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PubMed2001

Evolutionary HMMs: a Bayesian approach to multiple alignment.

MOTIVATION: We review proposed syntheses of probabilistic sequence alignment, profiling and phylogeny. We develop a multiple alignment algorithm for Bayesian inference in the links model proposed by Thorne et al. (1991, J. Mol. Evol., 33, 114-124). The algorithm, described in detail in Section 3, samples from and/or maximizes the posterior distribution over multiple alignments for any number of DNA or protein sequences, conditioned on a phylogenetic tree. The individual sampling and maximization steps of the algorithm require no more computational resources than pairwise alignment. METHODS: We present a software implementation (Handel) of our algorithm and report test results on (i) simulated data sets and (ii) the structurally informed protein alignments of BAliBASE (Thompson et al., 1999, Nucleic Acids Res., 27, 2682-2690). RESULTS: We find that the mean sum-of-pairs score (a measure of residue-pair correspondence) for the BAliBASE alignments is only 13% lower for Handelthan for CLUSTALW(Thompson et al., 1994, Nucleic Acids Res., 22, 4673-4680), despite the relative simplicity of the links model (CLUSTALW uses affine gap scores and increased penalties for indels in hydrophobic regions). With reference to these benchmarks, we discuss potential improvements to the links model and implications for Bayesian multiple alignment and phylogenetic profiling. AVAILABILITY: The source code to Handelis freely distributed on the Internet at http://www.biowiki.org/Handel under the terms of the GNU Public License (GPL, 2000, http://www.fsf.org./copyleft/gpl.html).

Algorithms↗

PubMed2003

Combined sequence and structure analysis of the fungal laccase family.

Plant and fungal laccases belong to the family of multi-copper oxidases and show much broader substrate specificity than other members of the family. Laccases have consequently been of interest for potential industrial applications. We have analyzed the essential sequence features of fungal laccases based on multiple sequence alignments of more than 100 laccases. This has resulted in identification of a set of four ungapped sequence regions, L1-L4, as the overall signature sequences that can be used to identify the laccases, distinguishing them within the broader class of multi-copper oxidases. The 12 amino acid residues in the enzymes serving as the copper ligands are housed within these four identified conserved regions, of which L2 and L4 conform to the earlier reported copper signature sequences of multi-copper oxidases while L1 and L3 are distinctive to the laccases. The mapping of regions L1-L4 on to the three-dimensional structure of the Coprinus cinerius laccase indicates that many of the non-copper-ligating residues of the conserved regions could be critical in maintaining a specific, more or less C-2 symmetric, protein conformational motif characterizing the active site apparatus of the enzymes. The observed intraprotein homologies between L1 and L3 and between L2 and L4 at both the structure and the sequence levels suggest that the quasi C-2 symmetric active site conformational motif may have arisen from a structural duplication event that neither the sequence homology analysis nor the structure homology analysis alone would have unraveled. Although the sequence and structure homology is not detectable in the rest of the protein, the relative orientation of region L1 with L2 is similar to that of L3 with L4. The structure duplication of first-shell and second-shell residues has become cryptic because the intraprotein sequence homology noticeable for a given laccase becomes significant only after comparing the conservation pattern in several fungal laccases. The identified motifs, L1-L4, can be useful in searching the newly sequenced genomes for putative laccase enzymes.

Amino Acid Sequence↗

PubMed2004

Complexity: an internet resource for analysis of DNA sequence complexity.

The search for DNA regions with low complexity is one of the pivotal tasks of modern structural analysis of complete genomes. The low complexity may be preconditioned by strong inequality in nucleotide content (biased composition), by tandem or dispersed repeats or by palindrome-hairpin structures, as well as by a combination of all these factors. Several numerical measures of textual complexity, including combinatorial and linguistic ones, together with complexity estimation using a modified Lempel-Ziv algorithm, have been implemented in a software tool called 'Complexity' (http://wwwmgs.bionet.nsc.ru/mgs/programs/low_complexity/). The software enables a user to search for low-complexity regions in long sequences, e.g. complete bacterial genomes or eukaryotic chromosomes. In addition, it estimates the complexity of groups of aligned sequences.

Algorithms↗

PubMed1997

Sequence variation of the glycoprotein gene identifies three distinct lineages within field isolates of viral haemorrhagic septicaemia virus, a fish rhabdovirus.

