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PubMed1994

Complete nucleotide sequence of Birmingham IncP alpha plasmids. Compilation and comparative analysis.

The IncP alpha promiscuous plasmid (R18, R68, RK2, RP1 and RP4) comprises 60,099 bp of nucleotide sequence, encoding at least 74 genes. About 40 kb of the genome, designated the IncP core and including all essential replication and transfer functions, can be aligned with equivalent sequences in the IncP beta plasmid R751. The compiled IncP alpha sequence revealed several previously unidentified reading frames that are potential genes. IncP alpha plasmids carry genetic information very efficiently: the coding sequences of the genes are closely packed but rarely overlap, and occupy almost 86% of the genome's nucleotide sequence. All of the 74 genes should be expressed, although there is as yet experimental evidence for expression of only 60 of them. Six examples of tandem-in-frame initiation sites specifying two gene products each are known. Two overlapping gene arrangements occupy different reading frames of the same region. Intergenic regions include most of the 25 promoters; transcripts are usually polycistronic. Translation of most of the open reading frames seems to be initiated independently, each from its own ribosomal binding and initiation site, although, a few cases of coupled translation have been reported. The most frequently used initiation codon is AUG but translation for a few open reading frames begins at GUG or UUG. The most common stop-codon is UGA followed by UAA and then UAG. Regulatory circuits are complex and largely dependent on two components of the central control operon. KorA and KorB are transcriptional repressors controlling at least seven operons. KorA and KorB act synergistically in several cases by recognizing and binding to conserved nucleotide sequences. Twelve KorB binding sites were found around the IncP alpha sequence and these are conserved in R751 (IncP beta) with respect to both sequence and location. Replication of IncP alpha plasmids requires oriV and the plasmid-encoded initiator protein TrfA in combination with the host-encoded replication machinery. Conjugative plasmid transfer depends on two separate regions occupying about half of the genome. The primary segregational stability system designated Par/Mrs consists of a putative site-specific recombinase, a possible partitioning apparatus and a post-segregational lethality mechanism, all encoded in two divergent operons. Proteins related to the products of F sop and P1 par partitioning genes are separately encoded in the central control operon.

Amino Acid Sequence↗
PubMed2006

Sigma: multiple alignment of weakly-conserved non-coding DNA sequence.

BACKGROUND: Existing tools for multiple-sequence alignment focus on aligning protein sequence or protein-coding DNA sequence, and are often based on extensions to Needleman-Wunsch-like pairwise alignment methods. We introduce a new tool, Sigma, with a new algorithm and scoring scheme designed specifically for non-coding DNA sequence. This problem acquires importance with the increasing number of published sequences of closely-related species. In particular, studies of gene regulation seek to take advantage of comparative genomics, and recent algorithms for finding regulatory sites in phylogenetically-related intergenic sequence require alignment as a preprocessing step. Much can also be learned about evolution from intergenic DNA, which tends to evolve faster than coding DNA. Sigma uses a strategy of seeking the best possible gapless local alignments (a strategy earlier used by DiAlign), at each step making the best possible alignment consistent with existing alignments, and scores the significance of the alignment based on the lengths of the aligned fragments and a background model which may be supplied or estimated from an auxiliary file of intergenic DNA. RESULTS: Comparative tests of sigma with five earlier algorithms on synthetic data generated to mimic real data show excellent performance, with Sigma balancing high "sensitivity" (more bases aligned) with effective filtering of "incorrect" alignments. With real data, while "correctness" can't be directly quantified for the alignment, running the PhyloGibbs motif finder on pre-aligned sequence suggests that Sigma's alignments are superior. CONCLUSION: By taking into account the peculiarities of non-coding DNA, Sigma fills a gap in the toolbox of bioinformatics.

Algorithms↗
PubMed1999

GenTHREADER: an efficient and reliable protein fold recognition method for genomic sequences.

A new protein fold recognition method is described which is both fast and reliable. The method uses a traditional sequence alignment algorithm to generate alignments which are then evaluated by a method derived from threading techniques. As a final step, each threaded model is evaluated by a neural network in order to produce a single measure of confidence in the proposed prediction. The speed of the method, along with its sensitivity and very low false-positive rate makes it ideal for automatically predicting the structure of all the proteins in a translated bacterial genome (proteome). The method has been applied to the genome of Mycoplasma genitalium, and analysis of the results shows that as many as 46 % of the proteins derived from the predicted protein coding regions have a significant relationship to a protein of known structure. In some cases, however, only one domain of the protein can be predicted, giving a total coverage of 30 % when calculated as a fraction of the number of amino acid residues in the whole proteome.

