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81
RSEARCH: Finding homologs of single structured RNA sequences
 BMC Bioinformatics
, 2003
"... Background: Many transacting noncoding RNA genes and cisacting RNA regulatory elements conserve secondary structure rather than primary sequence. Most homology search tools only look at the primary sequence level, however. ..."
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Cited by 144 (3 self)
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Background: Many transacting noncoding RNA genes and cisacting RNA regulatory elements conserve secondary structure rather than primary sequence. Most homology search tools only look at the primary sequence level, however.
COMPASS: a tool for comparison of multiple protein alignments with assessment of statistical significance
 J. Mol. Biol
, 2003
"... We present a novel method for the comparison of multiple protein alignments with assessment of statistical significance (COMPASS). The method derives numerical profiles from alignments, constructs optimal local profile–profile alignments and analytically estimates Evalues for the detected similari ..."
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Cited by 113 (33 self)
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We present a novel method for the comparison of multiple protein alignments with assessment of statistical significance (COMPASS). The method derives numerical profiles from alignments, constructs optimal local profile–profile alignments and analytically estimates Evalues for the detected similarities. The scoring system and Evalue calculation are based on a generalization of the PSIBLAST approach to profile–sequence comparison, which is adapted for the profile–profile case. Tested along with existing methods for profile–sequence (PSIBLAST) and profile– profile (prof_sim) comparison, COMPASS shows increased abilities for sensitive and selective detection of remote sequence similarities, as well as improved quality of local alignments. The method allows prediction of relationships between protein families in the PFAM database beyond the range of conventional methods. Two predicted relations with high significance are similarities between various Rossmanntype folds and between various helixturnhelixcontaining families. The potential value of COMPASS for structure/function predictions is illustrated by the detection of an intricate homology between the DNAbinding domain of the CTF/NFI family and the MH1 domain of the Smad family.
A NEW GENERATION OF HOMOLOGY SEARCH TOOLS BASED ON PROBABILISTIC INFERENCE
, 2009
"... Many theoretical advances have been made in applying probabilistic inference methods to improve the power of sequence homology searches, yet the BLAST suite of programs is still the workhorse for most of the field. The main reason for this is practical: BLAST’s programs are about 100fold faster tha ..."
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Many theoretical advances have been made in applying probabilistic inference methods to improve the power of sequence homology searches, yet the BLAST suite of programs is still the workhorse for most of the field. The main reason for this is practical: BLAST’s programs are about 100fold faster than the fastest competing implementations of probabilistic inference methods. I describe recent work on the HMMER software suite for protein sequence analysis, which implements probabilistic inference using profile hidden Markov models. Our aim in HMMER3 is to achieve BLAST’s speed while further improving the power of probabilistic inference based methods. HMMER3 implements a new probabilistic model of local sequence alignment and a new heuristic acceleration algorithm. Combined with efficient vectorparallel implementations on modern processors, these improvements synergize. HMMER3 uses more powerful logodds likelihood scores (scores summed over alignment uncertainty, rather than scoring a single optimal alignment); it calculates accurate expectation values (Evalues) for those scores without simulation using a generalization of Karlin/Altschul theory; it computes posterior distributions over the ensemble of possible alignments and returns posterior probabilities (confidences) in each aligned residue; and it does all this at an overall speed comparable to BLAST. The HMMER project aims to usher in a new generation of more powerful homology search tools based on probabilistic inference methods.
The CATH database: an extended protein family resource for structural and functional genomics. Nucleic Acids Res
, 2003
"... The CATH database of protein domain structures ..."
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Approximate pvalues for local sequence alignments
 Ann. Statist
, 2000
"... Siegmund and Yakir (2000) have given an approximate pvalue when two independent, identically distributed sequences from a nite alphabet are optimally aligned based on a scoring system that rewards similarities according to a general scoring matrix and penalizes gaps (insertions and deletions). The ..."
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Cited by 30 (1 self)
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Siegmund and Yakir (2000) have given an approximate pvalue when two independent, identically distributed sequences from a nite alphabet are optimally aligned based on a scoring system that rewards similarities according to a general scoring matrix and penalizes gaps (insertions and deletions). The approximation involves an innite sequence of difculttocompute parameters. In this paper, it is shown by numerical studies that these reduce to essentially two numerically distinct parameters, which can be computed as onedimensional numerical integrals. For an arbitrary scoring matrix and afne gap penalty, this modied approximation is easily evaluated. Comparison with published numerical results show that it is reasonably accurate. Key words: local alignment, afne gap penalty, pvalue, Markov renewal theory. 1.
Efficient TreeMatching Methods for Accurate Carbohydrate Database Queries
 Genome Informatics
, 2003
"... One aspect of glycome informatics is the analysis of carbohydrate sugar chains, or glycans, whose basic structure is not a sequence, but a tree structure. Although there has been much work in the development of sequence databases and matching algorithms for sequences (for performing queries and anal ..."