To evaluate the genetic diversity of viral haemorrhagic septicaemia virus (VHSV), the sequence of the glycoprotein genes (G) of 11 North American and European isolates were determined. Comparison with the G protein of representative members of the family Rhabdoviridae suggested that VHSV was a different virus species from infectious haemorrhagic necrosis virus (IHNV) and Hirame rhabdovirus (HIRRV). At a higher taxonomic level, VHSV, IHNV and HIRRV formed a group which was genetically closest to the genus Lyssavirus. Compared with each other, the G genes of VHSV displayed a dissimilar overall genetic diversity which correlated with differences in geographical origin. The multiple sequence alignment of the complete G protein, showed that the divergent positions were not uniformly distributed along the sequence. A central region (amino acid position 245-300) accumulated substitutions and appeared to be highly variable. The genetic heterogeneity within a single isolate was high, with an apparent internal mutation frequency of 1.2 x 10(-3) per nucleotide site, attesting the quasispecies nature of the viral population. The phylogeny separated VHSV strains according to the major geographical area of isolation: genotype I for continental Europe, genotype II for the British Isles, and genotype III for North America. Isolates from continental Europe exhibited the highest genetic variability, with sub-groups correlated partially with the serological classification. Neither neutralizing polyclonal sera, nor monoclonal antibodies, were able to discriminate between the genotypes. The overall structure of the phylogenetic tree suggests that VHSV genetic diversity and evolution fit within the model of random change and positive selection operating on quasispecies.

Amino Acid Sequence↗

PubMed1993

Deletion analysis of dengue virus type 4 nonstructural protein NS2B: identification of a domain required for NS2B-NS3 protease activity.

Most proteolytic cleavages in the nonstructural protein (NS) region of the flavivirus polyprotein are effected by a virus-encoded protease composed of two viral proteins, NS2B and NS3. The N-terminal 180-amino-acid-region of NS3 includes sequences with homology to the active sites of serine proteases, and there is evidence that this portion of NS3 can mediate proteolytic cleavages. In contrast, nothing is known about required sequences in NS2B. We constructed a series of deletion mutations in the NS2B portion of plasmid pTM/NS2B-30% NS3, which expresses dengue virus type 4 (DEN4) cDNA encoding NS2B and the N-terminal 184 residues of NS3 from the T7 RNA polymerase promoter. Mutant or wild-type plasmids were transfected into cells that had been infected with a recombinant vaccinia virus expressing T7 RNA polymerase, and the protease activities of the expressed polyproteins were assayed by examining the extent of self-cleavage at the NS2B-NS3 junction. The results identify a 40-amino-acid segment of NS2B (DEN4 amino acids 1396 to 1435) essential for protease activity. A hydrophobicity profile of DEN4 NS2B predicts this segment constitutes a hydrophilic domain surrounded by hydrophobic regions. Hydrophobicity profiles of the NS2B proteins of other flaviviruses show similar patterns. Amino acid sequence alignment of this domain of DEN4 NS2B with comparable regions of other proteins of flaviviruses indicates significant sequence conservation, especially at the N-terminal end. These observations suggest that the central hydrophilic domain of NS2B of these other flaviviruses will also prove to be essential for protease activity.

Amino Acid Sequence↗

PubMed2004

Improvement of alignment accuracy utilizing sequentially conserved motifs.

BACKGROUND: Multiple sequence alignment algorithms are very important tools in molecular biology today. Accurate alignment of proteins is central to several areas such as homology modelling, docking studies, understanding evolutionary trends and study of structure-function relationships. In recent times, improvement of existing progressing programs and implementation of new iterative algorithms have made a significant change in this field. RESULTS: We report an alignment algorithm that combines progressive dynamic algorithm, local substructure alignment and iterative refinement to achieve an improved, user-interactive tool. Large-scale benchmarking studies show that this FMALIGN server produces alignments that, aside from preservation of functional and structural conservation, have accuracy comparable to other popular multiple alignment programs. CONCLUSIONS: The FMALIGN server allows the user to fix conserved regions in equivalent position in the alignment thereby reducing the chance of global misalignment to a great extent. FMALIGN is available at http://caps.ncbs.res.in/FMALIGN/Home.html.

Algorithms↗

PubMed2006

Evolutionary coupling of structural and functional sequence information in the intracellular lipid-binding protein family.

