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PubMed2005

Intron-flanking EST-PCR markers: from genetic marker development to gene structure analysis in Rhododendron.

With a long-term goal of constructing a linkage map of Rhododendron enriched with gene-specific markers, we utilized Rhododendron catawbiense ESTs for the development of high-efficiency (in terms of generating polymorphism frequency) PCR-based markers. Using the gene-sequence alignment between Rhododendron ESTs and the genomic sequences of Arabidopsis homologs, we developed 'intron-flanking' EST-PCR-based primers that would anneal in conserved exon regions and amplify across the more highly diverged introns. These primers resulted in increased efficiency (61% vs. 13%; 4.7-fold) of polymorphism-detection compared with conventional EST-PCR methods, supporting the assumption that intron regions are more diverged than exons. Significantly, this study demonstrates that Arabidopsis genome database can be useful in developing gene-specific PCR-based markers for other non-model plant species for which the EST data are available but genomic sequences are not. The comparative analysis of intron sizes between Rhododendron and Arabidopsis (made possible in this study by aligning of Rhododendron ESTs with Arabidopsis genomic sequences and the sequencing of Rhododendron genomic PCR products) provides the first insight into the gene structure of Rhododendron.

Arabidopsis↗

PubMed2004

Homeologous recombination between AluSx-sequences as a cause of hemophilia.

Although large deletions from the coagulation factor VIII gene, F8, are responsible for 5% of severe hemophilia A (seHA), few of them have been fully characterised. A detailed description of a large partial deletion of the F8 caused by unequal recombination between homeologous AluSx-derived sequences is presented. The proband, a case of isolated hemophilia A with a high inhibitor titre (5700 BU), showed a consistent absence of PCR-amplification of exons 4 to 10, EX4_EX10del. Two approaches were used to narrow down the deletion breakpoints: a direct physical analysis based on PCR (that additionally permits carrier detection in the family); and, under the hypothesis that the mutation resulted from homologous recombination, sequence alignments of F8 intron 3 and 10. Both approaches indicate an unequal crossing over (CO) between two Alu-related sequences. Both elements involved were derived from the AluSx-subfamily consensus and demonstrate 86% sequence identity (with only single-base mismatches), with three gaps (of 2, 3 and 14-bases) and two main tracts of perfectly homologous sequence (28 and 24-bp). The short stretch of intron 10 embedded into intron 3 sequence, linked to the CO, represents a typical hallmark of homologous recombination (double-strand break repair model). A detailed description of EX4_EX10del mutation is c.[338+3485delins1687+2223_1687+2225; 338+3551_1687+2291 del]. The common involvement of unequal homologous recombination mediated by repetitive elements allowed us to suggest that our experimental design (based on intron sequence alignments) may be successfully applied to rearrangements involved in other X-linked inherited diseases. Like other Alu-rich genes throughout the human genome, Alu-mediated homologous recombination in F8 may be an important cause of hemophilia by promoting large DNA deletions.

Alu Elements↗

PubMed2003

Computational analysis of the evolution of the structure and function of 1-deoxy-D-xylulose-5-phosphate synthase, a key regulator of the mevalonate-independent pathway in plants.

We investigated molecular evolution of 1-deoxy-D-xylulose-5-phosphate synthase (DXS), an important regulatory enzyme of the mevalonate-independent pathway involved in terpenoid biosynthesis. Sequence alignment showed that some regions, likely to be functionally important, were highly conserved among all of the plant DXS sequences analysed. Phylogenetic trees were inferred using DXS sequences from 11 species of Angiosperms and showed the division of the sequences into two classes. Clustering of DXS sequences did not correspond to phylogenetic relationships among the plant species studied. There was no consistency in the similarity of the variable regions in the secondary structure of the DXS functional protein except for Capsicum and Lycopersicon, both members of the Solanaceae. Hydrophobicity plots for the functional region of DXS revealed great similarity in their hydrophobic structure, consistent with the phylogenetic trees inferred, and with eight prominent hydrophilic and hydrophobic peaks. We also observed a consistent set of features common to the DXS transit peptides studied. These features were the same hydrophobic slope, a hydrophobic region in residues 35-45, and, in eight of 12 sequences, a Pro-Pro-Thr sequence at the C-terminal end. The transit sequences are likely bipartite and contain features that suggest the DXS protein is not only targeted to the chloroplast, but also to the thylakoid. To our knowledge this is the first suggestion that DXS is located specifically in the chloroplast thylakoid.

