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PubMed2005

Differentiation of regions with atypical oligonucleotide composition in bacterial genomes.

BACKGROUND: Complete sequencing of bacterial genomes has become a common technique of present day microbiology. Thereafter, data mining in the complete sequence is an essential step. New in silico methods are needed that rapidly identify the major features of genome organization and facilitate the prediction of the functional class of ORFs. We tested the usefulness of local oligonucleotide usage (OU) patterns to recognize and differentiate types of atypical oligonucleotide composition in DNA sequences of bacterial genomes. RESULTS: A total of 163 bacterial genomes of eubacteria and archaea published in the NCBI database were analyzed. Local OU patterns exhibit substantial intrachromosomal variation in bacteria. Loci with alternative OU patterns were parts of horizontally acquired gene islands or ancient regions such as genes for ribosomal proteins and RNAs. OU statistical parameters, such as local pattern deviation (D), pattern skew (PS) and OU variance (OUV) enabled the detection and visualization of gene islands of different functional classes. CONCLUSION: A set of approaches has been designed for the statistical analysis of nucleotide sequences of bacterial genomes. These methods are useful for the visualization and differentiation of regions with atypical oligonucleotide composition prior to or accompanying gene annotation.

DNA, Bacterial↗
PubMed1999

Building dictionaries of 1D and 3D motifs by mining the Unaligned 1D sequences of 17 archaeal and bacterial genomes.

We have used the Teiresias algorithm to carry out unsupervised pattern discovery in a database containing the unaligned ORFs from the 17 publicly available complete archaeal and bacterial genomes and build a 1D dictionary of motifs. These motifs which we refer to as seqlets account for and cover 97.88% of this genomic input at the level of amino acid positions. Each of the seqlets in this 1D dictionary was located among the sequences in Release 38.0 of the Protein Data Bank and the structural fragments corresponding to each seqlet's instances were identified and aligned in three dimensions: those of the seqlets that resulted in RMSD errors below a pre-selected threshold of 2.5 Angstroms were entered in a 3D dictionary of structurally conserved seqlets. These two dictionaries can be thought of as cross-indices that facilitate the tackling of tasks such as automated functional annotation of genomic sequences, local homology identification, local structure characterization, comparative genomics, etc.

Algorithms↗
PubMed2001

Evolution of the Rab family of small GTP-binding proteins.

Rab proteins are small GTP-binding proteins that form the largest family within the Ras superfamily. Rab proteins regulate vesicular trafficking pathways, behaving as membrane-associated molecular switches. Here, we have identified the complete Rab families in the Caenorhabditis elegans (29 members), Drosophila melanogaster (29), Homo sapiens (60) and Arabidopsis thaliana (57), and we defined criteria for annotation of this protein family in each organism. We studied sequence conservation patterns and observed that the RabF motifs and the RabSF regions previously described in mammalian Rabs are conserved across species. This is consistent with conserved recognition mechanisms by general regulators and specific effectors. We used phylogenetic analysis and other approaches to reconstruct the multiplication of the Rab family and observed that this family shows a strict phylogeny of function as opposed to a phylogeny of species. Furthermore, we observed that Rabs co-segregating in phylogenetic trees show a pattern of similar cellular localisation and/or function. Therefore, animal and fungi Rab proteins can be grouped in "Rab functional groups" according to their segregating patterns in phylogenetic trees. These functional groups reflect similarity of sequence, localisation and/or function, and may also represent shared ancestry. Rab functional groups can help the understanding of the functional evolution of the Rab family in particular and vesicular transport in general, and may be used to predict general functions for novel Rab sequences.

Amino Acid Motifs↗
PubMed2006

Mining of relations between proteins over biomedical scientific literature using a deep-linguistic approach.

OBJECTIVE: The amount of new discoveries (as published in the scientific literature) in the biomedical area is growing at an exponential rate. This growth makes it very difficult to filter the most relevant results, and thus the extraction of the core information becomes very expensive. Therefore, there is a growing interest in text processing approaches that can deliver selected information from scientific publications, which can limit the amount of human intervention normally needed to gather those results. MATERIALS AND METHODS: This paper presents and evaluates an approach aimed at automating the process of extracting functional relations (e.g. interactions between genes and proteins) from scientific literature in the biomedical domain. The approach, using a novel dependency-based parser, is based on a complete syntactic analysis of the corpus. RESULTS: We have implemented a state-of-the-art text mining system for biomedical literature, based on a deep-linguistic, full-parsing approach. The results are validated on two different corpora: the manually annotated genomics information access (GENIA) corpus and the automatically annotated arabidopsis thaliana circadian rhythms (ATCR) corpus. CONCLUSION: We show how a deep-linguistic approach (contrary to common belief) can be used in a real world text mining application, offering high-precision relation extraction, while at the same time retaining a sufficient recall.