We have mined the evolutionary record for the large family of intracellular lipid-binding proteins (iLBPs) by calculating the statistical coupling of residue variations in a multiple sequence alignment using methods developed by Ranganathan and coworkers (Lockless and Ranganathan, Science 1999:286;295-299). The 213 sequences analyzed have a wide range of ligand-binding functions as well as highly divergent phylogenetic origins, assuring broad sampling of sequence space. Emerging from this analysis were two major clusters of coupled residues, which when mapped onto the structure of a representative iLBP under study in our laboratory, cellular retinoic-acid binding protein I, are largely contiguous and provide useful points of comparison to available data for the folding of this protein. One cluster comprises a predominantly hydrophobic core away from the ligand-binding site and likely represents key structural information for the iLBP fold. The other cluster includes the portal region where ligand enters its binding site, regions of the ligand-binding cavity, and the region where the 10-stranded beta-barrel characteristic of this family closes (between strands 1' and 10). Linkages between these two clusters suggest that evolutionary pressures on this family constrain structural and functional sequence information in an interdependent fashion. The necessity of the structure to wrap around a hydrophobic ligand confounds the typical sequestration of hydrophobic side chains. Additionally, ligand entry and exit require these structures to have a capacity for specific conformational change during binding and release. We conclude that an essential and structurally apparent separation of local and global sequence information is conserved throughout the iLBP family.

Amino Acid Sequence↗

PubMed1998

Nucleotide-dependent interaction of the N-terminal domain of MukB with microtubules.

The MukB protein from Escherichia coli has a domain structure that is reminiscent of the eukaryotic motor proteins kinesin and myosin: N-terminal globular domains, a region of coiled-coil, and a specialised C-terminal domain. Sequence alignment of the N-terminal domain of MukB with the kinesin motor domain indicated an approximately 22% sequence identity. These observations raised the possibility that MukB might be a prokaryotic motor protein and, due to the sequence homology shared with kinesin, might bind to microtubules (Mts). We found that a construct encoding the first 342 residues of MukB (Muk342) binds specifically to Mts and shares a number of properties with the motor domain of kinesin. Visualisation of the Muk342 decorated Mt complexes using negative stain electron microscopy indicated that the Muk342 smoothly decorates the outside of Mts. Biochemical data demonstrate that Muk342 decorates Mts with a binding stoichiometry of one Muk342 monomer per tubulin monomer. These findings strongly suggest that MukB has a role in force generation and that it is a prokaryotic homologue of kinesin and myosin.

Adenine Nucleotides↗

PubMed2005

Comparative sequence analysis of the eastern equine encephalitis virus pathogenic strains FL91-4679 and GA97 to other North American strains.

Eastern equine encephalitis (EEE) virus is a significant public health concern due to the high mortality rates observed in infected humans, equines and game birds. The EEE genomic sequences available prior to this report are based on laboratory strains with unknown passage histories that may contain an array of cell culture adaptations. Here we report the complete genomic sequences of two recently isolated EEE pathogenic strains with low passage histories. FL91-4697 was isolated in Florida from Aedes albopictus mosquitoes and GA97 was derived from brain tissue of a human fatality that occurred in 1997. Sequence alignment of these new genomes with the documented EEE's permitted us to generate a North American consensus sequence and identify regions of significant diversity. Sequence analysis of the FL91-4679 genome was essential to the production of an EEE infectious clone that is being used to create live attenuated vaccine candidates.

Aedes↗

PubMed2002

The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases.

We recently demonstrated that the major decapping activity in mammalian cells involves DcpS, a scavenger pyrophosphatase that hydrolyzes the residual cap structure following 3' to 5' decay of an mRNA. The association of DcpS with 3' to 5' exonuclease exosome components suggests that these two activities are linked and there is a coupled exonucleolytic decay-dependent decapping pathway. We purified DcpS from mammalian cells and identified the cDNA encoding a novel 40 kDa protein possessing DcpS activity. Consistent with purified DcpS, the recombinant protein specifically hydrolyzed methylated cap analog but did not hydrolyze unmethylated cap analog nor did it function on intact capped RNA. Sequence alignments of DcpS from different organisms revealed the presence of a conserved hexapeptide, containing a histidine triad (HIT) sequence with three histidines separated by hydrophobic residues. Mutagenesis analysis revealed that the central histidine within the DcpS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function.

