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PubMed2003

Web-based programs for the display and analysis of transmembrane alpha-helices in aligned protein sequences.

We developed novel programs for displaying and analyzing the transmembrane alpha-helical segments (TMSs) in the aligned sequences of homologous integral membrane proteins. TMS_ALIGN predicts the positions of putative TMSs in multiply aligned protein sequences and graphically shows the TMSs in the alignment. TMS_SPLIT (1). predicts the positions of TMSs for each sequence; (2). allows a user to select proteins with a specified number of TMSs, and (3). splits the sequences into groups of TMSs of equal numbers. TMS_CUT works like TMS_SPLIT, but it can cut sequences with any combination of TMSs. The BASS program similarly allows comparison of protein repeat elements, equivalent to TMS_SPLIT plus IC, but it provides the comparison data expressed in BLAST E values. These programs, together with the IntraCompare program, facilitate the identification of repeat sequences in integral membrane proteins. They also facilitate the estimation of protein topology and the determination of evolutionary pathways.

Amino Acid Sequence↗

PubMed2004

LEON: multiple aLignment Evaluation Of Neighbours.

Sequence alignments are fundamental to a wide range of applications, including database searching, functional residue identification and structure prediction techniques. These applications predict or propagate structural/functional/evolutionary information based on a presumed homology between the aligned sequences. If the initial hypothesis of homology is wrong, no subsequent application, however sophisticated, can be expected to yield accurate results. Here we present a novel method, LEON, to predict homology between proteins based on a multiple alignment of complete sequences (MACS). In MACS, weak signals from distantly related proteins can be considered in the overall context of the family. Intermediate sequences and the combination of individual weak matches are used to increase the significance of low-scoring regions. Residue composition is also taken into account by incorporation of several existing methods for the detection of compositionally biased sequence segments. The accuracy and reliability of the predictions is demonstrated in large-scale comparisons with structural and sequence family databases, where the specificity was shown to be >99% and the sensitivity was estimated to be approximately 76%. LEON can thus be used to reliably identify the complex relationships between large multidomain proteins and should be useful for automatic high-throughput genome annotations, 2D/3D structure predictions, protein-protein interaction predictions etc.

Algorithms↗

PubMed2001

An algorithm for statistical alignment of sequences related by a binary tree.

An algorithm is presented that allows the calculation of the probability of a set of sequences related by a binary tree that has evolved according to the Thorne-Kishino-Felsenstein model (1991) for a fixed set of parameters. There are two ideas underlying this algorithm. Firstly, a markov chain is defined that generates ancestral sequences and their alignment at two neighboring nodes in a tree. Secondly, a stochastic walk on the binary tree, that defines a markov chain generating ancestral sequences and their alignment at the internal nodes in the tree is described. The running time of this algorithm is O(l2 kappa), where l is the geometric average of the sequence lengths and kappa the number of sequences--leaves at the binary tree. This could be improved to O(l kappa).

Algorithms↗

PubMed1996

Alignment of possible secondary structures in multiple RNA sequences using simulated annealing.

Multiple sequence alignment has been a useful technique for identifying RNA secondary structures. In this paper, an algorithm for aligning multiple RNA sequences to identify possible secondary structure is presented. In this algorithm, dot matrices generated from intra-sequence comparisons are used to obtain possible common secondary structures. A hit probability for dot matrices is calculated and a score function based on this hit probability is defined. Simulated annealing is applied to optimize the score function. The solution set of multiple sequence alignment is introduced, and the effects on the solution set of increasing the number of alignment gaps and the alignment length are analyzed. Several additional strategies to reduce simulated annealing time are applied. A method is applied to reduce the computation time based on the solution set. Also, an optimized transition rule, double shuffle, which moves two positions in a sequence with each iteration, is applied to increase the rate of convergence. This algorithm was used to find possible common secondary structures in RNA sequences.

Algorithms↗

PubMed2004

Progressive multiple alignment using sequence triplet optimizations and three-residue exchange costs.