Amino Acid Sequence↗

PubMed1999

Evolution of the proximal promoter region of the mammalian growth hormone gene.

The evolutionary relationship between the proximal growth hormone (GH) gene promoter sequences of 12 mammalian species was explored by comparison of their trinucleotide composition and by multiple sequence alignment. Both approaches yielded results that were consistent with the known fossil record-based phylogeny of the analysed sequences, suggesting that the two methods of tree reconstruction might be equally efficient and reliable. The pattern of evolution inferred for the mammalian GH gene promoters was found to vary both temporally and spatially. Thus, two distinct regions devoid of any evolutionary changes exist in primates, but only one of these 'gaps' is also observed in rodents, and neither is seen in ruminants. Furthermore, different evolutionary rates must have prevailed during different periods of evolutionary time and in different lineages, with a dramatic increase in evolutionary rate apparent in primates. Since a similar pattern of discontinuity has been previously noted for the evolution of the GH-coding regions, it may reflect the action of positive selection operating upon the GH gene as a single cohesive unit. Strong evidence for the action of gene conversion between primate GH gene promoters is provided by the fact that the human GH1 and GH2 sequences, which are thought to have diverged before the divergence of Old World monkeys from great apes, are more similar to one another than either is to the rhesus monkey GH2 promoter. Finally, it was noted that a number of nucleotide positions in the GH1 gene promoter that are polymorphic in humans appear to be highly conserved in mammals. This apparent conundrum, which could represent a caveat for the interpretation of phylogenetic footprinting studies, is potentially explicable in terms either of reduced genetic diversity in highly inbred animal species or insufficient population data from non-human species.

Animals↗

PubMed2003

Disease-associated variants in PYPAF1 and NOD2 result in similar alterations of conserved sequence.

Sequence variations in the gene products PYPAF1/CIAS1 and NOD2/CARD15 have been associated with several autoinflammatory diseases that, although clinically different, share a similar inflammatory pathophysiology. A multiple sequence alignment of homologous proteins demonstrates that some of the missense variants are located in highly conserved regions of the NTPase domain and possibly impair NTP-hydrolysis. Intriguingly, one of the variations, which is found identically in PYPAF1 and NOD2, is located at the same alignment position. Our findings suggest that evolutionary gene duplication can give rise to disease families because variants affect conserved sequence in a similar fashion.

Animals↗

PubMed2004

Seq2Struct: a resource for establishing sequence-structure links.

UNLABELLED: Several methods for establishing cross-links between Protein Data Bank (PDB) structures or Structural Classification of Proteins (SCOP) domains and Swiss-Prot + TrEMBL sequences (or vice versa) rely on database annotations. Alternatively, sequence alignment procedures can be used. In this study, we describe Seq2Struct, a web resource for the identification of sequence-structure links. The resource consists of an exhaustive collection of annotated links between Swiss-Prot + TrEMBL and PDB + SCOP database entries. Links are based on pre-established highly reliable thresholds and stored in a relational database, which has been enhanced using annotations derived from Swiss-Prot, PDB, SCOP, GOA and DSSP databases. The Seq2Struct database contents, supported by a WWW web interface, can be queried both online and downloaded. AVAILABILITY: The Seq2Struct resource, with related documentation, is available at http://surface.bio.uniroma2.it/seq2struct/ CONTACT: seq2struct@cbm.bio.uniroma2.it.

Database Management Systems↗

PubMed2002

Exploration of novel motifs derived from mouse cDNA sequences.