Amino Acid Motifs↗

PubMed2002

Isolation of MADS-box genes from sweet potato (Ipomoea batatas (L.) Lam.) expressed specifically in vegetative tissues.

New MADS-domain genes, IbMADS3 and IbMADS4, were isolated from pigmented and tuber-forming root tissue in sweet potato (Ipomoea batatas L.). Both genes were expressed preferentially in vegetative tissues, especially root tissues; white fibrous roots, pigmented roots, and developing tuberous roots. On sequence alignment, these genes fell into the STMADS group composed of SVP, STMADS11, STMADS16 and AGL24, which share high sequence similarity, similar expression patterns and similar function. Transcripts of these two genes in roots were found in the vascular cambium region. This particular expression pattern of these genes may lead to a higher proliferative potential of vegetative tissues, and may facilitate tuber initiation in sweet potato. These genes may lead to important information on the morphogenesis of vegetative structures.

Amino Acid Sequence↗

PubMed1994

PRINTS--a protein motif fingerprint database.

The PRINTS database of protein 'fingerprints' is described. Fingerprints comprise sets of motifs excised from conserved regions of sequence alignments, their diagnostic power or potency being refined by iterative database scanning (in this case the OWL composite sequence database). Generally, the motifs do not overlap, but are separated along a sequence, though they may be contiguous in 3-D space. The use of groups of independent, linearly or spatially separate motifs allows particular protein folds and functionalities to be characterized more flexibly and powerfully than conventional single-component patterns or regular expressions. The current version of the database (4.0) contains 150 entries (encoding > 700 motifs), covering a wide range of globular and membrane proteins, modular polypeptides and so on. The growth of the database is influenced by a number of factors, e.g. the use of multiple motifs, the maximization of sequence information through iterative database scanning and the fact that the database searched is a large composite. The information contained within PRINTS is distinct from but complementary to the single consensus expressions stored in the widely used PROSITE dictionary of patterns.

Amino Acid Sequence↗

PubMed2006

Sequence diversity and rates of molecular evolution between sheep and cattle genes.

Experiments that aim to identify genes of importance in sheep are currently inhibited by a paucity of genomic resources. One approach, therefore, is to exploit the wealth of data and associated capabilities becoming available for the bovine genome. Cross-species application of microarrays and comparative sequencing to identify single nucleotide polymorphisms are two possibilities; however, both are dependant on the level of nucleotide sequence similarity between the two species. This study used 120 gene orthologues consisting of over 60 kb of aligned sequence to estimate the gene diversity between cattle and sheep. Less than 3% of protein-coding nucleotide positions were found to be different, indicating that the prospect for successfully using cross-species strategies is high. Substitution at synonymous sites ranged between 6.9 and 7.7% (+/- 0.3%), and was higher than at non-synonymous sites (1.4-1.7 +/- 0.1%). The relative rate test was used to determine whether the observed mutation rates were constant between the two lineages. While the rate at synonymous sites appeared constant, the rate at non-synonymous sites was significantly higher within the caprinae lineage (sheep) when compared with bovinae (cattle; chi2 = 10.03; d.f. = 1, P < 0.01). This is the first demonstration that variable rates of molecular evolution may be present within the family Bovidae.

Animals↗

PubMedDate not supplied

Investigating deep phylogenetic relationships among cyanobacteria and plastids by small subunit rRNA sequence analysis.

Small subunit rRNA sequence data were generated for 27 strains of cyanobacteria and incorporated into a phylogenetic analysis of 1,377 aligned sequence positions from a diverse sampling of 53 cyanobacteria and 10 photosynthetic plastids. Tree inference was carried out using a maximum likelihood method with correction for site-to-site variation in evolutionary rate. Confidence in the inferred phylogenetic relationships was determined by construction of a majority-rule consensus tree based on alternative topologies not considered to be statistically significantly different from the optimal tree. The results are in agreement with earlier studies in the assignment of individual taxa to specific sequence groups. Several relationships not previously noted among sequence groups are indicated, whereas other relationships previously supported are contradicted. All plastids cluster as a strongly supported monophyletic group arising near the root of the cyanobacterial line of descent.

Cyanobacteria↗

PubMed2000

The 5S rRNA gene diversity in Kengyilia rigidula (Keng and S.L. Chen) J.L. Yang, Yen, and Baum (Poaceae: Triticeae): possible contribution of the H genome to the origin of Kengyilia.