In this paper we demonstrate a practical approach to construct progressive multiple alignments using sequence triplet optimizations rather than a conventional pairwise approach. Using the sequence triplet alignments progressively provides a scope for the synthesis of a three-residue exchange amino acid substitution matrix. We develop such a 20 x 20 x 20 matrix for the first time and demonstrate how its use in optimal sequence triplet alignments increases the sensitivity of building multiple alignments. Various comparisons were made between alignments generated using the progressive triplet methods and the conventional progressive pairwise procedure. The assessment of these data reveal that, in general, the triplet based approaches generate more accurate sequence alignments than the traditional pairwise based procedures, especially between more divergent sets of sequences.

Algorithms↗

PubMed2003

Alignment-free sequence comparison-a review.

MOTIVATION: Genetic recombination and, in particular, genetic shuffling are at odds with sequence comparison by alignment, which assumes conservation of contiguity between homologous segments. A variety of theoretical foundations are being used to derive alignment-free methods that overcome this limitation. The formulation of alternative metrics for dissimilarity between sequences and their algorithmic implementations are reviewed. RESULTS: The overwhelming majority of work on alignment-free sequence has taken place in the past two decades, with most reports published in the past 5 years. Two main categories of methods have been proposed-methods based on word (oligomer) frequency, and methods that do not require resolving the sequence with fixed word length segments. The first category is based on the statistics of word frequency, on the distances defined in a Cartesian space defined by the frequency vectors, and on the information content of frequency distribution. The second category includes the use of Kolmogorov complexity and Chaos Theory. Despite their low visibility, alignment-free metrics are in fact already widely used as pre-selection filters for alignment-based querying of large applications. Recent work is furthering their usage as a scale-independent methodology that is capable of recognizing homology when loss of contiguity is beyond the possibility of alignment. AVAILABILITY: Most of the alignment-free algorithms reviewed were implemented in MATLAB code and are available at http://bioinformatics.musc.edu/resources.html

Algorithms↗

PubMed2001

Tsukuba BB: a branch and bound algorithm for local multiple alignment of DNA and protein sequences.

In this paper we present a branch and bound algorithm for local gapless multiple sequence alignment (motif alignment) and its implementation. The algorithm uses both score-based bounding and a novel bounding technique based on the "consistency" of the alignment. A sequence order independent search tree is used in conjunction with a technique for avoiding redundant calculations inherent in the structure of the tree. This is the first program to exploit the fact that the motif alignment problem is easier for short motifs. Indeed, for a short fixed motif width, the running time of the algorithm is asymptotically linear in the size of the input. We tested the performance of the program on a dataset of 300 E. coli promoter sequences and a dataset of 85 lipocalin protein sequences. For a motif width of 4, the optimal alignment of the entire set of sequences can be found. For the more natural motif width of 6, the program can align 21 sequences of length 100, more than twice the number of sequences which can be aligned by the best previous exact algorithm. The algorithm can relax the constraint of requiring each sequence to be aligned, and align 105 of the 300 promoter sequences with a motif width of 6. For the lipocalin dataset, we introduce a technique for reducing the effective alphabet size with a minimal loss of useful information. With this technique, we show that the program can find meaningful motifs in a reasonable amount of time by optimizing the score over three motif positions.

Algorithms↗

PubMed2004

Mulan: multiple-sequence local alignment and visualization for studying function and evolution.