We performed a systematic maximum density subgraph (MDS) detection of conserved sequence regions to discover new, biologically relevant motifs from a set of 21,050 conceptually translated mouse cDNA (FANTOM1) sequences. A total of 3202 candidate sequences, which shared similar regions over >20 amino acid residues, were screened against known conserved regions listed in Pfam, ProDom, and InterPro. The filtering procedure resulted in 139 FANTOM1 sequences belonging to 49 new motif candidates. Using annotations and multiple sequence alignment information, we removed by visual inspection 42 candidates whose members were found to be false positives because of sequence redundancy, alternative splicing, low complexity, transcribed retroviral repeat elements contained in the region of the predicted open reading frame, and reports in the literature. The remaining seven motifs have been expanded by hidden Markov model (HMM) profile searches of SWISS-PROT/TrEMBL from 28 FANTOM1 sequences to 164 members and analyzed in detail on sequence and structure level to elucidate the possible functions of motifs and members. The novel and conserved motif MDS00105 is specific for the mammalian inhibitor of growth (ING) family. Three submotifs MDS00105.1-3 are specific for ING1/ING1L, ING1-homolog, and ING3 subfamilies. The motif MDS00105 together with a PHD finger domain constitutes a module for ING proteins. Structural motif MDS00113 represents a leucine zipper-like motif. Conserved motif MDS00145 is a novel 1-acyl-SN-glycerol-3-phosphate acyltransferase (AGPAT) submotif containing a transmembrane domain that distinguishes AGPAT3 and AGPAT4 from all other acyltransferase domain-containing proteins. Functional motif MDS00148 overlaps with the kazal-type serine protease inhibitor domain but has been detected only in an extracellular loop region of solute carrier 21 (SLC21) (organic anion transporters) family members, which may regulate the specificity of anion uptake. Our motif discovery not only aided in the functional characterization of new mouse orthologs for potential drug targets but also allowed us to predict that at least 16 other new motifs are waiting to be discovered from the current SWISS-PROT/TrEMBL database.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed2005

Vestige: maximum likelihood phylogenetic footprinting.

BACKGROUND: Phylogenetic footprinting is the identification of functional regions of DNA by their evolutionary conservation. This is achieved by comparing orthologous regions from multiple species and identifying the DNA regions that have diverged less than neutral DNA. Vestige is a phylogenetic footprinting package built on the PyEvolve toolkit that uses probabilistic molecular evolutionary modelling to represent aspects of sequence evolution, including the conventional divergence measure employed by other footprinting approaches. In addition to measuring the divergence, Vestige allows the expansion of the definition of a phylogenetic footprint to include variation in the distribution of any molecular evolutionary processes. This is achieved by displaying the distribution of model parameters that represent partitions of molecular evolutionary substitutions. Examination of the spatial incidence of these effects across regions of the genome can identify DNA segments that differ in the nature of the evolutionary process. RESULTS: Vestige was applied to a reference dataset of the SCL locus from four species and provided clear identification of the known conserved regions in this dataset. To demonstrate the flexibility to use diverse models of molecular evolution and dissect the nature of the evolutionary process Vestige was used to footprint the Ka/Ks ratio in primate BRCA1 with a codon model of evolution. Two regions of putative adaptive evolution were identified illustrating the ability of Vestige to represent the spatial distribution of distinct molecular evolutionary processes. CONCLUSION: Vestige provides a flexible, open platform for phylogenetic footprinting. Underpinned by the PyEvolve toolkit, Vestige provides a framework for visualising the signatures of evolutionary processes across the genome of numerous organisms simultaneously. By exploiting the maximum-likelihood statistical framework, the complex interplay between mutational processes, DNA repair and selection can be evaluated both spatially (along a sequence alignment) and temporally (for each branch of the tree) providing visual indicators to the attributes and functions of DNA sequences.

Algorithms↗

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↗

PubMed2004

Multi-species sequence comparison reveals dynamic evolution of the elastin gene that has involved purifying selection and lineage-specific insertions/deletions.

