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PubMed2000

A large scale analysis of cDNA in Arabidopsis thaliana: generation of 12,028 non-redundant expressed sequence tags from normalized and size-selected cDNA libraries.

For comprehensive analysis of genes expressed in the model dicotyledonous plant, Arabidopsis thaliana, expressed sequence tags (ESTs) were accumulated. Normalized and size-selected cDNA libraries were constructed from aboveground organs, flower buds, roots, green siliques and liquid-cultured seedlings, respectively, and a total of 14,026 5'-end ESTs and 39,207 3'-end ESTs were obtained. The 3'-end ESTs could be clustered into 12,028 non-redundant groups. Similarity search of the non-redundant ESTs against the public non-redundant protein database indicated that 4816 groups show similarity to genes of known function, 1864 to hypothetical genes, and the remaining 5348 are novel sequences. Gene coverage by the non-redundant ESTs was analyzed using the annotated genomic sequences of approximately 10 Mb on chromosomes 3 and 5. A total of 923 regions were hit by at least one EST, among which only 499 regions were hit by the ESTs deposited in the public database. The result indicates that the EST source generated in this project complements the EST data in the public database and facilitates new gene discovery.

Arabidopsis↗
PubMed2005

Agouti-related proteins (AGRPs) and agouti-signaling peptide (ASIP) in fish and chicken.

We performed an intensive search on sequence databases to identify orthologues of ASIP and AGRP peptides in a number of different species, revealing a number of genomic fragments coding for the C-terminal part of agouti-related motifs, different from annotated peptide sequences, including one fragment from chicken, two from zebrafish, two from Fugu (Takifugu rubripes), and three from Tetraodon (Tetraodon nigroviridis). We have thus shown for the first time that both AGRP and ASIP genes exist in many species in "lower vertebrates" and were most probably present in early stages of vertebrate evolution.

Agouti Signaling Protein↗
PubMed2005

An annotation update via cDNA sequence analysis and comprehensive profiling of developmental, hormonal or environmental responsiveness of the Arabidopsis AP2/EREBP transcription factor gene family.

AP2/EREBP transcription factors (TFs) play functionally important roles in plant growth and development, especially in hormonal regulation and in response to environmental stress. Here we reported verification and correction of annotation through an exhaustive cDNA cloning and sequence analysis performed on 145 of 147 gene family members. A RACE analysis performed on genes with potential in-frame up-stream ATG codon resulted in identification of At2g28520 as an authentic AP2/EREBP member and corrected ORF annotations for three other members. A further phylogenetic analysis of this updated and likely complete family divided it into three major subfamilies. The expression patterns of the AP2/EREBP family members among the 11 organ or tissue types were examined using an oligo microarray and their hormonal and environmental responsiveness were further characterized using cDNA custom macroarrays. These detailed expression profile results provide strong support for a role for AP2/EREBP family members in development and in response to environmental stimuli, and a foundation for future functional analysis of this gene family.

Algorithms↗
PubMed2006

Genomic anatomy of the Tyrp1 (brown) deletion complex.

Chromosome deletions in the mouse have proven invaluable in the dissection of gene function. The brown deletion complex comprises >28 independent genome rearrangements, which have been used to identify several functional loci on chromosome 4 required for normal embryonic and postnatal development. We have constructed a 172-bacterial artificial chromosome contig that spans this 22-megabase (Mb) interval and have produced a contiguous, finished, and manually annotated sequence from these clones. The deletion complex is strikingly gene-poor, containing only 52 protein-coding genes (of which only 39 are supported by human homologues) and has several further notable genomic features, including several segments of >1 Mb, apparently devoid of a coding sequence. We have used sequence polymorphisms to finely map the deletion breakpoints and identify strong candidate genes for the known phenotypes that map to this region, including three lethal loci (l4Rn1, l4Rn2, and l4Rn3) and the fitness mutant brown-associated fitness (baf). We have also characterized misexpression of the basonuclin homologue, Bnc2, associated with the inversion-mediated coat color mutant white-based brown (B(w)). This study provides a molecular insight into the basis of several characterized mouse mutants, which will allow further dissection of this region by targeted or chemical mutagenesis.

Animals↗
PubMed2006

Standardization of microarray and pharmacogenomics data.