Multiple-sequence alignment analysis is a powerful approach for understanding phylogenetic relationships, annotating genes, and detecting functional regulatory elements. With a growing number of partly or fully sequenced vertebrate genomes, effective tools for performing multiple comparisons are required to accurately and efficiently assist biological discoveries. Here we introduce Mulan (http://mulan.dcode.org/), a novel method and a network server for comparing multiple draft and finished-quality sequences to identify functional elements conserved over evolutionary time. Mulan brings together several novel algorithms: the TBA multi-aligner program for rapid identification of local sequence conservation, and the multiTF program for detecting evolutionarily conserved transcription factor binding sites in multiple alignments. In addition, Mulan supports two-way communication with the GALA database; alignments of multiple species dynamically generated in GALA can be viewed in Mulan, and conserved transcription factor binding sites identified with Mulan/multiTF can be integrated and overlaid with extensive genome annotation data using GALA. Local multiple alignments computed by Mulan ensure reliable representation of short- and large-scale genomic rearrangements in distant organisms. Mulan allows for interactive modification of critical conservation parameters to differentially predict conserved regions in comparisons of both closely and distantly related species. We illustrate the uses and applications of the Mulan tool through multispecies comparisons of the GATA3 gene locus and the identification of elements that are conserved in a different way in avians than in other genomes, allowing speculation on the evolution of birds. Source code for the aligners and the aligner-evaluation software can be freely downloaded from http://www.bx.psu.edu/miller_lab/.

Animals↗

PubMed2003

Evolution and phylogenetic utility of alignment gaps within intron sequences of three nuclear genes in bumble bees (Bombus).

To test whether gaps resulting from sequence alignment contain phylogenetic signal concordant with those of base substitutions, we analyzed the occurrence of indel mutations upon a well-resolved, substitution-based tree for three nuclear genes in bumble bees (Bombus, Apidae: Bombini). The regions analyzed were exon and intron sequences of long-wavelength rhodopsin (LW Rh), arginine kinase (ArgK), and elongation factor-1alpha (EF-1alpha) F2 copy genes. LW Rh intron had only a few uninformative gaps, ArgK intron had relatively long gaps that were easily aligned, and EF-1alpha intron had many short gaps, resulting in multiple optimal alignments. The unambiguously aligned gaps within ArgK intron sequences showed no homoplasy upon the substitution-based tree, and phylogenetic signals within ambiguously aligned regions of EF-1alpha intron were highly congruent with those of base substitutions. We further analyzed the contribution of gap characters to phylogenetic reconstruction by incorporating them in parsimony analysis. Inclusion of gap characters consistently improved support for nodes recovered by substitutions, and inclusion of ambiguously aligned regions of EF-1alpha intron resolved several additional nodes, most of which were apical on the phylogeny. We conclude that gaps are an exceptionally reliable source of phylogenetic information that can be used to corroborate and refine phylogenies hypothesized by base substitutions, at least at lower taxonomic levels. At present, full use of gaps in phylogenetic reconstruction is best achieved in parsimony analysis, pending development of well-justified and generally applicable methods for incorporating indels in explicitly model-based methods.

Animals↗

PubMed1989

Prediction of surface loops of protein-folds from multiple alignments of homologous sequences.

Multiple alignments of distantly related homologous sequences may be used for the construction of consensus sequences that identify conserved motifs, variable segments and regions that tolerate gap events. It is suggested that such consensus sequences may be used for the prediction of key features of protein-folds. The validity of the proposed approach is illustrated in the case of the alpha 2 mu globulin superfamily: the consensus sequence derived from the multiple alignment of sequences succeeded in identifying conserved structural motifs and in predicting the location of surface loops that connect these motifs.

Amino Acid Sequence↗

PubMed1992

Molecular modeling of the 3-D structure of cytochrome P-450scc.

Sequence-alignment studies of the bovine mitochondrial cholesterol side-chain cleavage enzyme cytochrome P-450scc with the bacterial cytochrome P-450cam (camphor hydroxylating enzyme) have been undertaken. Our novel alignment of the sequences revealed 69 identical residues and many highly conserved regions. The results of the sequence alignment studies were used to model the 3-D structure of P-450scc based on the available crystal structure of P-450cam. The major insertions in the sequence are found mainly on four external-loop regions of the molecule, while the core structure of P-450cam is retained with subtle internal modifications. The most hydrophobic of these four external loops is proposed as a candidate for membrane attachment.

