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At least 19 recordsLinked to original sources
PubMed2005

Conservation analysis of large biochemical networks.

MOTIVATION: Large biochemical networks pose a unique challenge from the point of view of evaluating conservation laws. The computational problem in most cases exceeds the capability of available software tools, often resulting in inaccurate computation of the number and form of conserved cycles. Such errors have profound effects on subsequent calculations, particularly in the evaluation of the Jacobian which is a critical quantity in many other calculations. The goal of this paper is to outline a new algorithm that is computationally efficient and robust at extracting the correct conservation laws for very large biochemical networks. RESULTS: We show that our algorithm can perform the conservation analysis of large biochemical networks, and can evaluate the correct conserved cycles when compared with other similar software tools. Biochemical simulators such as Jarnac and COPASI are successful at extracting only a subset of the conservation laws that our algorithm can. This is illustrated with examples for some large networks which show the advantages of our method.

Algorithms↗
PubMed1992

Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains.

Src homology 2 (SH2) regions are short (approximately 100 amino acids), non-catalytic domains conserved among a wide variety of proteins involved in cytoplasmic signaling induced by growth factors. It is thought that SH2 domains play an important role in the intracellular response to growth factor stimulation by binding to phosphotyrosine containing proteins. In this paper we apply the techniques of multiple sequence alignment, secondary structure prediction and conservation analysis to 67 SH2 domain amino acid sequences. This combined approach predicts seven core secondary structure regions with the pattern beta-alpha-beta-beta-beta-beta-alpha, identifies those residues most likely to be buried in the hydrophobic core of the native SH2 domain, and highlights patterns of conservation indicative of secondary structural elements. Residues likely to be involved in phosphotyrosine binding are shown and orientations of the predicted secondary structures suggested which could enable such residues to cooperate in phosphate binding. We propose a consensus pattern that encapsulates the principal conserved features of the SH2 domains. Comparison of the proposed SH2 domain of akt to this pattern shows only 12/40 matches, suggesting that this domain may not exhibit SH2-like properties.

Amino Acid Sequence↗
PubMed2005

Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.

Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability, we performed an extensive, sequence and structure conservation analysis of the beta(2)-microglobulin (beta(2)-m) domain. Our dataset include 51 high resolution structures belonging to the "C1 set domain" family and 132 clustered PSI-BLAST search results. Segments of the beta(2)-m domain corresponding to strands A (residues 12-18), D (45-55) and G (91-95) were found to be less conserved and stable, while the central strands B (residues 22-28), C (36-41), E (62-70) and F (78-83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of beta(2)-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-beta structure.

Amyloid↗
PubMed2005

Evolutionary conservation analysis increases the colocalization of predicted exonic splicing enhancers in the BRCA1 gene with missense sequence changes and in-frame deletions, but not polymorphisms.

INTRODUCTION: Aberrant pre-mRNA splicing can be more detrimental to the function of a gene than changes in the length or nature of the encoded amino acid sequence. Although predicting the effects of changes in consensus 5' and 3' splice sites near intron:exon boundaries is relatively straightforward, predicting the possible effects of changes in exonic splicing enhancers (ESEs) remains a challenge. METHODS: As an initial step toward determining which ESEs predicted by the web-based tool ESEfinder in the breast cancer susceptibility gene BRCA1 are likely to be functional, we have determined their evolutionary conservation and compared their location with known BRCA1 sequence variants. RESULTS: Using the default settings of ESEfinder, we initially detected 669 potential ESEs in the coding region of the BRCA1 gene. Increasing the threshold score reduced the total number to 464, while taking into consideration the proximity to splice donor and acceptor sites reduced the number to 211. Approximately 11% of these ESEs (23/211) either are identical at the nucleotide level in human, primates, mouse, cow, dog and opossum Brca1 (conserved) or are detectable by ESEfinder in the same position in the Brca1 sequence (shared). The frequency of conserved and shared predicted ESEs between human and mouse is higher in BRCA1 exons (2.8 per 100 nucleotides) than in introns (0.6 per 100 nucleotides). Of conserved or shared putative ESEs, 61% (14/23) were predicted to be affected by sequence variants reported in the Breast Cancer Information Core database. Applying the filters described above increased the colocalization of predicted ESEs with missense changes, in-frame deletions and unclassified variants predicted to be deleterious to protein function, whereas they decreased the colocalization with known polymorphisms or unclassified variants predicted to be neutral. CONCLUSION: In this report we show that evolutionary conservation analysis may be used to improve the specificity of an ESE prediction tool. This is the first report on the prediction of the frequency and distribution of ESEs in the BRCA1 gene, and it is the first reported attempt to predict which ESEs are most likely to be functional and therefore which sequence variants in ESEs are most likely to be pathogenic.

