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PubMed2003

Conservation of structure and function among tyrosine recombinases: homology-based modeling of the lambda integrase core-binding domain.

Tyrosine recombinases participate in diverse biological processes by catalyzing recombination between specific DNA sites. Although a conserved protein fold has been described for the catalytic (CAT) domains of five recombinases, structural relationships between their core-binding (CB) domains remain unclear. Despite differences in the specificity and affinity of core-type DNA recognition, a conserved binding mechanism is suggested by the shared two-domain motif in crystal structure models of the recombinases Cre, XerD and Flp. We have found additional evidence for conservation of the CB domain fold. Comparison of XerD and Cre crystal structures showed that their CB domains are closely related; the three central alpha-helices of these domains are superposable to within 1.44 A. A structure-based multiple sequence alignment containing 25 diverse CB domain sequences provided evidence for widespread conservation of both structural and functional elements in this fold. Based upon the Cre and XerD crystal structures, we employed homology modeling to construct a three-dimensional structure for the lambda integrase CB domain. The model provides a conceptual framework within which many previously identified, functionally important amino acid residues were investigated. In addition, the model predicts new residues that may participate in core-type DNA binding or dimerization, thereby providing hypotheses for future genetic and biochemical experiments.

Amino Acid Sequence↗

PubMed1998

The phylogenetic relationships of Chlorobium tepidum and Chloroflexus aurantiacus based upon their RecA sequences.

Using RecA as the phylogenetic marker, the relationships of the green sulfur bacterium Chlorobium tepidum and the green non-sulfur bacterium Chloroflexus aurantiacus to other eubacteria were investigated. The recA genes of the two organisms were cloned, and the resulting protein sequences aligned with 86 other eubacterial RecA sequences. Cb. tepidum was placed as the nearest relative to the Cytophaga/Flexibacter/Bacteriodes group, a relationship supported by results obtained with several phylogenetic markers. Cf. aurantiacus was placed near Chlamydia trachomatis and the high-GC Gram-positives; however, this branching pattern was not strongly supported statistically by bootstrap analyses. Possible reasons for this ambiguity are discussed.

Amino Acid Sequence↗

PubMed1997

PCR-based isolation and chromosome assignment of members of the Em gene family from wheat.

Four members belonging to the wheat Em gene family were isolated by PCR, cloned and subsequently sequenced. One of the genes corresponds perfectly to a previous published cDNA sequence, the other three genes are new. The amplified sequences contain the entire coding region, which is interrupted by a short intron of variable length, and part of the 3' untranslated region. The chromosomal assignment of each of the four sequences and three extra, previously published, Em sequences was determined using PCR with sequence-specific primers on wheat aneuploid nullitetrasomic lines. Three sequences were shown to be encoded by the Em-A1 locus (on chromosome 1A), one by Em-B1 on chromosome 1B and two by Em-D1 on chromosome 1D. Hence, primer sets specific for each of the three homoeologous chromosomes of the group 1 are available. A lot of DNA sequence polymorphism exists among the sequences most of which is found in the non-coding parts and mainly in the introns. Sequence alignment groups the seven known Em sequences irrespective of their locus origin. The implication of these findings in relation to the organisation and evolution of the Em gene family are discussed.

Amino Acid Sequence↗

PubMed2002

[DNA sequencing and molecular identification of Patchouli and its substitute wrinkled gianthyssop].

AIM: To analyze sequences of the nuclear ribosomal RNA small subunit (18S rRNA) gene and the chloroplast matK gene of crude drug Patchouli (Pogostemon cablin) in order to provide molecular evidence for identification of Patchouli drug. METHODS: To sequence the entire 18S rRNA gene and partial matK gene of Patchouli from Guangzhou and its substitute Wrinkled Gianthyssop (Agastache rugosa) from Sichuan using PCR direct sequencing and to detect the homology of two gene sequences between these two crude drugs. RESULTS: The complete 18S rRNA gene sequence is 1,805 bp in length for Patchouli from Guangzhou whereas 1,794 bp for Wrinkled Gianthyssop from Sichuan. The 3'-end sequence of matK gene is 521 bp (747-1,268 nt from upstream of matK gene) for these two crude drugs. Based on multiple sequence alignment, it is found that there are 18 variable sites and 11 aligned gap sites in 18S rRNA sequence, 49 variable sites in 3'-matK sequence between these two crude drugs. The homology is 98.4% for 18S rRNA and 90.6% for 3'-matK between two crude drugs, respectively. CONCLUSION: DNA sequencing can provide an accurate and reliable tool in the crude drug identification of Patchouli and its substitute Wrinkled Gianthyssop.