Algorithms↗
PubMed2005

MicroRNA identification based on sequence and structure alignment.

MOTIVATION: MicroRNAs (miRNA) are approximately 22 nt long non-coding RNAs that are derived from larger hairpin RNA precursors and play important regulatory roles in both animals and plants. The short length of the miRNA sequences and relatively low conservation of pre-miRNA sequences restrict the conventional sequence-alignment-based methods to finding only relatively close homologs. On the other hand, it has been reported that miRNA genes are more conserved in the secondary structure rather than in primary sequences. Therefore, secondary structural features should be more fully exploited in the homologue search for new miRNA genes. RESULTS: In this paper, we present a novel genome-wide computational approach to detect miRNAs in animals based on both sequence and structure alignment. Experiments show this approach has higher sensitivity and comparable specificity than other reported homologue searching methods. We applied this method on Anopheles gambiae and detected 59 new miRNA genes. AVAILABILITY: This program is available at http://bioinfo.au.tsinghua.edu.cn/miralign. SUPPLEMENTARY INFORMATION: Supplementary information is available at http://bioinfo.au.tsinghua.edu.cn/miralign/supplementary.htm.

Algorithms↗
PubMed2003

Acute hepatitis C in a chronically HIV-infected patient: evolution of different viral genomic regions.

AIM: To analyze the molecular evolution of different viral genomic regions of HCV in an acute HCV infected patient chronically infected with HIV through a 42-month follow-up. METHODS: Serum samples of a chronically HIV infected patient that seroconverted to anti HCV antibodies were sequenced, from the event of superinfection through a period of 17 months and in a late sample (42nd month). Hypervariable genomic regions of HIV (V3 loop of the gp120) and HCV (HVR-1 on the E2 glycoprotein gene) were studied. In order to analyze genomic regions involved in different biological functions and with the cellular immune response, HCV core and NS5A were also chosen to be sequenced. Amplification of the different regions was done by RT-PCR and directly sequenced. Confirmation of sequences was done on reamplified material. Nucleotide sequences of the different time points were aligned with CLUSTAL W 1.5, and the corresponding amino acid ones were deduced. RESULTS: Hypervariable genomic regions of both viruses (HVR1 and gp120 V3 loop) presented several nonsynonymous changes but, while in the gp120 V3 loop mutations were detected in the sample obtained right after HCV superinfection and maintained throughout, they occurred following a sequential and cumulative pattern in the HVR1. In the NS5A region of HCV, two amino acid changes were detected during the follow-up period, whereas the core region presented several amino acid replacements, once the HCV chronic infection had been established. CONCLUSION: During the HIV-HCV superinfection, each genomic region analyzed shows a different evolutionary pattern. Most of the nucleotide substitutions observed are non-synonymous and clustered in previously described epitopes, thus suggesting an immune-driven evolutionary process.

Acute Disease↗
PubMedDate not supplied

Single molecule analysis of DNA replication.

We describe here a novel approach for the study of DNA replication. The approach is based on a process called molecular combing and allows for the genome wide analysis of the spatial and temporal organization of replication units and replication origins in a sample of genomic DNA. Molecular combing is a process whereby molecules of DNA are stretched and aligned on a glass surface by the force exerted by a receding air/water interface. Since the stretching occurs in the immediate vicinity of the meniscus, all molecules are identically stretched in a size and sequence independent manner. The application of fluorescence hybridization to combed DNA results in a high resolution (1 to 4 kb) optical mapping that is simple, controlled and reproducible. The ability to comb up to several hundred haploid genomes on a single coverslip allows for a statistically significant number of measurements to be made. Direct labeling of replicating DNA sequences in turn enables origins of DNA replication to be visualized and mapped. These features therefore make molecular combing an attractive tool for genomic studies of DNA replication. In the following, we discuss the application of molecular combing to the study of DNA replication and genome stability.

Animals↗
PubMed2006

Phytome: a platform for plant comparative genomics.

Phytome is an online comparative genomics resource that can be applied to functional plant genomics, molecular breeding and evolutionary studies. It contains predicted protein sequences, protein family assignments, multiple sequence alignments, phylogenies and functional annotations for proteins from a large, phylogenetically diverse set of plant taxa. Phytome serves as a glue between disparate plant gene databases both by identifying the evolutionary relationships among orthologous and paralogous protein sequences from different species and by enabling cross-references between different versions of the same gene curated independently by different database groups. The web interface enables sophisticated queries on lineage-specific patterns of gene/protein family proliferation and loss. This rich dataset is serving as a platform for the unification of sequence-anchored comparative maps across taxonomic families of plants. The Phytome web interface can be accessed at the following URL: http://www.phytome.org. Batch homology searches and bulk downloads are available upon free registration.