Amino Acid Sequence↗

PubMed2003

GS-Aligner: a novel tool for aligning genomic sequences using bit-level operations.

A novel algorithm, GS-Aligner, that uses bit-level operations was developed for aligning genomic sequences. GS-Aligner is efficient in terms of both time and space for aligning two very long genomic sequences and for identifying genomic rearrangements such as translocations and inversions. It is suitable for aligning fairly divergent sequences such as human and mouse genomic sequences. It consists of several efficient components: bit-level coding, search for matching segments between the two sequences as alignment anchors, longest increasing subsequence (LIS), and optimal local alignment. Efforts have been made to reduce the execution time of the program to make it truly practical for aligning very long sequences. Empirical tests suggest that for relatively divergent sequences such as sequences from different mammalian orders or from a mammal and a nonmammalian vertebrate GS-Aligner performs better than existing methods. The program and data can be downloaded from http://pondside.uchicago.edu/~lilab/ and http://webcollab.iis.sinica.edu.tw/~biocom.

Algorithms↗

PubMed1994

Biological evaluation of d2, an algorithm for high-performance sequence comparison.

A number of algorithms exist for searching sequence databases for biologically significant similarities based on the primary sequence similarity of aligned sequences. We have determined the biological sensitivity and selectivity of d2, a high-performance comparison algorithm that rapidly determines the relative dissimilarity of large datasets of genetic sequences. d2 uses sequence-word multiplicity as a simple measure of dissimilarity. It is not constrained by the comparison of direct sequence alignments and so can use word contexts to yield new information on relationships. It is extremely efficient, comparing a query of length 884 bases (INS1ECLAC) with 19,540,603 bases of the bacterial division of GenBank (release 76.0) in 51.77 CPU seconds on a Cray Y/MP-48 supercomputer. It is unique in that subsequences (words) of biological interest can be weighted to improve the sensitivity and selectivity of a search over existing methods. We have determined the ability of d2 to detect biologically significant matches between a query and large datasets of DNA sequences while varying parameters such as word-length and window size. We have also determined the distribution of dissimilarity scores within eukaryotic and prokaryotic divisions of GenBank. We have optimized parameters of the d2 program using Cray hardware and present an analysis of the sensitivity and selectivity of the algorithm. A theoretical analysis of the expectation for scores is presented. This work demonstrates that d2 is a unique, sensitive, and selective method of rapid sequence comparison that can detect novel sequence relationships which remain undetected by alternate methodologies.

Algorithms↗

PubMed1997

Protein secondary structure prediction using local alignments.

The accuracy of secondary structure prediction methods has been improved significantly by the use of aligned protein sequences. The PHD method and the NNSSP method reach 71 to 72% of sustained overall three-state accuracy when multiple sequence alignments are with neural networks and nearest-neighbor algorithms, respectively. We introduce a variant of the nearest-neighbor approach that can achieve similar accuracy using a single sequence as the query input. We compute the 50 best non-intersecting local alignments of the query sequence with each sequence from a set of proteins with known 3D structures. Each position of the query sequence is aligned with the database amino acids in alpha-helical, beta-strand or coil states. The prediction type of secondary structure is selected as the type of aligned position with the maximal total score. On the dataset of 124 non-membrane non-homologous proteins, used earlier as a benchmark for secondary structure predictions, our method reaches an overall three-state accuracy of 71.2%. The performance accuracy is verified by an additional test on 461 non-homologous proteins giving an accuracy of 71.0%. The main strength of the method is the high level of prediction accuracy for proteins without any known homolog. Using multiple sequence alignments as input the method has a prediction accuracy of 73.5%. Prediction of secondary structure by the SSPAL method is available via Baylor College of Medicine World Wide Web server.

Algorithms↗

PubMed2004

Evolution of vertebrate genes related to prion and Shadoo proteins--clues from comparative genomic analysis.