Agastache↗

PubMed2002

A Bayesian approach to discriminate between alternative DNA sequence segmentations.

MOTIVATION: As a result of recombination or rate variation, a DNA sequence alignment may have a mosaic structure, where different segments correspond to different evolutionary histories. While several methods have been developed to predict DNA mosaic structures, they do not properly address the question of whether the predicted segmentation itself is statistically significant, or whether it is significantly better than an alternative mosaic structure predicted with another method. The objective of the present article is to devise an approximate Bayesian hypothesis test to discriminate between alternative candidate mosaic structures. RESULTS: We have applied the proposed discrimination scheme to various synthetic and real-world DNA sequence alignments. On the synthetic data, the algorithm identified the true mosaic structure in nine out of ten cases. On the real-world sequence alignments, it selected the same mosaic structures as predicted in the literature.

Algorithms↗

PubMed1993

Secondary structure prediction for modelling by homology.

An improved method of secondary structure prediction has been developed to aid the modelling of proteins by homology. Selected data from four published algorithms are scaled and combined as a weighted mean to produce consensus algorithms. Each consensus algorithm is used to predict the secondary structure of a protein homologous to the target protein and of known structure. By comparison of the predictions to the known structure, accuracy values are calculated and a consensus algorithm chosen as the optimum combination of the composite data for prediction of the homologous protein. This customized algorithm is then used to predict the secondary structure of the unknown protein. In this manner the secondary structure prediction is initially tuned to the required protein family before prediction of the target protein. The method improves statistical secondary structure prediction and can be incorporated into more comprehensive systems such as those involving consensus prediction from multiple sequence alignments. Thirty one proteins from five families were used to compare the new method to that of Garnier, Osguthorpe and Robson (GOR) and sequence alignment. The improvement over GOR is naturally dependent on the similarity of the homologous protein, varying from a mean of 3% to 7% with increasing alignment significance score.

Algorithms↗

PubMed2006

TaxMan: a taxonomic database manager.

BACKGROUND: Phylogenetic analysis of large, multiple-gene datasets, assembled from public sequence databases, is rapidly becoming a popular way to approach difficult phylogenetic problems. Supermatrices (concatenated multiple sequence alignments of multiple genes) can yield more phylogenetic signal than individual genes. However, manually assembling such datasets for a large taxonomic group is time-consuming and error-prone. Additionally, sequence curation, alignment and assessment of the results of phylogenetic analysis are made particularly difficult by the potential for a given gene in a given species to be unrepresented, or to be represented by multiple or partial sequences. We have developed a software package, TaxMan, that largely automates the processes of sequence acquisition, consensus building, alignment and taxon selection to facilitate this type of phylogenetic study. RESULTS: TaxMan uses freely available tools to allow rapid assembly, storage and analysis of large, aligned DNA and protein sequence datasets for user-defined sets of species and genes. The user provides GenBank format files and a list of gene names and synonyms for the loci to analyse. Sequences are extracted from the GenBank files on the basis of annotation and sequence similarity. Consensus sequences are built automatically. Alignment is carried out (where possible, at the protein level) and aligned sequences are stored in a database. TaxMan can automatically determine the best subset of taxa to examine phylogeny at a given taxonomic level. By using the stored aligned sequences, large concatenated multiple sequence alignments can be generated rapidly for a subset and output in analysis-ready file formats. Trees resulting from phylogenetic analysis can be stored and compared with a reference taxonomy. CONCLUSION: TaxMan allows rapid automated assembly of a multigene datasets of aligned sequences for large taxonomic groups. By extracting sequences on the basis of both annotation and BLAST similarity, it ensures that all available sequence data can be brought to bear on a phylogenetic problem, but remains fast enough to cope with many thousands of records. By automatically assisting in the selection of the best subset of taxa to address a particular phylogenetic problem, TaxMan greatly speeds up the process of generating multiple sequence alignments for phylogenetic analysis. Our results indicate that an automated phylogenetic workbench can be a useful tool when correctly guided by user knowledge.