Breast Neoplasms↗
PubMed2004

Identifying functional genetic variants in DNA repair pathway using protein conservation analysis.

The role of DNA repair in initiation, promotion, and progression of malignancy suggests that variations in DNA repair genes confer altered cancer risk. Accordingly, DNA repair gene variants have been studied extensively in the context of cancer predisposition. Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome. A fraction of SNPs are located within the genes, which are likely to alter the gene expression and function. SNPs that change the encoded amino acid sequence of the proteins (non-synonymous; nsSNPs) are potentially genetic disease determinant variations. However, as not all amino acid substitutions are supposed to lead to a change in protein function, it will be necessary to have a priori prediction and determination of the functional consequences of amino acid substitutions per se, and then together with other genetic and environmental factors to study their possible association with a trait. Here we report the analysis of nsSNPs in 88 DNA repair genes and their functional evaluation based on the conservation of amino acids among the protein family members. Our analysis demonstrated that >30% of variants of DNA repair proteins are highly likely to affect the function of the proteins drastically. In this study, we have shown that three nsSNPs, which were predicted to have functional consequences (XRCC1-R399Q, XRCC3-T241M, XRCC1-R280H), were already found to be associated with cancer risk. The strategy developed and applied in this study has the potential to identify functional protein variants of DNA repair pathway that may be associated with cancer predisposition.

DNA Repair↗
PubMed2004

Eukaryotic regulatory element conservation analysis and identification using comparative genomics.

Comparative genomics is a promising approach to the challenging problem of eukaryotic regulatory element identification, because functional noncoding sequences may be conserved across species from evolutionary constraints. We systematically analyzed known human and Saccharomyces cerevisiae regulatory elements and discovered that human regulatory elements are more conserved between human and mouse than are background sequences. Although S. cerevisiae regulatory elements do not appear to be more conserved by comparison of S. cerevisiae to Schizosaccharomyces pombe, they are more conserved when compared with multiple other yeast genomes (Saccharomyces paradoxus, Saccharomyces mikatae, and Saccharomyces bayanus). Based on these analyses, we developed a sequence-motif-finding algorithm called CompareProspector, which extends Gibbs sampling by biasing the search in regions conserved across species. Using human-mouse comparison, CompareProspector identified known motifs for transcription factors Mef2, Myf, Srf, and Sp1 from a set of human-muscle-specific genes. It also discovered the NFAT motif from genes up-regulated by CD28 stimulation in T-cells, which implies the direct involvement of NFAT in mediating the CD28 stimulatory signal. Using Caenorhabditis elegans-Caenorhabditis briggsae comparison, CompareProspector found the PHA-4 motif and the UNC-86 motif. CompareProspector outperformed many other computational motif-finding programs, demonstrating the power of comparative genomics-based biased sampling in eukaryotic regulatory element identification.

Algorithms↗
PubMed1999

From fold predictions to function predictions: automation of functional site conservation analysis for functional genome predictions.

A database of functional sites for proteins with known structures, SITE, is constructed and used in conjunction with a simple pattern matching program SiteMatch to evaluate possible function conservation in a recently constructed database of fold predictions for Escherichia coli proteins (Rychlewski L et al., 1999, Protein Sci 8:614-624). In this and other prediction databases, fold predictions are based on algorithms that can recognize weak sequence similarities and putatively assign new proteins into already characterized protein families. It is not clear whether such sequence similarities arise from distant homologies or general similarity of physicochemical features along the sequence. Leaving aside the important question of nature of relations within fold superfamilies, it is possible to assess possible function conservation by looking at the pattern of conservation of crucial functional residues. SITE consists of a multilevel function description based on structure annotations and structure analyses. In particular, active site residues, ligand binding residues, and patterns of hydrophobic residues on the protein surface are used to describe different functional features. SiteMatch, a simple pattern matching program, is designed to check the conservation of residues involved in protein activity in alignments generated by any alignment method. Here, this procedure is used to study conservation of functional features in alignments between protein sequences from the E. coli genome and their optimal structural templates. The optimal templates were identified and alignments taken from the database of genomic structural predictions was described in a previous publication (Rychlewski L et al., 1999, Protein Sci 8:614-624). An automated assessment of function conservation is used to analyze the relation between fold and function similarity for a large number of fold predictions. For instance, it is shown that identifying low significance predictions with a high level of functional residue conservations can be used to extend the prediction sensitivity for fold prediction methods. Over 100 new fold/function predictions in this class were obtained in the E. coli genome. At the same time, about 30% of our previous fold predictions are not confirmed as function predictions, further highlighting the problem of function divergence in fold superfamilies.

