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Results for “evolutionary conservation”

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At least 19 recordsLinked to original sources

PubMed2005

Dyslipidemia and inflammation: an evolutionary conserved mechanism.

Inflammation leads to changes in lipid metabolism aimed at decreasing the toxicity of a variety of harmful agents and tissue repair by redistributing nutrients to cells involved in host defence. Acute phase response, mediated by cytokines, preserves the host from acute injury. When this inflammation becomes chronic, it might lead to chronic disorders as atherosclerosis and the metabolic syndrome. The activation of the inflammatory cascade will induce a decrease in HDL-cholesterol (HDL-C), with impairment in reverse cholesterol transport, and parallel changes in apolipoproteins, enzymes, anti-oxidant capacity and ATP binding cassette A1-dependent efflux. This decrease in HDL-C and phospholipids could stimulate compensatory changes, as synthesis and accumulation of phospholipid-rich VLDL which binds bacterial products and other toxic substances, resulting in hypertriglyceridemia. The final consequence is an increased accumulation of cholesterol in cells. When the compensatory response (inflammation) is not able to repair injury, it turns into a harmful reaction, and the lipid changes will become chronic, either by repeated or overwhelming stimulus, enhancing the formation of atherosclerotic lesions. Thus, the classical lipid changes associated with the metabolic syndrome (increased triglycerides and decreased HDL-C) may be envisioned as a highly conserved evolutionary response aimed at tissue repair. Under this assumption, the problem is not the response but the persistence of the stimulus.

Acute-Phase Reaction↗

PubMed1993

Human T cells respond to mouse mammary tumor virus-encoded superantigen: V beta restriction and conserved evolutionary features.

Mouse mammary tumor virus (MMTV)-encoded superantigens (SAGs) influence the murine T cell repertoire and stimulate a strong mixed lymphocyte response in vitro. These SAGs are encoded by the open reading frame of the 3' long terminal repeat of MMTV, termed MMTV SAGs. The T cell response to MMTV SAGs is V beta restricted and requires expression of the class II molecules of the major histocompatibility complex (MHC) on the presenting cells. While human T cells respond to bacterial SAGs, it is not known if human T cells or human MHC class II molecules can interact with MMTV SAGs. A fibroblastic cell line expressing the human MHC class II molecule HLA-DR1 and the Mtv-7 sag gene encoding Mls-1 was used to stimulate human T cells. We show here that human T cells efficiently proliferate in response to Mls-1 presented by HLA-DR1. This T cell response was inhibited by mAbs directed against CD4 or MHC class II molecules but not by mAbs specific for CD8 or MHC class I molecules. Moreover, the response to Mls-1 was limited to human T cells expressing a restricted set of T cell receptor V beta chains. Human T cells expressing V beta 12, 13, 14, 15, and 23 were selectively amplified after Mtv-7 sag stimulation. Interestingly, these human V beta s share the highest degree of homology with the mouse V beta s interacting with Mls-1. These results show a strong evolutionary conservation of the structures required for the presentation and the response to retrovirally encoded endogenous SAGs, raising the possibility that similar elements operate in humans to shape the T cell repertoire.

Animals↗

PubMed1988

The evolutionary conservation of DNA polymerase alpha.

The evolutionary conservation of DNA polymerase alpha was assessed by immunological and molecular genetic approaches. Four anti-human KB cell DNA polymerase alpha monoclonal antibodies were tested for their ability to recognize a phylogenetically broad array of eukaryotic DNA polymerases. While the single non-neutralizing antibody used in this study recognizes higher mammalian (human, simian, canine, and bovine) polymerases only, three neutralizing antibodies exhibit greater, but variable, extents of cross-reactivity among vertebrate species. The most highly cross-reactive antibody recognizes a unique epitope on a 165-180 kDa catalytic polypeptide in cell lysates from several eukaryotic sources, as distant from man as the amphibians. Genomic Southern hybridization studies with the cDNA of the human DNA polymerase alpha catalytic polypeptide identify the existence of many consensus DNA sequences within the DNA polymerase genes of vertebrate, invertebrate, plant and unicellular organisms. These findings illustrate the differential evolutionary conservation of four unique epitopes on DNA polymerase alpha among vertebrates and the conservation of specific genetic sequences, presumably reflective of critical functional domains, in the DNA polymerase genes from a broad diversity of living forms.