Animals↗
PubMed2003

Application of magnetic techniques in the field of drug discovery and biomedicine.

Magnetic separation technology, using magnetic particles, is quick and easy method for sensitive and reliable capture of specific proteins, genetic material and other biomolecules. The technique offers an advantage in terms of subjecting the analyte to very little mechanical stress compared to other methods. Secondly, these methods are non-laborious, cheap and often highly scalable. Moreover, techniques employing magnetism are more amenable to automation and miniaturization. Now that the human genome is sequenced and about 30,000 genes are annotated, the next step is to identify the function of these individual genes, carrying out genotyping studies for allelic variation and SNP analysis, ultimately leading to identification of novel drug targets. In this post-genomic era, technologies based on magnetic separation are becoming an integral part of todays biology laboratory. This article briefly reviews the selected applications of magnetic separation techniques in the field of biotechnology, biomedicine and drug discovery.

Journal Article↗
PubMed2005

Accurate prediction of scorpion toxin functional properties from primary structures.

Scorpion toxins are common experimental tools for studies of biochemical and pharmacological properties of ion channels. The number of functionally annotated scorpion toxins is steadily growing, but the number of identified toxin sequences is increasing at much faster pace. With an estimated 100,000 different variants, bioinformatic analysis of scorpion toxins is becoming a necessary tool for their systematic functional analysis. Here, we report a bioinformatics-driven system involving scorpion toxin structural classification, functional annotation, database technology, sequence comparison, nearest neighbour analysis, and decision rules which produces highly accurate predictions of scorpion toxin functional properties.

Algorithms↗
PubMed2006

AthaMap: from in silico data to real transcription factor binding sites.

AthaMap generates a map for cis-regulatory sequences for the whole Arabidopsis thaliana genome. AthaMap was initially developed by matrix-based detection of putative transcription factor binding sites (TFBS) mostly determined from random binding site selection experiments. Now, also experimentally verified TFBS have been included for 48 different Arabidopsis thaliana transcription factors (TF). Based on these sequences, 89,416 very similar putative TFBS were determined within the genome of A. thaliana and annotated to AthaMap. Matrix- and single sequence-based binding sites can be included in colocalization analysis for the identification of combinatorial cis-regulatory elements. As an example, putative target genes of the WRKY18 transcription factor that is involved in plant-pathogen interaction were determined. New functions of AthaMap include descriptions for all annotated Arabidopsis thaliana genes and direct links to TAIR, TIGR and MIPS. Transcription factors used in the binding site determination are linked to TAIR and TRANSFAC databases. AthaMap is freely available at http://www.athamap.de.

Arabidopsis↗
PubMed1999

Animation of the dynamical events of the elongation cycle based on cryoelectron microscopy of functional complexes of the ribosome.

Using three-dimensional cryoelectron microscopy, the binding positions of tRNA and elongation factors EF-G and EF-Tu (the latter complexed with aminoacyl tRNA and GTP) on the ribosome were determined in previous studies. On the basis of these studies, the dynamical events that take place in the course of the elongation cycle of protein synthesis have been animated. The resulting 3-min movie is accessible on the website of this journal (http://www. idealibrary.com). The following article provides a brief annotation of those frames of the movie for which experimental support is available.

Computer Simulation↗
PubMed2004

An evolutionary model for protein-coding regions with conserved RNA structure.