Algorithms↗
PubMed2003

Beta2-microglobulin amyloidosis: insights from conservation analysis and fibril modelling by protein docking techniques.

Current data suggest that globular domains may form amyloids via different mechanisms. Nevertheless, there are indications that the initiation of the process takes place invariably in the less stable segments of a protein domain. We have studied the sequence and structural conservation of beta(2)-microglobulin that deposits into fibrils in dialysis-related amyloidosis. The dataset includes 51 high-resolution non-redundant structures of the antibody constant domain-like proteins (C1) and 132 related sequences. We describe a set of 30 conserved residues. Among them, 23 are conserved structurally, 16 are conserved sequentially and nine are conserved both sequentially and structurally. Strands A (12-18), G (91-95) and D (45-55) are the less conserved and stable segments of the domain, while strands B (22-28), C (36-41), E (62-70) and F (78-83) are the conserved and stable segments. We find that the conserved residues form a cluster with a network of interactions. The observed pattern of conservation is consistent with experimental data including H/D exchange, urea denaturation and limited proteolysis that suggest that strands A and G do not participate in the amyloid fibril. Additionally, the low conservation of strand D is consistent with the observation that this strand may acquire different conformations as seen in crystal structures of bound and isolated beta(2)-microglobulin. We used a docking technique to suggest a model for a fibril via stacking of beta(2)-microglobulin monomers. Our analysis suggests that the favored monomer building block for fibril elongation is the conformation of the isolated beta(2)-microglobulin, without the beta-bulge on strand D and without strands A and G participating in the fibril beta-sheet structure. This monomer retains all the conserved residues and their network of interactions, increasing the likelihood of its existence in solution. The inter-strand interaction between the two (monomer) building blocks forms a new continuous beta-sheet such that addition of monomers results in a fibril model that has the characteristic cross-beta structure.

Amino Acid Sequence↗
PubMed2004

Conservation analysis of small RNA genes in Escherichia coli.

MOTIVATION: Small RNA (sRNA) genes in Escherichia coli have been in focus recently, as 44 out of 55 experimentally confirmed sRNA genes have been precisely located in the genome. The object of this study is to analyze quantitatively the conservation of these sRNA genes and compare it with the conservation of protein-encoding genes, function-unknown regions and tRNA genes. RESULTS: The results show that within an evolutionary distance of 0.26, both sRNA genes and protein-encoding genes display a similar tendency in their degrees of conservation at the nucleotide level. In addition, the conservation of sRNA genes is much stronger than function-unknown regions, but much weaker than tRNA genes. Based on the conservation of studied sRNA genes, we also give clues to estimate the total number of sRNA genes in E.coli. SUPPLEMENTARY INFORMATION: Supplementary information is available at http://www.bioinfo.org.cn/SM/sRNAconservation.htm

Algorithms↗
PubMed1994

Conservation analysis and structure prediction of the protein serine/threonine phosphatases. Sequence similarity with diadenosine tetraphosphatase from Escherichia coli suggests homology to the protein phosphatases.

A multiple sequence alignment of 44 serine/threonine-specific protein phosphatases has been performed. This reveals the position of a common conserved catalytic core, the location of invariant residues, insertions and deletions. The multiple alignment has been used to guide and improve a consensus secondary-structure prediction for the common catalytic core. The location of insertions and deletions has aided in defining the positions of surface loops and turns. The prediction suggests that the core protein phosphatase structure comprises two domains: the first has a single, beta sheet flanked by alpha helices, while the second is predominantly alpha helical. Knowledge of the core secondary structures provides a guide for the design of site-directed-mutagenesis experiments that will not disrupt the native phosphatase fold. A sequence similarity between eukaryotic serine/threonine protein phosphatases and the Escherichia coli diadenosine tetraphosphatase has been identified. This extends over the N-terminal 100 residues of bacteriophage phosphatases and E. coli diadenosine tetraphosphatase. Residues which are invariant amongst these classes are likely to be important in catalysis and protein folding. These include Arg92, Asn138, Asp59, Asp88, Gly58, Gly62, Gly87, Gly93, Gly137, His61, His139 and Val90 and fall into three clusters with the consensus sequences GD(IVTL)HG, GD(LYF)V(DA)RG and GNH, where brackets surround alternative amino acids. The first two consensus sequences are predicted to fall in the beta-alpha and beta-beta loops of a beta-alpha-beta-beta secondary-structure motif. This places the predicted phosphate-binding site at the N-terminus of the alpha helix, where phosphate binding may be stabilised by the alpha-helix dipole.

