In conclusion, the gene expression profiles of variant core proteins were implicated in HCV replication, pathogenesis, or oncogenesis in the Huh-7 cell line, which is useful for our understanding of HCV variant core protein biological function and its pathogenic mechanism.

Carcinoma, Hepatocellular↗
PubMed2026

Sex- and development-specific transcriptomic profiling of venom and silk genes in the wolf spider Pardosa astrigera provides insights into ecological adaptation and predatory strategies.

Spider venom and silk glands are two major secretory systems that contribute to prey capture, defense, and reproduction, but their sex- and development-specific molecular regulation in wandering wolf spiders remains poorly understood. Here, the transcriptome of Pardosa astrigera, an important agricultural natural enemy in China, revealed significant sex- and development-associated molecular differentiation among adult females, adult males, and spiderlings. A total of 100,025 unigenes were obtained, of which 23,852 were functionally annotated, providing a comprehensive transcriptomic resource for this species. Differential expression patterns showed marked variation among groups, with 531, 1792, and 832 DEGs detected in PAF vs PAS, PAM vs PAS, and PAF vs PAM, respectively. These genes were mainly associated with metabolic, oxidation-reduction, cuticle development, MAPK signaling, and lysosome pathways. Fifteen co-expression modules revealed distinct expression patterns. The turquoise, pink, yellow, and red modules were development-related, whereas the blue module was male-biased. Venom- and spidroin-related genes were distributed across multiple modules, suggesting coordinated regulation. Overall, 42 venom peptides, 21 venom proteins, and 11 spidroins were identified. Representative genes showed strongly biased expression, including spiderling-biased U3_Pp1a and U5_Pp1e, female-biased U4_Pp1a, and male-biased SMase D_108750 and PaTuSp_108466. These findings reveal sex- and development-biased expression patterns of venom- and silk-related candidate genes in P. astrigera and may provide molecular insights into ecological adaptation and predatory strategies in wandering wolf spiders.

Animals↗
PubMed2004

Overexpression of a novel small peptide ROTUNDIFOLIA4 decreases cell proliferation and alters leaf shape in Arabidopsis thaliana.

Leaf shape is determined by polar cell expansion and polar cell proliferation along the leaf axes. However, the genes controlling polar cell proliferation during leaf morphogenesis are largely unknown. We identified a dominant mutant of Arabidopsis thaliana, rotundifolia4-1D (rot4-1D), which possessed short leaves and floral organs. We showed that the altered leaf shape is caused by reduced cell proliferation, specifically in the longitudinal (proximal-distal) axis of the leaf, suggesting that the ROT4 gene controls polar cell proliferation in lateral organs. The ROT4 open-reading frame (ORF) encodes a novel small peptide that had not been identified in the Arabidopsis genome annotation. Overexpression of a ROT4-green fluorescence protein (GFP) fusion protein in transgenic plants recapitulated the rot4 phenotype, suggesting that ROT4 acts to restrict cell proliferation. The ROT4-GFP fusion protein localized to the plasma membrane when expressed in transgenic Arabidopsis plants. Phylogenetic analysis indicates that ROT4 defines a novel seed plant-specific family of small peptides with 22 members in Arabidopsis, ROT FOUR LIKE1-22 (RTFL1-22). All RTFL members share a conserved 29-amino acid domain, the RTF domain, and overexpression of the ROT4 RTF domain alone is sufficient to confer a rot4-1D phenotype. Loss-of-function mutations in several RTFL genes were aphenotypic, suggesting that there may be some functional redundancy between family members. Analyses by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization revealed that ROT4 is expressed in the shoot apex and young leaves of wild-type plants, consistent with a role for ROT4 in controlling polarity-dependent cell proliferation during wild-type leaf morphogenesis.

Amino Acid Sequence↗
PubMed2026

Comparative genomics approaches to identify genomic regions associated with the antimicrobial activity of Pseudomonas protegens PBL3.

