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PubMed2002

Genome scale comparison of Mycobacterium avium subsp. paratuberculosis with Mycobacterium avium subsp. avium reveals potential diagnostic sequences.

The genetic similarity between Mycobacterium avium subsp. paratuberculosis and other mycobacterial species has confounded the development of M. avium subsp. paratuberculosis-specific diagnostic reagents. Random shotgun sequencing of the M. avium subsp. paratuberculosis genome in our laboratories has shown >98% sequence identity with Mycobacterium avium subsp. avium in some regions. However, an in silico comparison of the largest annotated M. avium subsp. paratuberculosis contigs, totaling 2,658,271 bp, with the unfinished M. avium subsp. avium genome has revealed 27 predicted M. avium subsp. paratuberculosis coding sequences that do not align with M. avium subsp. avium sequences. BLASTP analysis of the 27 predicted coding sequences (genes) shows that 24 do not match sequences in public sequence databases, such as GenBank. These novel sequences were examined by PCR amplification with genomic DNA from eight mycobacterial species and ten independent isolates of M. avium subsp. paratuberculosis. From these analyses, 21 genes were found to be present in all M. avium subsp. paratuberculosis isolates and absent from all other mycobacterial species tested. One region of the M. avium subsp. paratuberculosis genome contains a cluster of eight genes, arranged in tandem, that is absent in other mycobacterial species. This region spans 4.4 kb and is separated from other predicted coding regions by 1,408 bp upstream and 1,092 bp downstream. The gene upstream of this eight-gene cluster has strong similarity to mycobacteriophage integrase sequences. The GC content of this 4.4-kb region is 66%, which is similar to the rest of the genome, indicating that this region was not horizontally acquired recently. Southern hybridization analysis confirmed that this gene cluster is present only in M. avium subsp. paratuberculosis. Collectively, these studies suggest that a genomics approach will help in identifying novel M. avium subsp. paratuberculosis genes as candidate diagnostic sequences.

Animals↗
PubMed2001

Extending traditional query-based integration approaches for functional characterization of post-genomic data.

MOTIVATION: To identify and characterize regions of functional interest in genomic sequence requires full, flexible query access to an integrated, up-to-date view of all related information, irrespective of where it is stored (within an organization or across the Internet) and its format (traditional database, flat file, web site, results of runtime analysis). Wide-ranging multi-source queries often return unmanageably large result sets, requiring non-traditional approaches to exclude extraneous data. RESULTS: Target Informatics Net (TINet) is a readily extensible data integration system developed at GlaxoSmith- Kline (GSK), based on the Object-Protocol Model (OPM) multidatabase middleware system of Gene Logic Inc. Data sources currently integrated include: the Mouse Genome Database (MGD) and Gene Expression Database (GXD), GenBank, SwissProt, PubMed, GeneCards, the results of runtime BLAST and PROSITE searches, and GSK proprietary relational databases. Special-purpose class methods used to filter and augment query results include regular expression pattern-matching over BLAST HSP alignments and retrieving partial sequences derived from primary structure annotations. All data sources and methods are accessible through an SQL-like query language or a GUI, so that when new investigations arise no additional programming beyond query specification is required. The power and flexibility of this approach are illustrated in such integrated queries as: (1) 'find homologs in genomic sequence to all novel genes cloned and reported in the scientific literature within the past three months that are linked to the MeSH term 'neoplasms"; (2) 'using a neuropeptide precursor query sequence, return only HSPs where the target genomic sequences conserve the G[KR][KR] motif at the appropriate points in the HSP alignment'; and (3) 'of the human genomic sequences annotated with exon boundaries in GenBank, return only those with valid putative donor/acceptor sites and start/stop codons'.

Animals↗
PubMed2000

Gene discovery using computational and microarray analysis of transcription in the Drosophila melanogaster testis.

Identification and annotation of all the genes in the sequenced Drosophila genome is a work in progress. Wild-type testis function requires many genes and is thus of potentially high value for the identification of transcription units. We therefore undertook a survey of the repertoire of genes expressed in the Drosophila testis by computational and microarray analysis. We generated 3141 high-quality testis expressed sequence tags (ESTs). Testis ESTs computationally collapsed into 1560 cDNA set used for further analysis. Of those, 11% correspond to named genes, and 33% provide biological evidence for a predicted gene. A surprising 47% fail to align with existing ESTs and 16% with predicted genes in the current genome release. EST frequency and microarray expression profiles indicate that the testis mRNA population is highly complex and shows an extended range of transcript abundance. Furthermore, >80% of the genes expressed in the testis showed onefold overexpression relative to ovaries, or gonadectomized flies. Additionally, >3% showed more than threefold overexpression at p <0.05. Surprisingly, 22% of the genes most highly overexpressed in testis match Drosophila genomic sequence, but not predicted genes. These data strongly support the idea that sequencing additional cDNA libraries from defined tissues, such as testis, will be important tools for refined annotation of the Drosophila genome. Additionally, these data suggest that the number of genes in Drosophila will significantly exceed the conservative estimate of 13,601.