Databases, Genetic↗
PubMed2002

Complete genome sequences and phylogenetic analysis of West Nile virus strains isolated from the United States, Europe, and the Middle East.

The complete nucleotide sequences of eight West Nile (WN) virus strains (Egypt 1951, Romania 1996-MQ, Italy 1998-equine, New York 1999-equine, MD 2000-crow265, NJ 2000MQ5488, NY 2000-grouse3282, and NY 2000-crow3356) were determined. Phylogenetic trees were constructed from the aligned nucleotide sequences of these eight viruses along with all other previously published complete WN virus genome sequences. The phylogenetic trees revealed the presence of two genetic lineages of WN viruses. Lineage 1 WN viruses have been isolated from the northeastern United States, Europe, Israel, Africa, India, Russia, and Australia. Lineage 2 WN viruses have been isolated only in sub-Saharan Africa and Madagascar. Lineage 1 viruses can be further subdivided into three monophyletic clades.

Animals↗
PubMed2003

Conserved noncoding sequences among cultivated cereal genomes identify candidate regulatory sequence elements and patterns of promoter evolution.

Surveys for conserved noncoding sequences (CNS) among genes from monocot cereal species were conducted to assess the general properties of CNS in grass genomes and their correlation with known promoter regulatory elements. Initial comparisons of 11 orthologous maize-rice gene pairs found that previously defined regulatory motifs could be identified within short CNS but could not be distinguished reliably from random sequence matches. Among the different phylogenetic footprinting algorithms tested, the VISTA tool yielded the most informative alignments of noncoding sequence. VISTA was used to survey for CNS among all publicly available genomic sequences from maize, rice, wheat, barley, and sorghum, representing >300 gene comparisons. Comparisons of orthologous maize-rice and maize-sorghum gene pairs identified 20 bp as a minimal length criterion for a significant CNS among grass genes, with few such CNS found to be conserved across rice, maize, sorghum, and barley. The frequency and length of cereal CNS as well as nucleotide substitution rates within CNS were consistent with the known phylogenetic distances among the species compared. The implications of these findings for the evolution of cereal gene promoter sequences and the utility of using the nearly completed rice genome sequence to predict candidate regulatory elements in other cereal genes by phylogenetic footprinting are discussed.

Algorithms↗
PubMed1993

Synaptic intermediates in bacteriophage lambda site-specific recombination: integrase can align pairs of attachment sites.

Bacteriophage lambda uses site-specific recombination to move its DNA into and out of the Escherichia coli genome. The recombination event is mediated by the recombinase integrase (Int) together with several accessory proteins through short specific DNA sequences known as attachment sites. A gel mobility shift assay has been used to show that, in the absence of accessory proteins, Int can align and hold together two DNA molecules, each with an attachment site, to form stable non-covalent 'bimolecular complexes'. Each attachment site must have both core and arm binding sites for Int to participate in a bimolecular complex. These stable structures can be formed between pairs of attL and attP attachment sites, but cannot include attB or attR sites; they are inhibited by integration host factor (IHF) protein. The bimolecular complexes are shown to represent a synaptic intermediate in the reaction in which Int protein promotes the IHF-independent recombination of two attL sites. These complexes should enable a detailed analysis of synapsis for this pathway.

Bacteriophage lambda↗
PubMed1997

16S rRNA gene sequence of Rubrobacter radiotolerans and its phylogenetic alignment with members of the genus Arthrobacter, gram-positive bacteria, and members of the family Deinococcaceae.

The nearly complete sequence of the 16S rRNA gene of an extremely highly radiotolerant bacterium, Rubrobacter radiotolerans (reclassified from Arthrobacter radiotolerans based on chemical characteristics), was determined by PCR amplification of the genomic DNA followed by cloning of the amplified gene and sequencing by the dideoxynucleotide method. The sequence was aligned with the sequences of members of the genus Arthrobacter and also with the sequences of representatives of the gram-positive bacteria having high G + C contents and the family Deinococcaceae (radioresistant micrococci and their relatives). The results of our phylogenetic analysis confirmed that R. radiotolerans is not a member of the Arthrobacter group and thus supported the previous reclassification. Moreover, although it is radioresistant and has a high G+C content, R. radiotolerans is more closely related to the gram-positive bacteria with high G+C contents than to the radioresistant members of the Deinococcaceae.