Here we present a model of nucleotide substitution in protein-coding regions that also encode the formation of conserved RNA structures. In such regions, apparent evolutionary context dependencies exist, both between nucleotides occupying the same codon and between nucleotides forming a base pair in the RNA structure. The overlap of these fundamental dependencies is sufficient to cause "contagious" context dependencies which cascade across many nucleotide sites. Such large-scale dependencies challenge the use of traditional phylogenetic models in evolutionary inference because they explicitly assume evolutionary independence between short nucleotide tuples. In our model we address this by replacing context dependencies within codons by annotation-specific heterogeneity in the substitution process. Through a general procedure, we fragment the alignment into sets of short nucleotide tuples based on both the protein coding and the structural annotation. These individual tuples are assumed to evolve independently, and the different tuple sets are assigned different annotation-specific substitution models shared between their members. This allows us to build a composite model of the substitution process from components of traditional phylogenetic models. We applied this to a data set of full-genome sequences from the hepatitis C virus where five RNA structures are mapped within the coding region. This allowed us to partition the effects of selection on different structural elements and to test various hypotheses concerning the relation of these effects. Of particular interest, we found evidence of a functional role of loop and bulge regions, as these were shown to evolve according to a different and more constrained selective regime than the nonpairing regions outside the RNA structures. Other potential applications of the model include comparative RNA structure prediction in coding regions and RNA virus phylogenetics.

Base Sequence↗
PubMed2001

Mining literature for protein-protein interactions.

MOTIVATION: A central problem in bioinformatics is how to capture information from the vast current scientific literature in a form suitable for analysis by computer. We address the special case of information on protein-protein interactions, and show that the frequencies of words in Medline abstracts can be used to determine whether or not a given paper discusses protein-protein interactions. For those papers determined to discuss this topic, the relevant information can be captured for the Database of Interacting PROTEINS: Furthermore, suitable gene annotations can also be captured. RESULTS: Our Bayesian approach scores Medline abstracts for probability of discussing the topic of interest according to the frequencies of discriminating words found in the abstract. More than 80 discriminating words (e.g. complex, interaction, two-hybrid) were determined from a training set of 260 Medline abstracts corresponding to previously validated entries in the Database of Interacting Proteins. Using these words and a log likelihood scoring function, approximately 2000 Medline abstracts were identified as describing interactions between yeast proteins. This approach now forms the basis for the rapid expansion of the Database of Interacting Proteins.

Algorithms↗
PubMed2006

Transcriptional profiling reveals a possible role for the timing of the inflammatory response in determining susceptibility to a viral infection.

Using a novel cDNA microarray prepared from sources of actively responding immune system cells, we have investigated the changes in gene expression in the target tissue during the early stages of infection of neonatal chickens with infectious bursal disease virus. Infections of two lines of chickens previously documented as genetically resistant and sensitive to infection were compared in order to ascertain early differences in the response to infection that might provide clues to the mechanism of differential genetic resistance. In addition to major changes that could be explained by previously described changes in infected tissue, some differences in gene expression on infection, and differences between the two chicken lines, were observed that led to a model for resistance in which a more rapid inflammatory response and more-extensive p53-related induction of apoptosis in the target B cells might limit viral replication and consequent pathology. Ironically, the effect in the asymptomatic neonatal infection is that more-severe B-cell depletion is seen in the more genetically resistant chicken. Changes of expression of many chicken genes of unknown function, indicating possible roles in the response to infection, may aid in the functional annotation of these genes.

Animals↗
PubMed2026

TET2 promotes monocyte inflammatory activation in asthma via ALKBH5-m6A regulation and PI3K signaling: evidence from m6A-SNP and single-cell analyses.

Asthma is a complex inflammatory airway disease with strong genetic determinants, yet the functional relevance of most asthma-associated non-coding variants remains unclear. Emerging evidence suggests that N6-methyladenosine (m6A) modification may serve as a critical epitranscriptomic link between genetic variation and immune regulation. In this study, we aimed to systematically identify functionally relevant m6A-regulated genes in asthma by integrating large-scale GWAS data, m6A-SNP annotations, and single-cell transcriptomic analyses, and to investigate their roles in monocyte-driven airway inflammation. We identified TET2 as a key m6A-regulated gene associated with both asthma and lung function, which was selectively upregulated in monocytes during asthma and accompanied by activation of inflammatory and PI3K signaling pathways. Mechanistic experiments further demonstrated that inflammatory stimulation induced ALKBH5 expression, reduced m6A modification of TET2 mRNA, and increased TET2 protein levels, thereby promoting PI3K/AKT signaling and pro-inflammatory cytokine production, whereas inhibition of TET2 or ALKBH5 attenuated these effects. Collectively, these findings demonstrate that ALKBH5-mediated m6A regulation of TET2 enhances PI3K/AKT signaling in monocytes, thereby promoting inflammatory responses in asthma. Our study establishes TET2 as a key m6A-regulated gene linking genetic susceptibility to monocyte-driven inflammation, and highlights the ALKBH5-m6A-TET2 axis as a potential therapeutic target for modulating aberrant immune responses in asthma.