Animals↗
PubMed2001

Human chromosome 19 and related regions in mouse: conservative and lineage-specific evolution.

To illuminate the function and evolutionary history of both genomes, we sequenced mouse DNA related to human chromosome 19. Comparative sequence alignments yielded confirmatory evidence for hypothetical genes and identified exons, regulatory elements, and candidate genes that were missed by other predictive methods. Chromosome-wide comparisons revealed a difference between single-copy HSA19 genes, which are overwhelmingly conserved in mouse, and genes residing in tandem familial clusters, which differ extensively in number, coding capacity, and organization between the two species. Finally, we sequenced breakpoints of all 15 evolutionary rearrangements, providing a view of the forces that drive chromosome evolution in mammals.

Animals↗
PubMed1996

Development of a diagnostic DNA probe to detect Setaria digitata: the causative parasite of cerebrospinal nematodiasis in goats, sheep and horses.

Two repetitive sequences (IpSdM and IpSdS) have been cloned and sequenced from the genome of Setaria digitata. When IpSdM (214 bp) and IpSdS (201 bp) were aligned, a high degree of homology (85%) was observed, indicating that they belong to the same family of repeats. IpSdM represents a complete repeating element while IpSdS consists of two partial repeating elements arranged in tandem. The elements are present in about 10 000 copies comprising 2.8% of the S. digitata genome. As a diagnostic probe IpSdM detects as little as 100 pg DNA of both S. digitata and S. labiato-papillosa. It can also detect a single microfilaria and a L3 larva making it a valuable tool to monitor cattle and mosquito vector populations in the prevention of cerebrospinal nematodiasis.

Animals↗
PubMed2007

Evolutionary history of LINE-1 in the major clades of placental mammals.

BACKGROUND: LINE-1 constitutes an important component of mammalian genomes. It has a dynamic evolutionary history characterized by the rise, fall and replacement of subfamilies. Most data concerning LINE-1 biology and evolution are derived from the human and mouse genomes and are often assumed to hold for all placentals. METHODOLOGY: To examine LINE-1 relationships, sequences from the 3' region of the reverse transcriptase from 21 species (representing 13 orders across Afrotheria, Xenarthra, Supraprimates and Laurasiatheria) were obtained from whole genome sequence assemblies, or by PCR with degenerate primers. These sequences were aligned and analysed. PRINCIPAL FINDINGS: Our analysis reflects accepted placental relationships suggesting mostly lineage-specific LINE-1 families. The data provide clear support for several clades including Glires, Supraprimates, Laurasiatheria, Boreoeutheria, Xenarthra and Afrotheria. Within the afrotherian LINE-1 (AfroLINE) clade, our tree supports Paenungulata, Afroinsectivora and Afroinsectiphillia. Xenarthran LINE-1 (XenaLINE) falls sister to AfroLINE, providing some support for the Atlantogenata (Xenarthra+Afrotheria) hypothesis. SIGNIFICANCE: LINEs and SINEs make up approximately half of all placental genomes, so understanding their dynamics is an essential aspect of comparative genomics. Importantly, a tree of LINE-1 offers a different view of the root, as long edges (branches) such as that to marsupials are shortened and/or broken up. Additionally, a robust phylogeny of diverse LINE-1 is essential in testing that site-specific LINE-1 insertions, often regarded as homoplasy-free phylogenetic markers, are indeed unique and not convergent.

Animals↗
PubMedDate not supplied

Improved gapped alignment in BLAST.

Homology search is a key tool for understanding the role, structure, and biochemical function of genomic sequences. The most popular technique for rapid homology search is BLAST, which has been in widespread use within universities, research centers, and commercial enterprises since the early 1990s. In this paper, we propose a new step in the BLAST algorithm to reduce the computational cost of searching with negligible effect on accuracy. This new step-semigapped alignment-compromises between the efficiency of ungapped alignment and the accuracy of gapped alignment, allowing BLAST to accurately filter sequences with lower computational cost. In addition, we propose a heuristic-restricted insertion alignment-that avoids unlikely evolutionary paths with the aim of reducing gapped alignment cost with negligible effect on accuracy. Together, after including an optimization of the local alignment recursion, our two techniques more than double the speed of the gapped alignment stages in BLAST. We conclude that our techniques are an important improvement to the BLAST algorithm. Source code for the alignment algorithms is available for download at http://www.bsg.rmit.edu.au/iga/.