BACKGROUND: The elastin gene (ELN) is implicated as a factor in both supravalvular aortic stenosis (SVAS) and Williams Beuren Syndrome (WBS), two diseases involving pronounced complications in mental or physical development. Although the complete spectrum of functional roles of the processed gene product remains to be established, these roles are inferred to be analogous in human and mouse. This view is supported by genomic sequence comparison, in which there are no large-scale differences in the ~1.8 Mb sequence block encompassing the common region deleted in WBS, with the exception of an overall reversed physical orientation between human and mouse. RESULTS: Conserved synteny around ELN does not translate to a high level of conservation in the gene itself. In fact, ELN orthologs in mammals show more sequence divergence than expected for a gene with a critical role in development. The pattern of divergence is non-conventional due to an unusually high ratio of gaps to substitutions. Specifically, multi-sequence alignments of eight mammalian sequences reveal numerous non-aligning regions caused by species-specific insertions and deletions, in spite of the fact that the vast majority of aligning sites appear to be conserved and undergoing purifying selection. CONCLUSIONS: The pattern of lineage-specific, in-frame insertions/deletions in the coding exons of ELN orthologous genes is unusual and has led to unique features of the gene in each lineage. These differences may indicate that the gene has a slightly different functional mechanism in mammalian lineages, or that the corresponding regions are functionally inert. Identified regions that undergo purifying selection reflect a functional importance associated with evolutionary pressure to retain those features.

Animals↗

PubMed2006

Involvement of some large immunophilins and their ligands in the protection and regeneration of neurons: a hypothetical mode of action.

The powerful immunosuppressive drugs such as FK506 and its derivatives induce some regeneration and protection of neurons from ischaemic brain injury and some other neurological disorders. The drugs form complexes with diverse FKBPs but apparently the FKBP52/FK506 complex was shown to be involved in the protection and regeneration of neurons. We used several different sequence attributes in searching diverse genomic databases for similar motifs as those present in the FKBPs. A Fortran library of algorithms (Par_Seq) has been designed and used in searching for the similarity of sequence motifs extracted from the multiple sequence alignments of diverse groups of proteins (query motifs) and the target motifs which are encoded in various genomes. The following sequence attributes were used in the establishment of the degree of convergence between: (A) amino acid (AA) sequence similarity (ID) of the query/target motifs and (B) their: (1) AA composition (AAC); (2) hydrophobicity (HI); (3) Jensen-Shannon entropy; and (4) AA propensity to form a particular secondary structure. The sequence hallmark of two different groups of peptidylprolyl cis/trans isomerases (PPIases), namely tetratricopetide repeat (TPR) motifs, which are present in the heat-shock cyclophilins and in the large FK506-binding proteins (FKBPs) were used to search various genomic databases. The Par_Seq algorithm has revealed that the TPR motifs have similar sequence attributes as a number of hydrophobic sequence segments of functionally unrelated membrane proteins, including some of the TMs from diverse G protein-coupled receptors (GPCRs). It is proposed that binding of the FKBP52/FK506 complex to the membranes via the TPR motifs and its interaction with some membrane proteins could be in part responsible for some neuro-regeneration and neuro-protection of the brain during some ischaemia-induced stresses.

Algorithms↗

PubMed2000

Identification and analysis of the polyhydroxyalkanoate-specific beta-ketothiolase and acetoacetyl coenzyme A reductase genes in the cyanobacterium Synechocystis sp. strain PCC6803.

Synechocystis sp. strain PCC6803 possesses a polyhydroxyalkanoate (PHA)-specific beta-ketothiolase encoded by phaA(Syn) and an acetoacetyl-coenzyme A (CoA) reductase encoded by phaB(Syn). A similarity search of the entire Synechocystis genome sequence identified a cluster of two putative open reading frames (ORFs) for these genes, slr1993 and slr1994. Sequence analysis showed that the ORFs encode proteins having 409 and 240 amino acids, respectively. The two ORFs are colinear and most probably coexpressed, as revealed by sequence analysis of the promoter regions. Heterologous transformation of Escherichia coli with the two genes and the PHA synthase of Synechocystis resulted in accumulation of PHAs that accounted for up to 12.3% of the cell dry weight under high-glucose growth conditions. Targeted disruption of the above gene cluster in Synechocystis eliminated the accumulation of PHAs. ORFs slr1993 and slr1994 thus encode the PHA-specific beta-ketothiolase and acetoacetyl-CoA reductase of Synechocystis and, together with the recently characterized PHA synthase genes in this organism (S. Hein, H. Tran, and A. Steinbüchel, Arch. Microbiol. 170:162-170, 1998), form the first complete PHA biosynthesis pathway known in cyanobacteria. Sequence alignment of all known short-chain-length PHA-specific acetoacetyl-CoA reductases also suggests an extended signature sequence, VTGXXXGIG, for this group of proteins. Phylogenetic analysis further places the origin of phaA(Syn) and phaB(Syn) in the gamma subdivision of the division Proteobacteria.