Acid Anhydride Hydrolases↗
PubMed2025

Whole-Genome Conservation Analysis for the Specific and Accurate Detection of Influenza A and B Viruses and Respiratory Syncytial Virus by Quadruplex RT-qPCR.

Influenza virus (Flu) and respiratory syncytial virus (RSV) are the primary pathogens responsible for acute respiratory infections. Both viruses are prone to mutations due to the seasonal epidemic, leading to an increasing rate of false-negative results. In this study, comprehensive meta-analyses of the genomes focusing on most conserved fragments have been performed for the four seasonal influenza viruses (two subtypes of Flu A: H1N1 and H3N2; two subtypes of Flu B: Yamagata and Victoria) and the two types of RSV: RSVA and RSVB), respectively. The most conserved sequences of 200 bp were identified as targets of the designed primer/probe sets for RT-qPCR were screened and optimized. Good sensitivities of the optimized primer/probe sets were obtained with the limits of detections of 2.95, 2.82, 1.57, 2.8, 1.19, and 2.12 copies/reaction for H1N1, H3N2, Yamagata, Victoria, RSVA and RSVB, respectively. Eventually, quadruplex qPCR using the four designed primer/probe sets can achieve simultaneous screening of the four viruses at a single tube. Furthermore, the assay's good performance in detecting target viruses from clinical throat swab samples demonstrated its potential for diagnosis of these viruses. The method, based on the identified conserved sequences and primer/probe sets, can effectively reduce false-negative results and rapidly respond to these viruses during respiratory disease outbreaks, or even before their widespread emergence, which aid in preventing outbreaks and guiding clinical treatment.

Humans↗
PubMed2004

Conservation analysis in biochemical networks: computational issues for software writers.

Large scale genomic studies are generating significant amounts of data on the structure of cellular networks. This is in contrast to kinetic data, which is frequently absent, unreliable or fragmentary. There is, therefore, a desire by many in the community to investigate the potential rewards of analyzing the more readily available topological data. This brief review is concerned with a particular property of biological networks, namely structural conservations (e.g. moiety conserved cycles). There has been much discussion in the literature on these cycles but a review on the computational issues related to conserved cycles has been missing. This review is concerned with the detection and characterization of conservation relations in arbitrary networks and related issues, which impinge on simulation simulation software writers. This review will not address flux balance constraints or small-world type analyses in any significant detail.

Biochemical Phenomena↗
PubMedDate not supplied

Conservation analysis of rat and human SP-A gene identifies 5' flanking sequences of rat SP-A that bind rat lung nuclear proteins.

As an initial step toward understanding regulation of tissue-specific expression of SP-A, 5' flanking sequences of the rat SP-A gene and human SP-A I gene were cloned, sequenced, and compared using dot matrix analysis. Two regions were identified, each with a considerable degree of homology between the two species. One region was proximal to the TATAA box, at position -225/-17 in rats and -226/-36 in humans, and the other at position -1115/-1026 in rats and -938/-851 in humans. Studies in rats revealed the specific binding of rat lung nuclear proteins to each of the conserved 5' flanking regions identified in rat SP-A. Binding studies using the rat proximal (rPPS) or distal (rDPS) promoter segments, or overlapping fragments of these segments, with rat nuclear extracts detected the presence of a number (1-4) of lung-specific DNA/protein complexes. When nuclear proteins from liver, a nonexpressing tissue, were used the binding profile of certain nuclear proteins differed from that of the lung. These studies, taken together, suggest that sequences within identified conserved DNA segments in the 5' flanking region of the rat SP-A gene contribute to its tissue-specific expression in rats.

Animals↗
PubMed2004

Prediction, conservation analysis, and structural characterization of mammalian mucin-type O-glycosylation sites.

O-GalNAc-glycosylation is one of the main types of glycosylation in mammalian cells. No consensus recognition sequence for the O-glycosyltransferases is known, making prediction methods necessary to bridge the gap between the large number of known protein sequences and the small number of proteins experimentally investigated with regard to glycosylation status. From O-GLYCBASE a total of 86 mammalian proteins experimentally investigated for in vivo O-GalNAc sites were extracted. Mammalian protein homolog comparisons showed that a glycosylated serine or threonine is less likely to be precisely conserved than a nonglycosylated one. The Protein Data Bank was analyzed for structural information, and 12 glycosylated structures were obtained. All positive sites were found in coil or turn regions. A method for predicting the location for mucin-type glycosylation sites was trained using a neural network approach. The best overall network used as input amino acid composition, averaged surface accessibility predictions together with substitution matrix profile encoding of the sequence. To improve prediction on isolated (single) sites, networks were trained on isolated sites only. The final method combines predictions from the best overall network and the best isolated site network; this prediction method correctly predicted 76% of the glycosylated residues and 93% of the nonglycosylated residues. NetOGlyc 3.1 can predict sites for completely new proteins without losing its performance. The fact that the sites could be predicted from averaged properties together with the fact that glycosylation sites are not precisely conserved indicates that mucin-type glycosylation in most cases is a bulk property and not a very site-specific one. NetOGlyc 3.1 is made available at www.cbs.dtu.dk/services/netoglyc.