The environmental bacterium Pseudomonas protegens PBL3 has antagonistic activity against the plant pathogenic bacterium Burkholderia glumae, an important pathogen in rice. The antimicrobial activity of P. protegens PBL3 was found in the bacteria-free secreted fraction (secretome), but the specific molecules, as well as the genetic basis of that activity, have not been identified. In this study, we integrated genomic information with antimicrobial assays on P. protegens PBL3 and additional six Pseudomonas spp. strains, to identify putative genomic regions in P. protegens PBL3 associated with antimicrobial activity. We hypothesized that Pseudomonas spp. strains with antimicrobial activity against B. glumae have conserved genes with P. protegens PBL3 that are absent in strains lacking activity. Comparative genomics analyses with anvi'o and progressiveMauve, and using P. protegens PBL3 as the reference genome, revealed 188 genes uniquely present in antimicrobial-producing strains. Seven of those genes were annotated as biosynthetic gene clusters predicted to encode secondary metabolites; additional genes were grouped into 25 contiguous clusters with functions annotated as secretion, signal transduction, regulation, transport/efflux, carbohydrate metabolism and one with an additional uncharacterized function. Altogether, this study uncovered a complex and multi-functional network of candidate genes, suggesting that the antimicrobial activity in P. protegens PBL3 is not limited to biosynthetic pathways but also involves additional regulatory, metabolic and export modules to synthesize and deploy antimicrobials.

Pseudomonas↗
PubMed2006

DRTF: a database of rice transcription factors.

SUMMARY: DRTF contains 2025 putative transcription factors (TFs) in Oryza sativa L. ssp. indica and 2384 in ssp. japonica, distributed in 63 families, identified by computational prediction and manual curation. It includes detailed annotations of each TF including sequence features, functional domains, Gene Ontology assignment, chromosomal localization, EST and microarray expression information, as well as multiple sequence alignment of the DNA-binding domains for each TF family. The database can be browsed and searched with a user-friendly web interface. AVAILABILITY: DRTF is available at http://drtf.cbi.pku.edu.cn

Database Management Systems↗
PubMed2006

Using local gene expression similarities to discover regulatory binding site modules.

BACKGROUND: We present an approach designed to identify gene regulation patterns using sequence and expression data collected for Saccharomyces cerevisae. Our main goal is to relate the combinations of transcription factor binding sites (also referred to as binding site modules) identified in gene promoters to the expression of these genes. The novel aspects include local expression similarity clustering and an exact IF-THEN rule inference algorithm. We also provide a method of rule generalization to include genes with unknown expression profiles. RESULTS: We have implemented the proposed framework and tested it on publicly available datasets from yeast S. cerevisae. The testing procedure consists of thorough statistical analyses of the groups of genes matching the rules we infer from expression data against known sets of co-regulated genes. For this purpose we have used published ChIP-Chip data and Gene Ontology annotations. In order to make these tests more objective we compare our results with recently published similar studies. CONCLUSION: Results we obtain show that local expression similarity clustering greatly enhances overall quality of the derived rules, both in terms of enrichment of Gene Ontology functional annotation and coherence with ChIP-Chip binding data. Our approach thus provides reliable hypotheses on co-regulation that can be experimentally verified. An important feature of the method is its reliance only on widely accessible sequence and expression data. The same procedure can be easily applied to other microbial organisms.

Binding Sites↗
PubMed2004

Extensive expansion of the claudin gene family in the teleost fish, Fugu rubripes.

In humans, the claudin superfamily consists of 19 homologous proteins that commonly localize to tight junctions of epithelial and endothelial cells. Besides being structural tight-junction components, claudins participate in cell-cell adhesion and the paracellular transport of solutes. Here, we identify and annotate the claudin genes in the whole-genome of the teleost fish, Fugu rubripes (Fugu), and determine their phylogenetic relationships to those in mammals. Our analysis reveals extensive gene duplications in the teleost lineage, leading to 56 claudin genes in Fugu. A total of 35 Fugu claudin genes can be assigned orthology to 17 mammalian claudin genes, with the remaining 21 genes being specific to the fish lineage. Thus, a significant number of the additional Fugu genes are not the result of the proposed whole-genome duplication in the fish lineage. Expression profiling shows that most of the 56 Fugu claudin genes are expressed in a more-or-less tissue-specific fashion, or at particular developmental stages. We postulate that the expansion of the claudin gene family in teleosts allowed the acquisition of novel functions during evolution, and that fish-specific novel members of gene families such as claudins contribute to a large extent to the distinct physiology of fishes and mammals.