Recent findings of new genes in fish related to the prion protein (PrP) gene PRNP, including our recent report of SPRN coding for Shadoo (Sho) protein found also in mammals, raise issues of their function and evolution. Here we report additional novel fish genes found in public databases, including a duplicated SPRN gene, SPRNB, in Fugu, Tetraodon, carp, and zebrafish encoding the Sho2 protein, and we use comparative genomic analysis to analyze the evolutionary relationships and to infer evolutionary trajectories of the complete data set. Phylogenetic footprinting performed on aligned human, mouse, and Fugu SPRN genes to define candidate regulatory promoter regions, detected 16 conserved motifs, three of which are known transcription factor-binding sites for a receptor and transcription factors specific to or associated with expression in brain. This result and other homology-based (VISTA global genomic alignment; protein sequence alignment and phylogenetics) and context-dependent (genomic context; relative gene order and orientation) criteria indicate fish and mammalian SPRN genes are orthologous and suggest a strongly conserved basic function in brain. Whereas tetrapod PRNPs share context with the analogous stPrP-2-coding gene in fish, their sequences are diverged, suggesting that the tetrapod and fish genes are likely to have significantly different functions. Phylogenetic analysis predicts the SPRN/SPRNB duplication occurred before divergence of fish from tetrapods, whereas that of stPrP-1 and stPrP-2 occurred in fish. Whereas Sho appears to have a conserved function in vertebrate brain, PrP seems to have an adaptive role fine-tuned in a lineage-specific fashion. An evolutionary model consistent with our findings and literature knowledge is proposed that has an ancestral prevertebrate SPRN-like gene leading to all vertebrate PrP-related and Sho-related genes. This provides a new framework for exploring the evolution of this unusual family of proteins and for searching for members in other fish branches and intermediate vertebrate groups.

Animals↗

PubMed1993

Improved alignment of weakly homologous protein sequences using structural information.

Protein sequence alignments can be improved when at least one of the proteins to be aligned has a known 3-D structure. In this work, geometrical constraints extracted from the target fold are evaluated in independent units that deal with complementary structural features. This information is used to set up mutation tables specific to the locally observed structural environments. The resulting partial evaluations are then combined linearly into a global function which is optimized by dynamic programming. Eventually, a score based on tertiary interactions can be used as a selection criterion to discriminate among a set of suboptimal alignments. The relevance of the scores given by each unit is tested on a representative set of protein families. Finally, a method for combining the different scores is described and its efficiency is evaluated on a few pairs of weakly homologous proteins.

Algorithms↗

PubMed2000

MASIA: recognition of common patterns and properties in multiple aligned protein sequences.

SUMMARY: MASIA is a software tool for pattern recognition in multiple aligned protein sequences. MASIA converts a sequence to a properties matrix that can be scanned in both vertical and horizontal steps. Consistent patterns are recognized based on the statistical significance of their occurrence. Preset macros can be altered on-line to seek any combination of amino acid properties or sequence characteristics. MASIA output can be used directly by our programs to predict the 3D structure of proteins. AVAILABILITY: Access MASIA at http://www.scsb.utmb.edu/masia/ma sia.html.

Sequence Alignment↗

PubMed2004

A novel method for multiple alignment of sequences with repeated and shuffled elements.

We describe ABA (A-Bruijn alignment), a new method for multiple alignment of biological sequences. The major difference between ABA and existing multiple alignment methods is that ABA represents an alignment as a directed graph, possibly containing cycles. This representation provides more flexibility than does a traditional alignment matrix or the recently introduced partial order alignment (POA) graph by allowing a larger class of evolutionary relationships between the aligned sequences. Our graph representation is particularly well-suited to the alignment of protein sequences with shuffled and/or repeated domain structure, and allows one to construct multiple alignments of proteins containing (1) domains that are not present in all proteins, (2) domains that are present in different orders in different proteins, and (3) domains that are present in multiple copies in some proteins. In addition, ABA is useful in the alignment of genomic sequences that contain duplications and inversions. We provide several examples illustrating the applications of ABA.

Algorithms↗