Animals↗

PubMed2006

ECRbase: database of evolutionary conserved regions, promoters, and transcription factor binding sites in vertebrate genomes.

Evolutionary conservation of DNA sequences provides a tool for the identification of functional elements in genomes. We have created a database of evolutionary conserved regions (ECRs) in vertebrate genomes, entitled ECRbase, which is constructed from a collection of whole-genome alignments produced by the ECR Browser. ECRbase features a database of syntenic blocks that recapitulate the evolution of rearrangements in vertebrates and a comprehensive collection of promoters in all vertebrate genomes generated using multiple sources of gene annotation. The database also contains a collection of annotated transcription factor binding sites (TFBSs) in evolutionary conserved and promoter elements. ECRbase currently includes human, rhesus macaque, dog, opossum, rat, mouse, chicken, frog, zebrafish and fugu genomes. It is freely accessible at http://ecrbase.dcode.org.

Animals↗

PubMed2004

Evolutionary conservation and selection of human disease gene orthologs in the rat and mouse genomes.

BACKGROUND: Model organisms have contributed substantially to our understanding of the etiology of human disease as well as having assisted with the development of new treatment modalities. The availability of the human, mouse and, most recently, the rat genome sequences now permit the comprehensive investigation of the rodent orthologs of genes associated with human disease. Here, we investigate whether human disease genes differ significantly from their rodent orthologs with respect to their overall levels of conservation and their rates of evolutionary change. RESULTS: Human disease genes are unevenly distributed among human chromosomes and are highly represented (99.5%) among human-rodent ortholog sets. Differences are revealed in evolutionary conservation and selection between different categories of human disease genes. Although selection appears not to have greatly discriminated between disease and non-disease genes, synonymous substitution rates are significantly higher for disease genes. In neurological and malformation syndrome disease systems, associated genes have evolved slowly whereas genes of the immune, hematological and pulmonary disease systems have changed more rapidly. Amino-acid substitutions associated with human inherited disease occur at sites that are more highly conserved than the average; nevertheless, 15 substituting amino acids associated with human disease were identified as wild-type amino acids in the rat. Rodent orthologs of human trinucleotide repeat-expansion disease genes were found to contain substantially fewer of such repeats. Six human genes that share the same characteristics as triplet repeat-expansion disease-associated genes were identified; although four of these genes are expressed in the brain, none is currently known to be associated with disease. CONCLUSIONS: Most human disease genes have been retained in rodent genomes. Synonymous nucleotide substitutions occur at a higher rate in disease genes, a finding that may reflect increased mutation rates in the chromosomal regions in which disease genes are found. Rodent orthologs associated with neurological function exhibit the greatest evolutionary conservation; this suggests that rodent models of human neurological disease are likely to most faithfully represent human disease processes. However, with regard to neurological triplet repeat expansion-associated human disease genes, the contraction, relative to human, of rodent trinucleotide repeats suggests that rodent loci may not achieve a 'critical repeat threshold' necessary to undergo spontaneous pathological repeat expansions. The identification of six genes in this study that have multiple characteristics associated with repeat expansion-disease genes raises the possibility that not all human loci capable of facilitating neurological disease by repeat expansion have as yet been identified.

Animals↗

PubMed2023

Utilizing evolutionary conservation to detect deleterious mutations and improve genomic prediction in cassava.

INTRODUCTION: Cassava (Manihot esculenta) is an annual root crop which provides the major source of calories for over half a billion people around the world. Since its domestication ~10,000 years ago, cassava has been largely clonally propagated through stem cuttings. Minimal sexual recombination has led to an accumulation of deleterious mutations made evident by heavy inbreeding depression. METHODS: To locate and characterize these deleterious mutations, and to measure selection pressure across the cassava genome, we aligned 52 related Euphorbiaceae and other related species representing millions of years of evolution. With single base-pair resolution of genetic conservation, we used protein structure models, amino acid impact, and evolutionary conservation across the Euphorbiaceae to estimate evolutionary constraint. With known deleterious mutations, we aimed to improve genomic evaluations of plant performance through genomic prediction. We first tested this hypothesis through simulation utilizing multi-kernel GBLUP to predict simulated phenotypes across separate populations of cassava. RESULTS: Simulations showed a sizable increase of prediction accuracy when incorporating functional variants in the model when the trait was determined by<100 quantitative trait loci (QTL). Utilizing deleterious mutations and functional weights informed through evolutionary conservation, we saw improvements in genomic prediction accuracy that were dependent on trait and prediction. CONCLUSION: We showed the potential for using evolutionary information to track functional variation across the genome, in order to improve whole genome trait prediction. We anticipate that continued work to improve genotype accuracy and deleterious mutation assessment will lead to improved genomic assessments of cassava clones.

cassava (Manihot esculenta)↗

PubMed2005

Evolutionary conservation and mutational spectrum of BMPR2 gene.