Acetyl-CoA C-Acyltransferase↗

PubMed1993

Detection of correlations in tRNA sequences with structural implications.

Using an flexible representation of biological sequences, we have performed a comparative analysis of 1208 known tRNA sequences. We believe we our technique is a more sensitive method for detecting structural and functional relationships in sets of aligned sequences because we use a flexible representation (for sequences), as well as a general statistical method that can detect a wide range of relationships between positions in a sequence. Our method utilizes functional classifications of the sequence building-blocks (nucleotide bases and amino acids) based on physical or chemical properties. This flexibility in sequence representation improves the significance of finding sequence relationships mediated by the defining property. For example, using a purine/pyrimidine classification, we can detect base-stacking interactions in sets of nucleotide sequences that form base-paired helices. We use several statistical measures, including chi 2-tests, Monte Carlo simulations and an information measure to detect significant correlations in sequences. In this paper we illustrate our method by analyzing a set of tRNA sequences and showing that the correlations our program discovers, in each case, correspond to the known base-pairing and higher order interactions observed in tRNA crystal structures. Furthermore, we show that novel and interesting features of tRNAs are detected when sequence correlations with the charged amino acid (and anticodon) are evaluated. This technique is a powerful method for predicting the structure of RNAs and for analyzing specific functional characteristics.

Base Composition↗

PubMed2003

Spatial clustering of isozyme-specific residues reveals unlikely determinants of isozyme specificity in fructose-1,6-bisphosphate aldolase.

Vertebrate fructose-1,6-bisphosphate aldolase exists as three isozymes (A, B, and C) that demonstrate kinetic properties that are consistent with their physiological role and tissue-specific expression. The isozymes demonstrate specific substrate cleavage efficiencies along with differences in the ability to interact with other proteins; however, it is unknown how these differences are conferred. An alignment of 21 known vertebrate aldolase sequences was used to identify all of the amino acids that are specific to each isozyme, or isozyme-specific residues (ISRs). The location of ISRs on the tertiary and quaternary structures of aldolase reveals that ISRs are found largely on the surface (24 out of 27) and are all outside of hydrogen bonding distance to any active site residue. Moreover, ISRs cluster into two patches on the surface of aldolase with one of these patches, the terminal surface patch, overlapping with the actin-binding site of aldolase A and overlapping an area of higher than average temperature factors derived from the x-ray crystal structures of the isozymes. The other patch, the distal surface patch, comprises an area with a different electrostatic surface potential when comparing isozymes. Despite their location distal to the active site, swapping ISRs between aldolase A and B by multiple site mutagenesis on recombinant expression plasmids is sufficient to convert the kinetic properties of aldolase A to those of aldolase B. This implies that ISRs influence catalysis via changes that alter the structure of the active site from a distance or via changes that alter the interaction of the mobile C-terminal portion with the active site. The methods used in the identification and analysis of ISRs discussed here can be applied to other protein families to reveal functionally relevant residue clusters not accessible by conventional primary sequence alignment methods.

Amino Acid Sequence↗

PubMed1988

Profile scanning for three-dimensional structural patterns in protein sequences.

Profile analysis measures the similarity between a target sequence and a group of aligned sequences (the probe). The probe sequences are used to produce a position-specific scoring table (the profile) that can be aligned with any sequence (the target) using standard dynamic programming methods. We are developing a library of profiles, each describing a different structural motif. This allows any target sequence to be rapidly scanned for the presence of structural motifs. Levels of significance for the comparison of target sequences with the profile are determined in advance, permitting an objective decision to be made as to whether a protein is likely to possess a structural motif.