Algorithms↗
PubMed2005

Amelogenin: lessons from evolution.

Amelogenin plays a crucial role in enamel structure and mineralization, but the function of its various domains is far to be understood. Evolutionary analysis seems to be a promising way to approach structure/function relationships. In this paper, we review the knowledge of amelogenin with a particular focus on what we have learnt from evolution, and we bring new data on the origin and evolution of this molecule. The comparison of amniote (reptiles and mammals) amelogenin sequences reveals that, in contrast to the well-conserved C- and N-terminal domains, the central region (most of exon 6) is highly variable. The evolutionary analysis indicates that it was created by repeated insertion of three amino acids (triplets ProXGlu or ProXX). In several mammalian lineages a new run of triplet insertions and deletions has occurred independently in a locus considered a hot spot of mutation for mammalian amelogenin. In lizard and snake amelogenin evolves rapidly. Sequence alignment reveals that several residues in the N- and C-terminal regions were kept unchanged during 250 million years (MY), proving their importance for amelogenin structure and function. This alignment permits a rapid validation of the amelogenin mutations in human. Genome sequencing and gene mapping permitted to refine the amelogenin story, in relation to the common location (chromosome 4 in human) of several genes coding for dental proteins and SPARCL1, a SPARC (osteonectin) relative. Amelogenin shares a similar organisation with these genes and a blast search in databanks indicates a strong relationship between amelogenin, ameloblastin and enamelin. Taken together these data suggest that amelogenin could have originated from either ameloblastin or enamelin, themselves being created from SPARCL1, which itself originated from a SPARC duplication, 600 millions years ago.

Amelogenesis↗
PubMed2000

Human and mouse mitochondrial orthologs of bacterial ClpX.

We have determined the cDNA sequence and exon/intron structure of the human CLPX gene encoding a human ortholog of the E. coli ClpX chaperone and protease subunit. The CLPX gene comprises 14 exons and encodes a 633-amino acid-long precursor polypeptide. The polypeptide contains an N-terminal putative mitochondrial transit peptide, and expression of a full-length ClpX cDNA tagged at its C-terminus (Myc-His) shows that the polypeptide is transported into mitochondria. FISH analysis localized the CLPX gene to human Chromosome (Chr) 15q22.1-22.32. This localization was refined by radiation hybrid mapping placing the CLPX gene 4.6 cR distal to D15S159. Murine ClpX cDNA was sequenced, and the mouse Clpx locus was mapped to a position between 31 and 42 cM offset from the centromere on mouse Chr 9. Experimental observations indicate the presence of a pseudogene in the mouse genome and sequence variability between mouse ClpX cDNAs from different strains. Alignment of the human and mouse ClpX amino acid sequences with ClpX sequences from other organisms shows that they display the typical modular organization of domains with one AAA(+) domain common to a large group of ATPases and several other domains conserved in ClpX orthologs linked by non-conserved sequences. Notably, a C-4 zinc finger type motif is recognized in human and mouse ClpX. This motif of so far unknown function is present only in a subset of the known ClpX sequences.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2003

FIE2: A program for the extraction of genomic DNA sequences around the start and translation initiation site of human genes.

FIE2 (5' end Information Extraction v2) is a web-based program for easy identification and extraction of nucleotide sequence around the start of genes (promoter region) and their translation initiation site (TIS). Using information provided by the National Center for Biotechnology Information's (NCBI's) LocusLink, FIE2 identifies the 5'-most end of a gene on its respective chromosome based on alignment of a selected set of mRNAs representative of the gene. FIE2 then uses currently available human genome sequence information to extract the desired sequences. The accuracy of the information extracted is therefore limited by the accuracy and completeness of the sequence annotation and sequence alignment provided by LocusLink. In addition, multiple TIS positions are also occasionally presented, for example, as a result of multiple alignments of transcript variants. One of the key criteria of FIE2 is that it should extract only the correct information or attempt no extraction at all. To date, the authors are not aware of any publicly available web-based tool that uses the human genomic sequence to extract pertinent promoter- and TIS-region information in this fashion. FIE2 is freely available at http://sdmc.lit.org.sg/FIE2.0.