Database Management Systems↗

PubMed1998

Nativelike topology assembly of small proteins using predicted restraints in Monte Carlo folding simulations.

By incorporating predicted secondary and tertiary restraints derived from multiple sequence alignments into ab initio folding simulations, it has been possible to assemble native-like tertiary structures for a test set of 19 nonhomologous proteins ranging from 29 to 100 residues in length and representing all secondary structural classes. Secondary structural restraints are provided by the PHD secondary structure prediction algorithm that incorporates multiple sequence information. Multiple sequence alignments also provide predicted tertiary restraints via a two-step process: First, seed side chain contacts are selected from a correlated mutation analysis, and then an inverse folding algorithm expands these seed contacts. The predicted secondary and tertiary restraints are incorporated into a lattice-based, reduced protein model for structure assembly and refinement. The resulting native-like topologies exhibit a coordinate root-mean-square deviation from native for the whole chain between 3.1 and 6.7 A, with values ranging from 2.6 to 4.1 A over approximately 80% of the structure. Overall, this study suggests that the use of restraints derived from multiple sequence alignments combined with a fold assembly algorithm is a promising approach to the prediction of the global topology of small proteins.

Algorithms↗

PubMedDate not supplied

Microsomal and soluble epoxide hydrolases are members of the same family of C-X bond hydrolase enzymes.

Sequence alignments of mammalian microsomal (MEH) and soluble epoxide hydrolases (SEH) with bacterial haloalkane dehalogenase (HAD) and haloacetate dehalogenase (HAcD) together with structural and functional evidence suggest that these four enzymes are structurally and mechanistically related. The catalytic mechanism of HAD and MEH have been recently shown to involve an ester intermediate formed by alkylation of an active site carboxyl group. Very pronounced sequence similarities of regions of MEH, SEH, and HAcD with the active site of HAD suggest that all four enzymes belong to the same family of C-X bond hydrolases which involve an alkyl-enzyme intermediate. The catalytic triads (nucleophile-base-acid) of MEH and SEH are proposed to be Asp226-His431-Asp352 and Asp333-His523-Asp495, respectively, on the basis of sequence alignments with HAD. Although compelling arguments, through sequence alignments, can be made for the assignment of the nucleophile-base pair of the triad, the identity of the acid residue (e.g., Asp352 and Asp495) is more speculative. The three-dimensional structures of both MEH and SEH are suggested to contain structural elements of the alpha/beta hydrolase fold.

Amino Acid Sequence↗

PubMed1995

Recurring local sequence motifs in proteins.

We describe a completely automated approach to identifying local sequence motifs that transcend protein family boundaries. Cluster analysis is used to identify recurring patterns of variation at single positions and in short segments of contiguous positions in multiple sequence alignments for a non-redundant set of protein families. Parallel experiments on simulated data sets constructed with the overall residue frequencies of proteins but not the inter-residue correlations show that naturally occurring protein sequences are significantly more clustered than the corresponding random sequences for window lengths ranging from one to 13 contiguous positions. The patterns of variation at single positions are not in general surprising: chemically similar amino acids tend to be grouped together. More interesting patterns emerge as the window length increases. The patterns of variation for longer window lengths are in part recognizable patterns of hydrophobic and hydrophilic residues, and in part less obvious combinations. A particularly interesting class of patterns features highly conserved glycine residues. The patterns provide a means to abstract the information contained in multiple sequence alignments and may be useful for comparison of distantly related sequences or sequence families and for protein structure prediction.

Cluster Analysis↗

PubMed1994

Molecular and genetic analyses of Drosophila Prat, which encodes the first enzyme of de novo purine biosynthesis.