Arthrobacter↗
PubMed2026

fRagmentomics: an R package for integrating cell-free DNA fragment features with mutational status to support liquid biopsy interpretation.

SUMMARY: Liquid biopsy offers a non-invasive approach to study tumor-derived genetic material circulating in plasma. Beyond genetic alterations, the fragmentomic features of cell-free DNA-such as fragment size, genomic position, and end-motifs-provide valuable insights into the biological and clinical context of DNA release. fRagmentomics is a user-friendly R package designed to characterize cfDNA fragments overlapping one or multiple small mutations of any type, starting from an aligned sequencing file (BAM). It supports multiple mutation input formats, accommodates one-based and zero-based genomic conventions, resolves mutation representation ambiguities, and accepts any reference file in FASTA format. For each fragment overlapping a mutation of interest, fRagmentomics outputs fragment-level features including its fragment size, end-motifs, and mutational status, along with additional fragment-level or read-level information. The package implements an indel-aware and optionally soft-clip-preserving fragment size computation that improves accuracy over conventional size estimates based solely on aligned positions. AVAILABILITY AND IMPLEMENTATION: fRagmentomics is licensed under GNU General Public License v3.0 and available at https://github.com/ElsaB-Lab/fRagmentomics, https://anaconda.org/elsab-lab/r-fragmentomics and https://bioconductor.org/packages/fRagmentomics, with documentation and a tutorial. CONTACT: yoann.pradat@gustaveroussy.fr, elsa.bernard@gustaveroussy.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Software↗
PubMed2006

Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues.

MicroRNAs are small approximately 22 nucleotide-long noncoding RNAs capable of controlling gene expression by inhibiting translation. Alignment of human microRNA stem-loop sequences (mir) against a recent draft sequence assembly of the bovine genome resulted in identification of 334 predicted bovine mir. We sequenced five tissue-specific cDNA libraries derived from the small RNA fractions of bovine embryo, thymus, small intestine, and lymph node to validate these predictions and identify new mir. This strategy combined with comparative sequence analysis identified 129 sequences that corresponded to mature microRNAs (miR). A total of 107 sequences aligned to known human mir, and 100 of these matched expressed miR. The other seven sequences represented novel miR expressed from the complementary strand of previously characterized human mir. The 22 sequences without matches displayed characteristic mir secondary structures when folded in silico, and 10 of these retained sequence conservation with other vertebrate species. Expression analysis based on sequence identity counts revealed that some miR were preferentially expressed in certain tissues, while bta-miR-26a and bta-miR-103 were prevalent in all tissues examined. These results support the premise that species differences in regulation of gene expression by miR occur primarily at the level of expression and processing.

Animals↗
PubMed2005

The Adaptive Evolution Database (TAED): a phylogeny based tool for comparative genomics.

From 138,662 embryophyte (higher plant) and 348,142 chordate genes, 4216 embryophyte and 15,452 chordate gene families were generated. For each of these gene families, multiple sequence alignments, phylogenetic trees, ratios of non-synonymous to synonymous nucleotide substitution rates (K(a)/K(s)), mappings from gene trees to the NCBI taxonomy and structural links to solved three-dimensional protein structures in the Protein Data Bank (PDB) with Grantham-weighted mutational factors were all calculated. Of the 'gene family trees', 173 embryophyte and 505 chordate branches show K(a)/K(s) >> 1 and are candidates for functional adaptation. The calculated information is available both as a gene family database and as a phylogenetically indexed resource, called 'The Adaptive Evolution Database' (TAED), available at http://www.bioinfo.no/tools/TAED.

Animals↗
PubMed2002

Full-length messenger RNA sequences greatly improve genome annotation.

BACKGROUND: Annotation of eukaryotic genomes is a complex endeavor that requires the integration of evidence from multiple, often contradictory, sources. With the ever-increasing amount of genome sequence data now available, methods for accurate identification of large numbers of genes have become urgently needed. In an effort to create a set of very high-quality gene models, we used the sequence of 5,000 full-length gene transcripts from Arabidopsis to re-annotate its genome. We have mapped these transcripts to their exact chromosomal locations and, using alignment programs, have created gene models that provide a reference set for this organism. RESULTS: Approximately 35% of the transcripts indicated that previously annotated genes needed modification, and 5% of the transcripts represented newly discovered genes. We also discovered that multiple transcription initiation sites appear to be much more common than previously known, and we report numerous cases of alternative mRNA splicing. We include a comparison of different alignment software and an analysis of how the transcript data improved the previously published annotation. CONCLUSIONS: Our results demonstrate that sequencing of large numbers of full-length transcripts followed by computational mapping greatly improves identification of the complete exon structures of eukaryotic genes. In addition, we are able to find numerous introns in the untranslated regions of the genes.