Fifty-three units of 5S rDNA sequences from five accessions of Kengyilia rigidula, a member of the tribe Triticeae that also includes wheat, barley, rye, and their wild relatives, have been amplified by the polymerase chain reaction (PCR), cloned, and sequenced. The genome of K. rigidula consists of three haplomes, St, P, and Y. An evaluation of the aligned sequences of the diverse 53 different 5S DNA units yielded three 5S-unit classes. One unit class, Long S1, was assignable to the St haplome, one unit class, the Long P1, was assignable to the P haplome, and a third unit class, Long H1, was assignable to the H haplome. The last was expected to be assignable to the Y haplome, based on previous knowledge. Evolutionary scenarios are put forward to explain this finding. Among those possibilities is that the number of copies of units assignable to the Y haplome is very small and difficult to detect. Short units, reported earlier in K. alatavica, were not found in K. rigidula.

Base Sequence↗

PubMed2003

Automated identification of single nucleotide polymorphisms from sequencing data.

The single nucleotide polymorphism (SNP) is the difference of the DNA sequence between individuals and provides abundant information about genetic variation. Large scale discovery of high frequency SNPs is being undertaken using various methods. However, the publicly available SNP data sometimes need to be verified. If only a particular gene locus is concerned, locus-specific polymerase chain reaction amplification may be useful. Problem of this method is that the secondary peak has to be measured. We have analyzed trace data from conventional sequencing equipment and found an applicable rule to discern SNPs from noise. The rule is applied to multiply aligned sequences with a trace and the peak height of the traces are compared between samples. We have developed software that integrates this function to automatically identify SNPs. The software works accurately for high quality sequences and also can detect SNPs in low quality sequences. Further, it can determine allele frequency, display this information as a bar graph and assign corresponding nucleotide combinations. It is also designed for a person to verify and edit sequences easily on the screen. It is very useful for identifying de novo SNPs in a DNA fragment of interest.

Algorithms↗

PubMed2001

Kabat Database and its applications: future directions.

The Kabat Database was initially started in 1970 to determine the combining site of antibodies based on the available amino acid sequences. The precise delineation of complementarity determining regions (CDR) of both light and heavy chains provides the first example of how properly aligned sequences can be used to derive structural and functional information of biological macromolecules. This knowledge has subsequently been applied to the construction of artificial antibodies with prescribed specificities, and to many other studies. The Kabat database now includes nucleotide sequences, sequences of T cell receptors for antigens (TCR), major histocompatibility complex (MHC) class I and II molecules, and other proteins of immunological interest. While new sequences are continually added into this database, we have undertaken the task of developing more analytical methods to study the information content of this collection of aligned sequences. New examples of analysis will be illustrated on a yearly basis. The Kabat Database and its applications are freely available at http://immuno.bme.nwu.edu.

Animals↗

PubMed1994

Conservation and prediction of solvent accessibility in protein families.

Currently, the prediction of three-dimensional (3D) protein structure from sequence alone is an exceedingly difficult task. As an intermediate step, a much simpler task has been pursued extensively: predicting 1D strings of secondary structure. Here, we present an analysis of another 1D projection from 3D structure: the relative solvent accessibility of each residue. We show that solvent accessibility is less conserved in 3D homologues than is secondary structure, and hence is predicted less accurately from automatic homology modeling; the correlation coefficient of relative solvent accessibility between 3D homologues is only 0.77, and the average accuracy of predictions based on sequence alignments is only 0.68. The latter number provides an effective upper limit on the accuracy of predicting accessibility from sequence when homology modeling is not possible. We introduce a neural network system that predicts relative solvent accessibility (projected onto ten discrete states) using evolutionary profiles of amino acid substitutions derived from multiple sequence alignments. Evaluated in a cross-validation test on 238 unique proteins, the correlation between predicted and observed relative accessibility is 0.54. Interpreted in terms of a three-state (buried, intermediate, exposed) description of relative accessibility, the fraction of correctly predicted residue states is about 58%. In absolute terms this accuracy appears poor, but given the relatively low conservation of accessibility in 3D families, the network system is not far from its likely optimal performance. The most reliably predicted fraction of the residues (50%) is predicted as accurately as by automatic homology modeling. Prediction is best for buried residues, e.g., 86% of the completely buried sites are correctly predicted as having 0% relative accessibility.

Biological Evolution↗