Humans↗
PubMed2005

Complete genome sequence of the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1 and comparison with Pyrococcus genomes.

The genus Thermococcus, comprised of sulfur-reducing hyperthermophilic archaea, belongs to the order Thermococcales in Euryarchaeota along with the closely related genus Pyrococcus. The members of Thermococcus are ubiquitously present in natural high-temperature environments, and are therefore considered to play a major role in the ecology and metabolic activity of microbial consortia within hot-water ecosystems. To obtain insight into this important genus, we have determined and annotated the complete 2,088,737-base genome of Thermococcus kodakaraensis strain KOD1, followed by a comparison with the three complete genomes of Pyrococcus spp. A total of 2306 coding DNA sequences (CDSs) have been identified, among which half (1165 CDSs) are annotatable, whereas the functions of 41% (936 CDSs) cannot be predicted from the primary structures. The genome contains seven genes for probable transposases and four virus-related regions. Several proteins within these genetic elements show high similarities to those in Pyrococcus spp., implying the natural occurrence of horizontal gene transfer of such mobile elements among the order Thermococcales. Comparative genomics clarified that 1204 proteins, including those for information processing and basic metabolisms, are shared among T. kodakaraensis and the three Pyrococcus spp. On the other hand, among the set of 689 proteins unique to T. kodakaraensis, there are several intriguing proteins that might be responsible for the specific trait of the genus Thermococcus, such as proteins involved in additional pyruvate oxidation, nucleotide metabolisms, unique or additional metal ion transporters, improved stress response system, and a distinct restriction system.

Amino Acid Substitution↗
PubMed2006

Genomic analysis of carbon source metabolism of Shewanella oneidensis MR-1: Predictions versus experiments.

Genomic sequences have been used to find the genetic foundation for carbon source metabolism in Shewanella oneidensis MR-1. Annotated S. oneidensis MR-1 gene products were examined for their sequence similarity to enzymes participating in pathways for utilization of carbon and energy as described in the BioCyc database (http://www.biocyc.org/) or in the primary literature. A picture emerges that relegates five- and six-carbon sugars to minor roles as carbon sources, whereas multiple pathways for utilization of up to three-carbon carbohydrates seem to be present. Capacity to utilize amino acids for carbon and energy is also present. A few contradictions emerged in which enzymes appear to be present by annotations but are not active in the cell according to physiological experiments. Annotations are based on close sequence similarity and will not reveal inactivity due to deleterious mutations or due to lack of coordination of regulation and transport. Genes for a few enzymes known by experiment to be active are not found in the genome. This may be due to extensive divergence after duplication or convergence of function in separate lines in evolution rendering activities undetectable by sequence similarity. To minimize false predictions from protein sequences, we have been conservative in predicting pathways. We did not predict any pathway when, although a partial pathway was seen it was composed largely of enzymes already accounted for in any other complete pathway. This is an example of how a biochemically oriented sequence analysis can generate questions and direct further experimental investigation.

Bacterial Proteins↗
PubMed2026

Exploring the Mitochondrial Genomes of Phoebe Species (Lauraceae): Structural Dynamics and Functional Conservation.

Plant mitochondrial genomes (mitogenomes) vary markedly in size and architecture despite generally slow rates of sequence evolution. Phoebe is an ecologically and economically valuable genus of Lauraceae, yet its mitogenome diversity remains poorly characterized. In this study, we newly sequenced, assembled, and annotated the mitogenomes of three nationally protected Class II wild plants (P. bournei, P. chekiangensis, P. zhennan) from China and compared their mitogenomic characteristics. The three assemblies were resolved into representative circular configurations ranging from 808 to 864 kb, with similar GC contents and conserved protein-coding capacity. Each mitogenome contained distinct 41 protein-coding genes, 27-28 transfer RNAs, and three ribosomal RNAs. Synteny analysis revealed extensive changes in homologous-block order and orientation despite substantial sequence homology among the three species. Abundant repeats occurred predominantly in noncoding regions, while plastid-derived fragments documented historical intracellular DNA transfer. The three species exhibited similar codon usage and predicted RNA-editing patterns, whereas low synonymous divergence limited inference from pairwise ratios. Phylogenetic analysis based on mitochondrial protein-coding genes recovered Phoebe as a well-supported monophyletic lineage. These results reveal substantial structural divergence accompanied by conserved nucleotide composition and coding capacity, providing valuable data for further understanding the evolutionary variation of plant mitogenomes of Phoebe and the Lauraceae.