Alternative Splicing↗
PubMed2006

Novel phylogenetic studies of genomic sequence fragments derived from uncultured microbe mixtures in environmental and clinical samples.

A self-organizing map (SOM) was developed as a novel bioinformatics strategy for phylogenetic classification of sequence fragments obtained from pooled genome samples of uncultured microbes in environmental and clinical samples. This phylogenetic classification was possible without either orthologous sequence sets or sequence alignments. We first constructed SOMs for tetranucleotide frequencies in 210,000 5 kb sequence fragments obtained from 1502 prokaryotes for which at least 10 kb of genomic sequence has been deposited in public DNA databases. The sequences could be classified primarily according to phylogenetic groups without information regarding the species. We used the SOM method to classify sequence fragments derived from environmental samples of the Sargasso Sea and of an acidophilic biofilm growing in acid mine drainage. Phylogenetic diversity of the environmental sequences was effectively visualized on a single map. Sequences that were derived from a single genome but cloned independently could be reassociated in silico. G + C% has been used for a long period as a fundamental parameter for phylogenetic classification of microbes, but the G + C% is apparently too simple a parameter to differentiate a wide variety of known species. Oligonucleotide frequency can be used to distinguish the species because oligonucleotide frequencies vary significantly among their genomes.

Algorithms↗
PubMed1995

Isolation of an 800 kb contiguous DNA fragment encompassing a 3.5-cM region of chromosome 1 in Arabidopsis using YAC clones.

The apetala1 mutation of Arabidopsis affects floral meristem identity and the development of sepal and petal primordia of the flower. We mapped the available RFLP markers on chromosome 1 that are in the general vicinity of apetala1 on a fine structure map and then chose the closest RFLP as a starting point for contiguous DNA (contig) generation. We report here a contig of about 800 kilobases (kb) that spans a 3.5 cM region of chromosome 1. We used genomic libraries of Arabidopsis prepared in yeast artificial chromosome (YAC) vectors and the detailed characterization of 19 YACs is reported. RFLPs displayed by the end fragments from the walk were mapped to align and correlate the genetic and physical maps for this region of chromosome 1. In this segment of the genome, 1 cM corresponds to a little over 200 kb of physical distance.

Arabidopsis↗
PubMed2000

JESAM: CORBA software components to create and publish EST alignments and clusters.

MOTIVATION: Expressed Sequence Tags (ESTs) are cheap, easy and quick to obtain relative to full genomic sequencing and currently sample more eukaryotic genes than any other data source. They are particularly useful for developing Sequence Tag Sites (STSs for mapping), polymorphism discovery, disease gene hunting, mass spectrometer proteomics, and most ironically for finding genes and predicting gene structure after the great effort of genomic sequencing. However, ESTs have many problems and the public EST databases contain all the errors and high redundancy intrinsic to the submitted data so it is often found that derived database views, which reduce both errors and redundancy, are more effective starting points for research than the original raw submissions. Existing derived views such as EST cluster databases and consensus databases have never published supporting evidence or intermediary results leading to difficulties trusting, correcting, and customizing the final published database. These difficulties have lead many groups to wastefully repeat the complex intermediary work of others in order to offer slightly different final views. A better approach might be to discover the most expensive common calculations used by all the approaches and then publish all intermediary results. Given a globally accessible database with a suitable component interface, like the JESAM software described in this paper, the creation of customized EST-derived databases could be achieved with minimum effort. RESULTS: Databases of EST and full-length mRNA sequences for four model organisms have been self-compared by searching for overlaps consistent with contiguity. The sequence comparisons are performed in parallel using a PVM process farm and previous results are stored to allow incremental updates with minimal effort. The overlap databases have been published with CORBA interfaces to enable flexible global access as demonstrated by example Java applet browsers. Simple cDNA supercluster databases built as alignment database clients are themselves published via CORBA interfaces browsable with prototypical applets. A comparison with UniGene Mouse and Rat databases revealed undesirable features in both and the advantages of contrasting perspectives on complex data. AVAILABILITY: The software is packaged as two Jar files available from: URL: http://corba.ebi.ac.uk/EST/jesam/jesam. html. One jar contains all the Java source code, and the other contains all the C, C++ and IDL code. Links to working examples of the alignment and cluster viewers (if remote firewall permits) can be found at http://corba.ebi.ac.uk/EST. All the Washington University mouse EST traces are available for browsing at the same URL.

Animals↗