Base Sequence↗
PubMed2005

Automatic gene collection system for genome-scale overview of G-protein coupled receptors in eukaryotes.

We have developed an automatic system for identifying GPCR (G-protein coupled receptor) genes from various kinds of genomes, which is finally deposited in the SEVENS database (http://sevens.cbrc.jp/), by integrating such software as a gene finder, a sequence alignment tool, a motif and domain assignment tool, and a transmembrane helix predictor. SEVENS enables us to perform a genome-scale overview of the "GPCR universe" using sequences that are identified with high accuracy (99.4% sensitivity and 96.6% specificity). Using this system, we surveyed the complete genomes of 7 eukaryotes and 224 prokaryotes, and found that there are 4 to 1016 GPCR genes in the 7 eukaryotes, and only a total of 16 GPCR genes in all the prokaryotes. Our preliminary results indicate that 11 subfamilies of the Class A family, the Class 2(B) family, the Class 3(C) family and the fz/smo family are commonly found among human, fly, and nematode genomes. We also analyzed the chromosomal locations of the GPCR genes with the Kolmogorov-Smirnov test, and found that species-specific families, such as olfactory, taste, and chemokine receptors in human and nematode chemoreceptor in worm, tend to form clusters extensively, whereas no significant clusters were detected in fly and plant genomes.

Animals↗
PubMed2026

IQ-NET: fast and accurate quartet phylogenetic inference using deep learning trained on empirical DNA alignments.

Phylogenetic inference is fundamental to modern biology, with many applications including evolutionary biology, epidemiology, and comparative genomics. While maximum likelihood and Bayesian methods remain the gold standard for phylogenetic analysis, they rely on simplifying assumptions and are computationally intensive. Recent machine learning approaches for phylogenetics offer speed advantages, but have several limitations: exclusive reliance on simulated data for training, inadequate handling of gaps, and sensitivity to input sequence order. Here, we introduce IQ-NET (Intelligent Quartet NETwork), a deep learning framework that solves these limitations to infer four-taxon trees. IQ-NET estimates both tree topology and branch lengths directly from gapped alignments. IQ-NET outperforms existing machine learning methods in terms of accuracy, and obtained a 24-fold speedup compared with the widely used maximum likelihood software, IQ-TREE. We finally introduce a pipeline using IQ-NET and the ASTRAL software to reconstruct a larger species tree, i.e., with more than four taxa.

Empirical data training↗
PubMed2005

SSEP-Domain: protein domain prediction by alignment of secondary structure elements and profiles.

MOTIVATION: The prediction of protein domains is a crucial task for functional classification, homology-based structure prediction and structural genomics. In this paper, we present the SSEP-Domain protein domain prediction approach, which is based on the application of secondary structure element alignment (SSEA) and profile-profile alignment (PPA) in combination with InterPro pattern searches. SSEA allows rapid screening for potential domain regions while PPA provides us with the necessary specificity for selecting significant hits. The combination with InterPro patterns allows finding domain regions without solved structural templates if sequence family definitions exist. RESULTS: A preliminary version of SSEP-Domain was ranked among the top-performing domain prediction servers in the CASP 6 and CAFASP 4 experiments. Evaluation of the final version shows further improvement over these results together with a significant speed-up. AVAILABILITY: The server is available at http://www.bio.ifi.lmu.de/SSEP/

Algorithms↗
PubMed2006

Genome-wide prediction of conserved and nonconserved enhancers by histone acetylation patterns.

Comparative genomic studies have been useful in identifying transcriptional regulatory elements in higher eukaryotic genomes, but many important regulatory elements cannot be detected by such analyses due to evolutionary variations and alignment tool limitations. Therefore, in this study we exploit the highly conserved nature of epigenetic modifications to identify potential transcriptional enhancers. By using a high-resolution genome-wide mapping technique, which combines the chromatin immunoprecipitation and serial analysis of gene expression assays, we have recently determined the distribution of lysine 9/14-diacetylated histone H3 in human T cells. We showed the existence of 46,813 regions with clusters of histone acetylation, termed histone acetylation islands, some of which correspond to known transcriptional regulatory elements. In the present study, we find that 4679 sequences conserved between human and pufferfish coincide with histone acetylation islands, and random sampling shows that 33% (13/39) of these can function as transcriptional enhancers in human Jurkat T cells. In addition, by comparing the human histone acetylation island sequences with mouse genome sequences, we find that despite the conservation of many of these regions between these species, 21,855 of these sequences are not conserved. Furthermore, we demonstrate that about 50% (26/51) of these nonconserved sequences have enhancer activity in Jurkat cells, and that many of the orthologous mouse sequences also have enhancer activity in addition to conserved epigenetic modification patterns in mouse T-cell chromatin. Therefore, by combining epigenetic modification and sequence data, we have established a novel genome-wide method for identifying regulatory elements not discernable by comparative genomics alone.