This chapter provides a bottom-up perspective on bioinformatics data standards, beginning with a historical perspective on biochemical nomenclature standards. Various file format standards were soon developed to convey increasingly complex and voluminous data that nomenclature alone could not effectively organize without additional structure and annotation. As areas of biochemistry and molecular biology have become more integral to the practice of modern medicine, broader data representation models have been created, from corepresentation of genomic and clinical data as a framework for drug research and discovery to the modeling of genotyping and pharmacogenomic therapy within the broader process of the delivery of health care.

Computational Biology↗
PubMedDate not supplied

Fuzzy measures on the Gene Ontology for gene product similarity.

One of the most important objects in bioinformatics is a gene product (protein or RNA). For many gene products, functional information is summarized in a set of Gene Ontology (GO) annotations. For these genes, it is reasonable to include similarity measures based on the terms found in the GO or other taxonomy. In this paper, we introduce several novel measures for computing the similarity of two gene products annotated with GO terms. The fuzzy measure similarity (FMS) has the advantage that it takes into consideration the context of both complete sets of annotation terms when computing the similarity between two gene products. When the two gene products are not annotated by common taxonomy terms, we propose a method that avoids a zero similarity result. To account for the variations in the annotation reliability, we propose a similarity measure based on the Choquet integral. These similarity measures provide extra tools for the biologist in search of functional information for gene products. The initial testing on a group of 194 sequences representing three proteins families shows a higher correlation of the FMS and Choquet similarities to the BLAST sequence similarities than the traditional similarity measures such as pairwise average or pairwise maximum.

Algorithms↗
PubMed2006

Functional grouping based on signatures in protein termini.

The two ends of each protein are known as the amino (N-) and carboxyl (C-) termini. Short signatures in a protein's termini often carry vital cellular function. No systematic research has been conducted to address the importance of short signatures (3 to 10 amino acids) in protein termini at the proteomic level. Specifically, it is unknown whether such signatures are evolutionarily conserved, and if so, whether this conservation confers shared biological functions. Current signature detection methods fail to detect such short signatures due to inadequate statistical scores. The findings presented in this study strongly support the notion that functional significance of protein sets may be captured by short signatures at their termini. A positional search method was applied to over one million proteins from the UniProt database. The result is a collection of about a thousand significant signature groups (SIGs) that include previously identified as well as many novel signatures in protein termini. These SIGs represent protein sets with minimal or no overall sequence similarity excepting the similarity at their termini. The most significant SIGs are assigned by their strong correspondence to functional annotations derived from external databases such as Gene Ontology. Each of the SIGs is associated with the statistical significance of its functional association. These SIGs provide a valuable source for testing previously overlooked signatures in protein termini and allow for the investigation of the role played by such signatures throughout evolution. The SIGs archive and advanced search options are available at http://www.proteus.cs.huji.ac.il.

Amino Acid Sequence↗
PubMed2005

Cloning of a sea urchin sarco/endoplasmic reticulum Ca2+ ATPase.

Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), a vesicular integral membrane protein, is the best-characterized member of the P-type ion translocating ATPase superfamily. Here we describe the cloning and structural analysis of a sea urchin SERCA (suSERCA) cloned from testis cDNA. The approximately 112 kDa suSERCA is 1022 amino acids with approximately 70% identity and 80% similarity to all known mammalian SERCA isoforms. suSERCA shares all the structural features of mammalian SERCAs, including domains: A, actuator; N, nucleotide-binding; and P, phosphorylation, and also 10 transmembrane helices. Like human SERCA2, the suSERCA has a possible 11th transmembrane segment in its extreme C-terminus. The alignment of three sequences (suSERCA, human SERCA2, and rabbit SERCA1a) shows that the Ca2+ binding residues and kinks (required to form the ion-binding pocket) are 100% conserved. The annotated suSERCA gene consists of 24 exons separated by 23 introns and is approximately 30 kb. Western blots show that suSERCA is present in sea urchin eggs and testis, but not in mature spermatozoa. Treatment of live sperm with SERCA inhibitors has no effect on intracellular calcium, suggesting the absence of SERCA in sea urchin spermatozoa.

Amino Acid Sequence↗
PubMed2001

The invertebrate growth factor/CECR1 subfamily of adenosine deaminase proteins.