The Drosophila Prat gene encodes phosphoribosylamidotransferase (PRAT), the enzyme that performs the first committed step of the de novo purine nucleotide biosynthesis pathway. Using information from amino acid sequence alignments of PRAT from other organisms, a polymerase chain reaction-based approach was employed to clone Prat. Amino acid sequence alignment of Drosophila PRAT with PRAT from bacteria, yeast, and vertebrates indicates that it is most identical (at least 60%) to the vertebrate PRATs. It shares putative amino-terminal propeptide and iron-binding domains seen only in Bacillus subtilis and vertebrate PRATs. Prat was localized to the right arm of chromosome 3 at polytene band 84E1-2. Owing to the fact that this region had been well characterized previously, Prat was localized to a 30-kilobase region between two deficiency breakpoints. By making the prediction that Prat would have a similar "purine syndrome" phenotype as mutations in the genes ade2 and ade3, which encode enzymes downstream in the pathway, five alleles of Prat were isolated. Three of the alleles were identified as missense mutations. A comparison of PRAT enzyme activity with phenotype in three of the mutants indicates that a reduction to 40% of the wild-type allele's activity is sufficient to cause the purine syndrome, suggesting that PRAT activity is limiting in Drosophila.

Amidophosphoribosyltransferase↗

PubMed2005

Consensus shapes: an alternative to the Sankoff algorithm for RNA consensus structure prediction.

MOTIVATION: The well-known Sankoff algorithm for simultaneous RNA sequence alignment and folding is currently considered an ideal, but computationally over-expensive method. Available tools implement this algorithm under various pragmatic restrictions. They are still expensive to use, and it is difficult to judge if the moderate quality of results is because of the underlying model or to its imperfect implementation. RESULTS: We propose to redefine the consensus structure prediction problem in a way that does not imply a multiple sequence alignment step. For a family of RNA sequences, our method explicitly and independently enumerates the near-optimal abstract shape space, and predicts as the consensus an abstract shape common to all sequences. For each sequence, it delivers the thermodynamically best structure which has this common shape. Since the shape space is much smaller than the structure space, and identification of common shapes can be done in linear time (in the number of shapes considered), the method is essentially linear in the number of sequences. Our evaluation shows that the new method compares favorably with available alternatives. AVAILABILITY: The new method has been implemented in the program RNAcast and is available on the Bielefeld Bioinformatics Server. CONTACT: jreeder@TechFak.Uni-Bielefeld.DE, robert@TechFak.Uni-Bielefeld.DE SUPPLEMENTARY INFORMATION: Available at http://bibiserv.techfak.uni-bielefeld.de/rnacast/supplementary.html

Algorithms↗

PubMed1988

Statistical analysis of DNA sequences.

Developments in the statistical analysis of DNA sequence data since 1984 are reviewed. Mathematical methods employing dynamic programming or incorporating Markov chain theory have been developed to search sequences for regions of similarity and to align sequences. When the biological forces of mutation and genetic drift are included in models, distances between aligned sequences allow the construction of evolutionary trees. Theory based on models may lead to estimates of variation of parameter estimates and so give a means of assessing the statistical significance of observed patterns and relationships. The complexity of DNA sequences, however, suggests that most statistical inferences will rest on random permutations of sequences.

Base Sequence↗

PubMed2000

Covariance analysis of protein families: the case of the variable domains of antibodies.

A nonrestrictive method for identifying covariance in protein families is described and applied to human and mouse germline Vkappa and VH sequence alignments. Amino acids that occur at each position in a sequence alignment are divided into two sets, called a word, by generating all possible combinations of alternative amino acids. Each word is associated with a pattern of changes. Words with identical patterns identify covariant positions. In antibody variable domains, the number of words generated ranged between 1103 and 2195 depending on the alignment, of which 4 to 12 % occurred in covariant pairs. Despite the nonrestrictive character of pattern generation, covariant residues did not reflect a random selection with respect to the nature of amino acid changes and/or their spatial proximity in a reference crystallographic structure. This approach allowed the identification of a covariance signal for positions with high variability, mostly located in the outer part of the common structural framework of antibody variable domains. Covariance in these regions may reflect the existence of alternative and mutually exclusive atomic arrangements that are compatible with antibody function. The method may be of general applicability to rationalize residue variability in protein families.

Algorithms↗

PubMed2006

SNAP: Combine and Map modules for multilocus population genetic analysis.