Amino Acid Sequence↗

PubMed2006

The amelogenin story: origin and evolution.

Genome sequencing and gene mapping have permitted the identification of HEVIN (SPARC-Like1) as the probable ancestor of the enamel matrix proteins (EMPs), amelogenin (AMEL), ameloblastin (AMBN) and enamelin (ENAM). We have undertaken a phylogenetic analysis to elucidate their relationships. AMEL genes available in databases, and new sequences obtained in blast searching genomes or expressed sequence tags, were compiled (22 full-length sequences), aligned, and the ancestral sequence calculated and used to search for similarities using psi-blast. Hits were obtained with the N-terminal region of AMBN, ENAM, and HEVIN. We retrieved all available AMBN (n=8), ENAM (n=3), and HEVIN (n=4) sequences. The sequences of the four proteins were aligned and analyzed phylogenetically. AMEL and AMBN are sister genes, which diverged after duplication of a common ancestor issued from ENAM. The latter derived from a copy of HEVIN. Comparisons of gene organization, amino acid sequences and location of ENAM and AMBN, adjacent on the same chromosome, suggest that AMBN is closer to ENAM than AMEL. This supports AMEL as being derived from AMBN duplication. This duplication occurred long before tetrapod differentiation, probably in an ancestral osteichthyan. The story of AMEL origin is completed as follows: SPARC-->HEVIN-->ENAM-->AMBN-->AMEL.

Amelogenin↗

PubMed1999

Two strategies for sequence comparison: profile-preprocessed and secondary structure-induced multiple alignment.

Multiple sequence alignment remains one of the most powerful tools for assessing sequence relateness and the identification of structurally and functionally important protein regions. In this work, two new techniques are introduced to increase the sensitivity of dynamic programming and to enable checks for alignment consistency: Profile-preprocessed and secondary structure-induced alignments. Both strategies are based upon the hierarchical dynamic programming technique and can be applied separately or used in combination. Alignments resulting from the strategies are shown in comparison with the multiple alignment methods CLUSTALX and MULTAL for distant sequence sets of the flavoxin and cupredoxin protein families.

Amino Acid Sequence↗

PubMed2003

Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity--targets--functions.

Information recovered from genome sequencing projects, multiple sequence alignments, structural analyses of PPIase and published records were used in deciphering the biological diversity, functions and targets of four groups of proteins encoded by dissimilar sets of sequences whose spatial representations exhibit peptidylprolyl cis/trans isomerase activity (PPIase). In the human genome there are encoded fifteen proteins whose segments have significant homology with the sequence of 12 kDa protein which is the target of the potent immunosuppressive macrolides FK506 or rapamycin. The 12 kDa archetype of the FK506-binding protein (FKBP), known as FKBP-12a, is an abundant intracellular protein whereas other FKBPs possessing from one to four FK506-like binding domains (FKBDs) have nominal masses varying from 13 to 135 kDa. The human genome contains at least sixteen genes encoding proteins comprising one cyclosporin-A (CsA) binding domain (CLD) called cyclophilins whose nominal masses vary from 17 to 324 kDa and multiple coding segments for small cyclophilins (17-19 kDa) whose transcription levels and functions remain unknown. The third group of PPIases encoded in the genome comprises two proteins (hPin1 and hParv14) where hPin1 is an important PPIase for cell cycle. The A. thaliana, C. elegans, D. melanogaster and S. cerevisiae genomes encode a less diverse spectrum of PPIases whereas the prokaryotic genomes contain from none to three cyclophilins, from none to four genes encoding FKBPs, one distant homologue of the Pin1 protein named parvulin and the fourth group of PPIases known as trigger factors. PPIases are discretely distributed to different cellular compartments and interact with a number of targets that control a range of cellular processes. Analyses of the sequence alignments of the two groups of PPIases, namely cyclophilins and FKBPs from diverse phyla, show that in each group their sequences diverge but the amino acid residues which form the PPIase activity site and macrolide binding cavity remain well conserved in the majority of them which suggests that the spatial structures and functions of each group of PPIases remain conserved.

Amino Acid Sequence↗