Adenosine deaminase (ADA) catalyzes the hydrolysis of adenosine to inosine. Its lack determines severe combined immunodeficiency in mammals, possibly due to accumulation of extracellular adenosine, which induces apoptosis in lymphocytes (Franco et al., 1998). Thus, presence of normal levels of ADA leads to normal growth and proliferation of lymphocytes. Several vertebrate and microbial ADA amino-acid sequences are known, with substantial similarity to each other. On the other hand, there are invertebrate growth factors as well as a candidate gene for the human cat eye syndrome (CECR1) (Riazi et al., 2000. Genomics 64, 277-285), which share substantial similarity to each other, and also to ADA. In this study, we report the expression and ADA enzymatic activity of a cDNA from the salivary glands of Lutzomyia longipalpis, a blood-sucking insect, with substantial similarity to insect growth factors and to human CECR1. We also demonstrate the existence of a subfamily of the adenosine deaminase family characterized by their unique amino-terminal region. Both Drosophila melanogaster and humans have both types of adenosine deaminases. Results indicate that these invertebrate proteins previously annotated as growth factors, as well as the human CECR1 gene product, may exert their actions through adenosine depletion. The different roles played by each type of adenosine deaminase in humans and Drosophila remains to be fully investigated.

Adenosine↗
PubMed2006

Sebida: a database for the functional and evolutionary analysis of genes with sex-biased expression.

UNLABELLED: We describe Sebida, a database of genes with sex-biased expression. The database integrates results from multiple, independent microarray studies comparing male and female gene expression in Drosophila melanogaster, Drosophila simulans and Anopheles gambiae. Sebida uses standard nomenclature, which allows individual genes to be compared across different microarray platforms and to be queried by gene name, symbol, or annotation number. In addition to ratios of male/female expression for each gene, Sebida also contains information useful for evolutionary studies, such as local recombination rate, degree of codon bias and interspecific divergence at synonymous and non-synonymous sites. AVAILABILITY: Sebida can be accessed at http://www.sebida.de

Animals↗
PubMed2006

Contribution of penicillin-binding protein homologs to antibiotic resistance, cell morphology, and virulence of Listeria monocytogenes EGDe.

Seven open reading frames, annotated as potential penicillin-binding-protein-encoding genes (lmo0441, lmo0540, lmo1438, lmo1892, lmo2039, lmo2229, and lmo2754), were targeted for insertional mutagenesis in Listeria monocytogenes EGDe. These genes were found to contribute in various degrees to beta-lactam resistance, cell morphology, or the virulence potential of this organism.

Amino Acid Sequence↗
PubMed2006

Electron transport in the pathway of acetate conversion to methane in the marine archaeon Methanosarcina acetivorans.

A liquid chromatography-hybrid linear ion trap-Fourier transform ion cyclotron resonance mass spectrometry approach was used to determine the differential abundance of proteins in acetate-grown cells compared to that of proteins in methanol-grown cells of the marine isolate Methanosarcina acetivorans metabolically labeled with 14N versus 15N. The 246 differentially abundant proteins in M. acetivorans were compared with the previously reported 240 differentially expressed genes of the freshwater isolate Methanosarcina mazei determined by transcriptional profiling of acetate-grown cells compared to methanol-grown cells. Profound differences were revealed for proteins involved in electron transport and energy conservation. Compared to methanol-grown cells, acetate-grown M. acetivorans synthesized greater amounts of subunits encoded in an eight-gene transcriptional unit homologous to operons encoding the ion-translocating Rnf electron transport complex previously characterized from the Bacteria domain. Combined with sequence and physiological analyses, these results suggest that M. acetivorans replaces the H2-evolving Ech hydrogenase complex of freshwater Methanosarcina species with the Rnf complex, which generates a transmembrane ion gradient for ATP synthesis. Compared to methanol-grown cells, acetate-grown M. acetivorans synthesized a greater abundance of proteins encoded in a seven-gene transcriptional unit annotated for the Mrp complex previously reported to function as a sodium/proton antiporter in the Bacteria domain. The differences reported here between M. acetivorans and M. mazei can be attributed to an adaptation of M. acetivorans to the marine environment.

Acetates↗
PubMed2006

Structural and functional analysis of Rv3214 from Mycobacterium tuberculosis, a protein with conflicting functional annotations, leads to its characterization as a phosphatase.