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Cited by 26 (13 self)
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One aspect of glycome informatics is the analysis of carbohydrate sugar chains, or glycans, whose basic structure is not a sequence, but a tree structure. Although there has been much work in the development of sequence databases and matching algorithms for sequences (for performing queries and analyzing similarity), the more complicated tree structure of glycans does not allow a direct implementation of such a database for glycans, and further, does not allow for the direct application of sequence alignment algorithms for performing searches or analyzing similarity. Therefore, we have utilized...
Rapid Significance Estimation in Local Sequence Alignment with Gaps
, 2001
"... In order to assess the significance of sequence alignments it is crucial to know the distribution of alignment scores of pairs of random sequences. For gapped local alignment it is empirically known that the shape of this distribution is of the Gumbel form. However, the determination of the paramete ..."
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Cited by 21 (1 self)
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In order to assess the significance of sequence alignments it is crucial to know the distribution of alignment scores of pairs of random sequences. For gapped local alignment it is empirically known that the shape of this distribution is of the Gumbel form. However, the determination of the parameters of this distribution is a computationally very expensive task. We present a new algorithmic approach which allows to estimate the more important of the Gumbel parameters at least five times faster than the traditional methods. Actual runtimes of our algorithm between less than a second and a few minutes on a workstation bring significance estimation into the realm of interactive applications.
The FOLDALIGN web server for pairwise structural RNA alignment and mutual motif search. Nucleic Acids Res
, 2005
"... FOLDALIGN is a Sankoffbased algorithm for making structural alignments of RNA sequences. Here, we present a web server for making pairwise alignments between two RNA sequences, using the recently updated version of FOLDALIGN. The server can be used to scan two sequences for a common structural RNA ..."
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FOLDALIGN is a Sankoffbased algorithm for making structural alignments of RNA sequences. Here, we present a web server for making pairwise alignments between two RNA sequences, using the recently updated version of FOLDALIGN. The server can be used to scan two sequences for a common structural RNA motif of limited size, or the entire sequences can be aligned locally or globally. The web server offers a graphical interface, which makes it simple to make alignments and manually browse the results. The web server can be accessed at
A metric model of amino acid substitution
 Bioinformatics
"... Motivation: We address the question of whether there exists an effective evolutionary model of aminoacid substitution that forms a metricdistance function. There is always a tradeoff between speed and sensitivity among competing computational methods of determining sequence homology. A metric mo ..."
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Cited by 20 (6 self)
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Motivation: We address the question of whether there exists an effective evolutionary model of aminoacid substitution that forms a metricdistance function. There is always a tradeoff between speed and sensitivity among competing computational methods of determining sequence homology. A metric model of evolution is a prerequisite for the development of an entire class of fast sequence analysis algorithms that are both scalable, O(log n) and sensitive. Results: We have reworked the mathematics of the point accepted mutation model (PAM) by calculating the expected time between accepted mutations in lieu of calculating logodds probabilities. The resulting substitution matrix (mPAM) forms a metric. We validate the application of the mPAM evolutionary model for sequence homology by executing sequence queries from a controlled yeast protein homology search benchmark. We compare the accuracy of the results of mPAM and PAM similarity matrices as well as three prior metric models.The experiment shows that mPAM significantly outperforms the other three metrics and sufficiently approaches the sensitivity of PAM250 to make it applicable to the management of protein sequence databases. Contact:
Statistical Significance of Probabilistic Sequence Alignment and Related Local Hidden Markov Models
 J. COMP. BIOL
, 2001
"... The score statistics of probabilistic gapped local alignment of random sequences is investigated both analytically and numerically. The full probabilistic algorithm (e.g., the “local” version of maximumlikelihood or hidden Markov model method) is found to have anomalous statistics. A modified “semi ..."
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Cited by 20 (4 self)
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The score statistics of probabilistic gapped local alignment of random sequences is investigated both analytically and numerically. The full probabilistic algorithm (e.g., the “local” version of maximumlikelihood or hidden Markov model method) is found to have anomalous statistics. A modified “semiprobabilistic” alignment consisting of a hybrid of Smith–Waterman and probabilistic alignment is then proposed and studied in detail. It is predicted that the score statistics of the hybrid algorithm is of the Gumbel universal form, with the key Gumbel parameter l taking on a fixed asymptotic value for a wide variety of scoring systems and parameters. A simple recipe for the computation of the “relative entropy,” and from it the finite size correction to l, is also given. These predictions compare well with direct numerical simulations for sequences of lengths between 100 and 1,000 examined using various PAM substitution scores and affine gap functions. The sensitivity of the hybrid method in the detection of sequence homology is also studied using correlated sequences generated from toy mutation models. It is found to be comparable to that of the Smith–Waterman alignment and significantly better than the Viterbi version of the probabilistic alignment.