We have added two software tools to our Suite of Nucleotide Analysis Programs (SNAP) for working with DNA sequences sampled from populations. SNAP Map collapses DNA sequence data into unique haplotypes, extracts variable sites and manipulates output into multiple formats for input into existing software packages for evolutionary analyses. Map collapses DNA sequence data into unique haplotypes, extracts variable sites and manipulates output into multiple formats for input into existing software packages for evolutionary analyses. Map includes novel features such as recoding insertions or deletions, including or excluding variable sites that violate an infinite-sites model and the option of collapsing sequences with corresponding phenotypic information, important in testing for significant haplotype-phenotype associations. SNAP Combine merges multiple DNA sequence alignments into a single multiple alignment file. The resulting file can be the union or intersection of the input files. SNAP Combine currently reads from and writes to several sequence alignment file formats including both sequential and interleaved formats. Combine also keeps track of the start and end positions of each separate alignment file allowing the user to exclude variable sites or taxa, important in creating input files for multilocus analyses.

Algorithms↗

PubMed2003

Reduction of protein sequence complexity by residue grouping.

It is well known that there are some similarities among various naturally occurring amino acids. Thus, the complexity in protein systems could be reduced by sorting these amino acids with similarities into groups and then protein sequences can be simplified by reduced alphabets. This paper discusses how to group similar amino acids and whether there is a minimal amino acid alphabet by which proteins can be folded. Various reduced alphabets are obtained by reserving the maximal information for the simplified protein sequence compared with the parent sequence using global sequence alignment. With these reduced alphabets and simplified similarity matrices, we achieve recognition of the protein fold based on the similarity score of the sequence alignment. The coverage in dataset SCOP40 for various levels of reduction on the amino acid types is obtained, which is the number of homologous pairs detected by program BLAST to the number marked by SCOP40. For the reduced alphabets containing 10 types of amino acids, the ability to detect distantly related folds remains almost at the same level as that by the alphabet of 20 types of amino acids, which implies that 10 types of amino acids may be the degree of freedom for characterizing the complexity in proteins.

Amino Acid Sequence↗

PubMed1998

A polyhedral approach to RNA sequence structure alignment.

Ribonucleic acid (RNA) is a polymer composed of four bases denoted A, C, G, and U. It generally is a single-stranded molecule where the bases form hydrogen bonds within the same molecule leading to structure formation. In comparing different homologous RNA molecules it is important to consider both the base sequence and the structure of the molecules. Traditional alignment algorithms can only account for the sequence of bases, but not for the base pairings. Considering the structure leads to significant computational problems because of the dependencies introduced by the base pairings. In this paper we address the problem of optimally aligning a given RNA sequence of unknown structure to one of known sequence and structure. We phrase the problem as an integer linear program and then solve it using methods from polyhedral combinatorics. In our computational experiments we could solve large problem instances--23S ribosomal RNA with more than 1400 bases--a size intractable for former algorithms.

Algorithms↗

PubMed2007

VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines.

BACKGROUND: Vaccine development in the post-genomic era often begins with the in silico screening of genome information, with the most probable protective antigens being predicted rather than requiring causative microorganisms to be grown. Despite the obvious advantages of this approach--such as speed and cost efficiency--its success remains dependent on the accuracy of antigen prediction. Most approaches use sequence alignment to identify antigens. This is problematic for several reasons. Some proteins lack obvious sequence similarity, although they may share similar structures and biological properties. The antigenicity of a sequence may be encoded in a subtle and recondite manner not amendable to direct identification by sequence alignment. The discovery of truly novel antigens will be frustrated by their lack of similarity to antigens of known provenance. To overcome the limitations of alignment-dependent methods, we propose a new alignment-free approach for antigen prediction, which is based on auto cross covariance (ACC) transformation of protein sequences into uniform vectors of principal amino acid properties. RESULTS: Bacterial, viral and tumour protein datasets were used to derive models for prediction of whole protein antigenicity. Every set consisted of 100 known antigens and 100 non-antigens. The derived models were tested by internal leave-one-out cross-validation and external validation using test sets. An additional five training sets for each class of antigens were used to test the stability of the discrimination between antigens and non-antigens. The models performed well in both validations showing prediction accuracy of 70% to 89%. The models were implemented in a server, which we call VaxiJen. CONCLUSION: VaxiJen is the first server for alignment-independent prediction of protective antigens. It was developed to allow antigen classification solely based on the physicochemical properties of proteins without recourse to sequence alignment. The server can be used on its own or in combination with alignment-based prediction methods. It is freely-available online at the URL: http://www.jenner.ac.uk/VaxiJen.

Algorithms↗