The availability of complete genome sequences has highlighted the problems of functional annotation of the many gene products that have only limited sequence similarity with proteins of known function. The predicted protein encoded by open reading frame Rv3214 from the Mycobacterium tuberculosis H37Rv genome was originally annotated as EntD through sequence similarity with the Escherichia coli EntD, a 4'-phosphopantetheinyl transferase implicated in siderophore biosynthesis. An alternative annotation, based on slightly higher sequence identity, grouped Rv3214 with proteins of the cofactor-dependent phosphoglycerate mutase (dPGM) family. The crystal structure of this protein has been solved by single-wavelength anomalous dispersion methods and refined at 2.07-Angstroms resolution (R = 0.229; R(free) = 0.245). The protein is dimeric, with a monomer fold corresponding to the classical dPGM alpha/beta structure, albeit with some variations. Closer comparisons of structure and sequence indicate that it most closely corresponds with a broad-spectrum phosphatase subfamily within the dPGM superfamily. This functional annotation has been confirmed by biochemical assays which show negligible mutase activity but acid phosphatase activity with a pH optimum of 5.4 and suggests that Rv3214 may be important for mycobacterial phosphate metabolism in vivo. Despite its weak sequence similarity with the 4'-phosphopantetheinyl transferases (EntD homologues), there is little evidence to support this function.

Amino Acid Sequence↗
PubMed2026

Disruption of GAD1 protein architecture by a novel missense variant in a consanguineous family with autosomal recessive intellectual disability.

BACKGROUND: Intellectual disability represents a heterogeneous group of neurodevelopmental disorders marked by significant impairments in intellectual functioning and adaptive behavior. Among the various causes, genetic factors play a major role, with autosomal recessive intellectual disability (ARID) constituting a genetically diverse subgroup. ARID is prevalent in consanguineous families and arises from homozygous mutations that disrupt critical genes involved in brain development and function. OBJECTIVE: This study aimed to identify disease-causing genetic variants responsible for ARID in a consanguineous Pakistani family and to evaluate the structural and functional impact of a novel variant identified in GAD1 through protein modeling. METHODS: A consanguineous family affected with intellectual disability was enrolled. Whole-exome sequencing was performed on an affected individual, followed by bioinformatics analysis including alignment to the GRCh38 reference genome, variant calling, and annotation. Variants were filtered based on rarity, predicted functional impact, and autosomal recessive inheritance pattern. Candidate variants were validated and assessed by Sanger sequencing and segregation analysis. Protein modeling was performed to evaluate the structural impact of the identified variant. RESULTS: A novel homozygous missense variant NM_000817:c.1700G>A;p.Arg567Gln in GAD1 was identified. Segregation analysis confirmed co-segregation of the variant with the affected phenotype. Protein modeling suggested that the variant may disrupt GAD1 enzymatic function involved in gamma-aminobutyric acid synthesis. CONCLUSION: This study emphasizes the significance of genetic investigation in familial cases and the crucial role that GAD1 mutations play in neurodevelopmental disorders with intellectual disability. The results advance the knowledge of molecular causes of ARID and broaden the mutational range.

Pakistani↗
PubMed2003

The Schistosoma mansoni gene index: gene discovery and biology by reconstruction and analysis of expressed gene sequences.

Expressed sequence tag (EST) sequencing and analysis is a primary research tool to identify and characterize the Schistosoma mansoni transcriptome. As part of our gene discovery effort, a total of 5,793 ESTs have been generated from clones selected randomly from complementary DNA (cDNA) libraries constructed from male and female adult worms. Assembly analysis of all the 16,813 public S. mansoni ESTs has identified 1,920 distinct tentative consensus sequences (TCs) and 5,571 nonoverlapping ESTs (singletons). Of these, 376 TCs (20%) and 1,449 singletons (26%) are unique to the SUNY/TIGR sequencing effort. Tentative consensus sequences and singletons were distributed into various categories of biological roles associated with cell structure, metabolism, protein fate, signal transduction, transcription, protein synthesis, transporters, and cell growth. The TCs and singletons represent transcripts that can be used as a resource for functional annotation of genomic sequence data, comparative sequence analysis, and cDNA clone selection for microarray projects. The utility of EST analysis is demonstrated by identifying new protease genes, which may be involved in hemoglobin degradation.