Acetylation↗
PubMed2004

Function-dependent clustering of orthologues and paralogues of cyclophilins.

The 18 kDa archetypal cyclosporin-A binding protein, cyclophilin-A, has multiple paralogues in the human genome. Only 18 of those paralogues have been detected as mRNAs or proteins whose masses vary from 18 to 354 kDa, whereas the functional significance of the open reading frames (ORFs) encoding other paralogues of cyclophilin-A remains unknown. The genomes of Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Schizosaccharomyces pombe, and Saccharomyces cerevisiae encode different numbers of the cyclophilin paralogues, some of which are orthologous to the human cyclophilins. A library of novel algorithms was developed and used for computation of the conservation levels for hydrophobicity and bulkiness profiles, and amino acid compositions (AACs) of 303 aligned sequences of cyclophilins. The majority of the paralogues and orthologues encoded in these 6 genomes differ considerably from each other. Some of the orthologues and paralogues have high correlation coefficients (CCFs) for pairwise compared hydrophobicity and bulkiness profiles, and whose AACs differ to a low degree. Convergence of these three properties of the polypeptide chain and apparent conservation of the typical sequence hallmarks and parameters allowed for the clustering of the functionally related orthologues and paralogues of the cyclophilins. The clustering method allowed for sorting out the cyclophilins into several distinct classes. Analyses of the overlapping clusters of sequences permitted delineation of some hypothetical pathways that might have led to the creation of certain paralogues of cyclophilins in the eukaryotic genomes.

Amino Acid Sequence↗
PubMed2003

THoR: a tool for domain discovery and curation of multiple alignments.

We describe a tool, THoR, that automatically creates and curates multiple sequence alignments representing protein domains. This exploits both PSI-BLAST and HMMER algorithms and provides an accurate and comprehensive alignment for any domain family. The entire process is designed for use via a web-browser, with simple links and cross-references to relevant information, to assist the assessment of biological significance. THoR has been benchmarked for accuracy using the SMART and pufferfish genome databases.

Algorithms↗
PubMed2000

Genetic variability within the VP1 coding region of echovirus type 30 isolates.

Genetic relationships of the prototype Bastianni strain of 1958 and of 13 echovirus type 30 (ECV30) isolates associated with meningitis cases in Germany during a period from 1966 to 1997 were investigated using direct sequencing of amplicons derived from a part of the capsid protein VP1 gene. Sequences were aligned both with each other and with known sequences of other type 30 echovirus strains. Phylogenetic analysis indicated that isolates investigated in this work fell into at least three genetic clusters apart from the prototype Bastianni strain. This suggests that genetically distinct groups of ECV30 variants have developed over time.

Amino Acid Sequence↗
PubMed2006

MCALIGN2: faster, accurate global pairwise alignment of non-coding DNA sequences based on explicit models of indel evolution.

BACKGROUND: Non-coding DNA sequences comprise a very large proportion of the total genomic content of mammals, most other vertebrates, many invertebrates, and most plants. Unraveling the functional significance of non-coding DNA depends on how well we are able to align non-coding DNA sequences. However, the alignment of non-coding DNA sequences is more difficult than aligning protein-coding sequences. RESULTS: Here we present an improved pair-hidden-Markov-Model (pair HMM) based method for performing global pairwise alignment of non-coding DNA sequences. The method uses an explicit model of indel length frequency distribution which can be specified, and allows any time reversible model of nucleotide substitution. The method uses a deterministic global optimiser to find the alignment with the highest posterior probability. We test MCALIGN2 in simulations, and compare it to a previous Monte Carlo based method (MCALIGN), to the pair HMM method of Knudsen and Miyamoto, and to a heuristic method (AVID) that performed very well in a previous simulation study. We show that the pair HMM methods have excellent performance for all combinations of parameter values we have considered. MCALIGN2 is up to ten times faster than MCALIGN. MCALIGN2 is more accurate in resolving indels given an accurate explicit model than heuristic methods, but is computationally slower. CONCLUSION: MCALIGN2 produces better quality alignments by explicitly using biological knowledge about the indel length distribution and time reversible models of nucleotide substitution. As a result, it can outperform other available sequence alignment methods for the cases we have considered to align non-coding DNA sequences.

Algorithms↗