Animals↗
PubMed2006

sgTarget: a target selection resource for structural genomics.

sgTarget (http://www.ysbl.york.ac.uk/sgTarget) is a web-based resource to aid the selection and prioritization of candidate proteins for structure determination. The system annotates user submitted gene or protein sequences, identifying sequence families with no homologues of known structure, and characterizing each protein according to a range of physicochemical properties that may affect its expression, solubility and likelihood to crystallize. Summaries of these analyses are available for individual sequences, as well as whole datasets. This type of analysis enables structural biologists to iteratively select targets from their genomic sequences of interest and according to their research needs. All sequence datasets submitted to sgTarget are available for users to select and rank using their choice of criteria. sgTarget was developed to support individual laboratories collaborating in structural and functional genomics projects and should be valuable to structural biologists wishing to employ the wealth of available genome sequences in their structural quests.

Animals↗
PubMed2003

Expressed sequence tag profiling identifies developmental and anatomic partitioning of gene expression in the mouse prostate.

BACKGROUND: The prostate gland is an organ with highly specialized functional attributes that serves to enhance the fertility of mammalian species. Much of the information pertaining to normal and pathological conditions affecting the prostate has been obtained through extensive developmental, biochemical and genetic analyses of rodent species. Although important insights can be obtained through detailed anatomical and histological assessments of mouse and rat models, further mechanistic explanations are greatly aided through studies of gene and protein expression. RESULTS: In this article we characterize the repertoire of genes expressed in the normal developing mouse prostate through the analysis of 50,562 expressed sequence tags derived from 14 mouse prostate cDNA libraries. Sequence assemblies and annotations identified 15,009 unique transcriptional units of which more than 600 represent high quality assemblies without corresponding annotations in public gene expression databases. Quantitative analyses demonstrate distinct anatomical and developmental partitioning of prostate gene expression. This finding may assist in the interpretation of comparative studies between human and mouse and guide the development of new transgenic murine disease models. The identification of several novel genes is reported, including a new member of the beta-defensin gene family with prostate-restricted expression. CONCLUSIONS: These findings suggest a potential role for the prostate as a defensive barrier for entry of pathogens into the genitourinary tract and, further, serve to emphasize the utility of the continued evaluation of transcriptomes from a diverse repertoire of tissues and cell types.

Amino Acid Sequence↗
PubMed2000

Comparative analysis of expressed sequences in Phytophthora sojae.

Phytophthora sojae (Kaufmann and Gerdemann) is an oomycete that causes stem and root rot on soybean (Glycine max L. Merr) plants. We have constructed three cDNA libraries using mRNA isolated from axenically grown mycelium and zoospores and from tissue isolated from plant hypocotyls 48 h after inoculation with zoospores. A total of 3,035 expressed sequence tags (ESTs) were generated from the three cDNA libraries, representing an estimated 2,189 cDNA transcripts. The ESTs were classified according to putative function based on similarity to known proteins, and were analyzed for redundancy within and among the three source libraries. Distinct expression patterns were observed for each library. By analysis of the percentage G+C content of the ESTs, we estimate that two-thirds of the ESTs from the infected plant library are derived from P. sojae cDNA transcripts. The ESTs originating from this study were also compared with a collection of Phytophthora infestans ESTs and with all other non-human ESTs to assess the similarity of the P. sojae sequences to existing EST data. This collection of cDNA libraries, ESTs, and accompanying annotation will provide a new resource for studies on oomycetes and on soybean responses to pathogen challenge.

DNA, Complementary↗
PubMed2004

Genome-wide prediction and analysis of function-specific transcription factor binding sites.

DNA-binding transcription factors play a central role in transcription regulation, and the annotation of transcription-factor binding sites in upstream regions of human genes is essential for building a genome-wide regulatory network. We describe methodology to accurately predict the transcription-factor binding sites in the proximal-promoter region of function-specific genes. In order to increase the accuracy of transcription factor binding-site prediction, we rely on recent genome sequence data, known transcription factor binding-site matrices, and Gene Ontology biological-function-based gene classification. Using TRANSFAC position-frequency matrices, we detected individual and cooperating transcription-factor binding sites in proximal promoters of ENSEMBL annotated human genes. We used the over representation of detected binding sites in the proximal promoters as compared to the second exons to control specificity. We confirmed the majority of transcription-factor binding sites predicted in proximal promoters of immune-response genes with evidence from existing literature. We validated the predicted cooperation between transcription factors NF-kappa B and IRF in the regulation of gene expression with microarray transcript profiling data and literature-derived protein-protein interaction network. We also identified over-represented individual and pairs of transcription-factor binding sites in the proximal promoters of each Gene Ontology biological-process gene group. Our tools and analysis provide a new resource for deciphering transcription regulation in different biological paradigms.

Computational Biology↗