Amino Acid Sequence↗
PubMed2004

HCVDB: hepatitis C virus sequences database.

UNLABELLED: To date, more than 30 000 hepatitis C virus (HCV) sequences have been deposited in the generalist databases DNA Data Bank of Japan (DDBJ), EMBL Nucleotide Sequence Database (EMBL) and GenBank. The main difficulties with HCV sequences in these databases are their retrieval, annotation and analyses. To help HCV researchers face the increasing needs of HCV sequence analyses, we developed a specialised database of computer-annotated HCV sequences, called HCVDB. HCVDB is re-built every month from an up-to-date EMBL database by an automated process. HCVDB provides key data about the HCV sequences (e.g. genotype, genomic region, protein names and functions, known 3-dimensional structures) and ensures consistency of the annotations, which enables reliable keyword queries. The database is highly integrated with sequence and structure analysis tools and the SRS (LION bioscience) keywords query system. Thus, any user can extract subsets of sequences matching particular criteria or enter their own sequences and analyse them with various bioinformatics programs available on the same server. AVAILABILITY: HCVDB is available from http://hepatitis.ibcp.fr.

Amino Acid Sequence↗
PubMed2006

Annotation of novel neuropeptide precursors in the migratory locust based on transcript screening of a public EST database and mass spectrometry.

BACKGROUND: For holometabolous insects there has been an explosion of proteomic and peptidomic information thanks to large genome sequencing projects. Heterometabolous insects, although comprising many important species, have been far less studied. The migratory locust Locusta migratoria, a heterometabolous insect, is one of the most infamous agricultural pests. They undergo a well-known and profound phase transition from the relatively harmless solitary form to a ferocious gregarious form. The underlying regulatory mechanisms of this phase transition are not fully understood, but it is undoubtedly that neuropeptides are involved. However, neuropeptide research in locusts is hampered by the absence of genomic information. RESULTS: Recently, EST (Expressed Sequence Tag) databases from Locusta migratoria were constructed. Using bioinformatical tools, we searched these EST databases specifically for neuropeptide precursors. Based on known locust neuropeptide sequences, we confirmed the sequence of several previously identified neuropeptide precursors (i.e. pacifastin-related peptides), which consolidated our method. In addition, we found two novel neuroparsin precursors and annotated the hitherto unknown tachykinin precursor. Besides one of the known tachykinin peptides, this EST contained an additional tachykinin-like sequence. Using neuropeptide precursors from Drosophila melanogaster as a query, we succeeded in annotating the Locusta neuropeptide F, allatostatin-C and ecdysis-triggering hormone precursor, which until now had not been identified in locusts or in any other heterometabolous insect. For the tachykinin precursor, the ecdysis-triggering hormone precursor and the allatostatin-C precursor, translation of the predicted neuropeptides in neural tissues was confirmed with mass spectrometric techniques. CONCLUSION: In this study we describe the annotation of 6 novel neuropeptide precursors and the neuropeptides they encode from the migratory locust, Locusta migratoria. By combining the manual annotation of neuropeptides with experimental evidence provided by mass spectrometry, we demonstrate that the genes are not only transcribed but also translated into precursor proteins. In addition, we show which neuropeptides are cleaved from these precursor proteins and how they are post-translationally modified.

Amino Acid Sequence↗
PubMed2000

Sequence annotation of nuclear receptor ligand-binding domains by automated homology modeling.

The quality of three-dimensional homology models derived from protein sequences provides an independent measure of the suitability of a protein sequence for a certain fold. We have used automated homology modeling and model assessment tools to identify putative nuclear hormone receptor ligand-binding domains in the genome of Caenorhabditis elegans. Our results indicate that the availability of multiple crystal structures is crucial to obtaining useful models in this receptor family. The majority of annotated mammalian nuclear hormone receptors could be assigned to a ligand-binding domain fold by using the best model derived from any of four template structures. This strategy also assigned the ligand-binding domain fold to a number of C.elegans. sequences without prior annotation. Interestingly, the retinoic acid receptor crystal structure contributed most to the number of sequences that could be assigned to a ligand-binding domain fold. Several causes for this can be suggested, including the high quality of this protein structure in terms of our assessment tools, similarity between the biological function or ligand of this receptor and the modeled genes and gene duplication in C.elegans.

Animals↗