Algorithms↗
PubMed2001

Field ecology of toxic Pfiesteria complex species and a conservative analysis of their role in estuarine fish kills.

Within the past decade, toxic Pfiesteria outbreaks have been documented in poorly flushed, eutrophic areas of the largest and second largest estuaries on the U.S. mainland. Here we summarize a decadal field effort in fish kill assessment, encompassing kills related to Pfiesteria (49 major kills in North Carolina estuaries since 1991 and 4 in Maryland estuaries in 1997) and to other factors such as low oxygen stress (79 major fish kills in North Carolina estuaries). The laboratory and field data considered in developing our protocols are described, including toxic Pfiesteria behavior, environmental conditions conducive to toxic Pfiesteria activity, and impacts of toxic clonal Pfiesteria on fish health. We outline the steps of the standardized fish bioassay procedure that has been used since 1991 to diagnose whether actively toxic Pfiesteria was present during estuarine fish kills. Detailed data are given for a 1998 toxic Pfiesteria outbreak in the Neuse Estuary in North Carolina to illustrate of the full suite of diagnostic steps completed. We demonstrate that our conservative approach in implicating toxic Pfiesteria involvement in fish kills has biased in favor of causes other than Pfiesteria. Data are summarized from experiments that have shown stimulation of toxic Pfiesteria strains by nutrient (N, P) enrichment, supporting field observations of highest abundance of toxic strains in eutrophic estuaries. On the basis of a decade of research on toxic Pfiesteria, we present a conceptual model of the seasonal dynamics of toxic strains as affected by changing food resources and weather patterns. We also recommend protocols and research approaches that will strengthen the science of fish kill assessment related to Pfiesteria and/or other causative factors.

Animals↗
PubMed2000

Predictive accuracy of population viability analysis in conservation biology.

Population viability analysis (PVA) is widely applied in conservation biology to predict extinction risks for threatened species and to compare alternative options for their management. It can also be used as a basis for listing species as endangered under World Conservation Union criteria. However, there is considerable scepticism regarding the predictive accuracy of PVA, mainly because of a lack of validation in real systems. Here we conducted a retrospective test of PVA based on 21 long-term ecological studies--the first comprehensive and replicated evaluation of the predictive powers of PVA. Parameters were estimated from the first half of each data set and the second half was used to evaluate the performance of the model. Contrary to recent criticisms, we found that PVA predictions were surprisingly accurate. The risk of population decline closely matched observed outcomes, there was no significant bias, and population size projections did not differ significantly from reality. Furthermore, the predictions of the five PVA software packages were highly concordant. We conclude that PVA is a valid and sufficiently accurate tool for categorizing and managing endangered species.

Animals↗
PubMed1996

Conservation of amino acids in multiple alignments: aspartic acid has unexpected conservation.

Analysis of the relationship between surface accessibility and amino acid conservation in multiple sequence alignments of homologous proteins confirms expected trends for hydrophobic amino acids, but reveals an unexpected difference between the conservation of Asp, Glu and Gln. Even when not in an active site, Asp is more highly conserved than Glu. There is a clear preference for conserved and buried Asp to be present in coil, but there is no tendency for Asp to conserve phi/psi in the ++ region of the Ramachandran map. Glu does not show any preference to be conserved in a particular secondary structure. Analysis of recently derived substitution matrices (e.g. BLOSUM) confirms that Glu tends to substitute more frequently with other amino acids than does Asp. Analysis of relative accessibility versus relative conservation for individual amino acid positions in alignments shows a negative correlation for all amino acid types. With the exception of Arg, Lys, Gly, Glu, Asp and Tyr, a relative conservation of > 2 suggests the amino acid will have a relative accessibility of < 50%. Observation of conserved Cys, Gly or Asp in a reliable multiple alignment suggests a position important for the structure of the protein. Furthermore, the Asp is likely to be involved in polar interactions through its side chain oxygen atoms. In contrast, Gln is the least conserved amino acid overall.

Amino Acid Sequence↗