Phoebe↗
PubMed2006

A general model of G protein-coupled receptor sequences and its application to detect remote homologs.

G protein-coupled receptors (GPCRs) constitute a large superfamily involved in various types of signal transduction pathways triggered by hormones, odorants, peptides, proteins, and other types of ligands. The superfamily is so diverse that many members lack sequence similarity, although they all span the cell membrane seven times with an extracellular N and a cytosolic C terminus. We analyzed a divergent set of GPCRs and found distinct loop length patterns and differences in amino acid composition between cytosolic loops, extracellular loops, and membrane regions. We configured GPCRHMM, a hidden Markov model, to fit those features and trained it on a large dataset representing the entire superfamily. GPCRHMM was benchmarked to profile HMMs and generic transmembrane detectors on sets of known GPCRs and non-GPCRs. In a cross-validation procedure, profile HMMs produced an error rate nearly twice as high as GPCRHMM. In a sensitivity-selectivity test, GPCRHMM's sensitivity was about 15% higher than that of the best transmembrane predictors, at comparable false positive rates. We used GPCRHMM to search for novel members of the GPCR superfamily in five proteomes. All in all we detected 120 sequences that lacked annotation and are potentially novel GPCRs. Out of those 102 were found in Caenorhabditis elegans, four in human, and seven in mouse. Many predictions (65) belonged to Pfam domains of unknown function. GPCRHMM strongly rejected a family of arthropod-specific odorant receptors believed to be GPCRs. A detailed analysis showed that these sequences are indeed very different from other GPCRs. GPCRHMM is available at http://gpcrhmm.cgb.ki.se.

Amino Acids↗
PubMed2005

PISCES: recent improvements to a PDB sequence culling server.

PISCES is a database server for producing lists of sequences from the Protein Data Bank (PDB) using a number of entry- and chain-specific criteria and mutual sequence identity. Our goal in culling the PDB is to provide the longest list possible of the highest resolution structures that fulfill the sequence identity and structural quality cut-offs. The new PISCES server uses a combination of PSI-BLAST and structure-based alignments to determine sequence identities. Structure alignment produces more complete alignments and therefore more accurate sequence identities than PSI-BLAST. PISCES now allows a user to cull the PDB by-entry in addition to the standard culling by individual chains. In this scenario, a list will contain only entries that do not have a chain that has a sequence identity to any chain in any other entry in the list over the sequence identity cut-off. PISCES also provides fully annotated sequences including gene name and species. The server allows a user to cull an input list of entries or chains, so that other criteria, such as function, can be used. Results from a search on the re-engineered RCSB's site for the PDB can be entered into the PISCES server by a single click, combining the powerful searching abilities of the PDB with PISCES's utilities for sequence culling. The server's data are updated weekly. The server is available at http://dunbrack.fccc.edu/pisces.

Databases, Protein↗
PubMed2003

Proteomic analysis of an extreme halophilic archaeon, Halobacterium sp. NRC-1.

Halobacterium sp. NRC-1 insoluble membrane and soluble cytoplasmic proteins were isolated by ultracentrifugation of whole cell lysate. Using an ion trap mass spectrometer equipped with a C18 trap electrospray ionization emitter/micro-liquid chromatography column, a number of trypsin-generated peptide tags from 426 unique proteins were identified. This represents approximately one-fifth of the theoretical proteome of Halobacterium. Of these, 232 proteins were found only in the soluble fraction, 165 were only in the insoluble membrane fraction, and 29 were in both fractions. There were 72 and 61% previously annotated proteins identified in the soluble and membrane protein fractions, respectively. Interestingly, 57 of previously unannotated proteins found only in Halobacterium NRC-1 were identified. Such proteins could be interesting targets for understanding unique physiology of Halobacterium NRC-1. A group of proteins involved in various metabolic pathways were identified among the expressed proteins, suggesting these pathways were active at the time the cells were collected. This data containing a list of expressed proteins, their cellular locations, and biological functions could be used in future studies to investigate the interaction of the genes and proteins in relation to genetic or environmental perturbations.

Archaeal Proteins↗