A variety of mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been identified in patients with pulmonary arterial hypertension. In this study, using our BMPR2 mutation database and BMPR-II protein sequences from eight distantly related species, we defined the relationship among evolutionary conservation, mutation frequency and mutation distribution. As a whole, BMPR2 is evolving slower than the average for mammalian protein-encoding genes. As expected, the kinase domain is evolving more slowly than the extracellular ligand-binding and C-terminal domains. A detailed map of evolutionary conservation shows that there are repeating peaks and valleys within the C-terminal domain, representing higher and lower evolutionary conservation. We observed a strong correlation between evolutionary conservation and the distribution of mutations along the gene. All except two, of the nineteen missense mutations occur in absolutely conserved amino acids among the vertebrate homologs. In addition, we identified six mutational hotspots (P<0.05) by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Furthermore, analysis of the sequence environment surrounding the mutations revealed a specific pattern of mutagenesis. Over 22% of all single base-paired substitutions and 30% of all deletions and insertions are situated within tandem or non-tandem direct repeats of at least 5-bp and may be explained by slipped-mispairing model of mutagenesis. Also, over 59% of single base-paired substitutions versus 20% of deletions and insertions are located in perfect palindromic sequences that could produce "hairpin-loop" secondary structures with relatively high thermodynamic stability under physiological conditions. In addition, 3.7% of single base-paired substitutions versus 30% of deletions and insertions are located either within or in close proximity to the Krawczak and Cooper consensus sequence (TG A/G A/G G/T A/C). Further study of the mechanism of mutagenesis in BMPR2 may help identify other potentially mutable sites and differentiate between deleterious mutations and harmless polymorphic variants.

Amino Acid Sequence↗

PubMed2000

Recursive use of evolutionary conservation data in molecular modeling of membrane proteins A model of the multidrug H+ antiporter emrE.

Membrane proteins are currently the most biomedically important family of proteins, serving as targets for the majority of pharmaceutical agents. It is also clear that they are invariably abundant in all of the genomes sequence so far, representing up to a third of all open reading frames. Finally, and regrettably, it is clear that they are highly resistant to structural elucidation, representing less than 0.2% of the Protein Data Bank. Recent accomplishments in genome sequencing efforts, however, may help offset this imbalance through the availability of evolutionary conservation data. Herein, we develop a novel approach, utilizing a combination of evolutionary conservation data and global searching molecular dynamics simulations to model membrane proteins, deriving a model for the multidrug H+ antiporter EmrE, a transmembrane four-helix bundle. Structures resulting from an extensive, rotational molecular dynamics search, were evaluated by comparing the residue specific interaction energy and the evolutionary conservation data. Subsequent rounds of molecular dynamics, in which confinement of the search space was undertaken in order to achieve a self consistent result, point to a structure that best satisfies the evolutionary conservation data. As the conservation patterns calculated for each of the helices suggested that the different conservation pattern for helix 3 (as well as being the most conserved) might be due to the oligomeric nature of EmrE, a dodecamer of helices was constructed based on the result of a search of helix 3 as a trimer. The resulting interaction energy per residue in the final model is in reasonable agreement with the evolutionary data and consistent with recent site directed mutagenesis experiments, pointing to the strength of this method as a general tool.

Amino Acid Sequence↗

PubMed1998

Evolutionary conservation and tissue-specific processing of Hoxa 11 antisense transcripts.

We previously described the existence of abundant, processed, polyadenylated murine Hoxa 11 antisense transcripts. Of particular interest, in the developing limbs the antisense transcripts were observed to be present in a pattern complementary to that of the sense transcripts, suggesting a possible regulatory function (Hsieh-Li et al. 1995). We have analyzed the human HOXA 11 genomic locus, showing strong evolutionary conservation of regions potentially encoding antisense transcripts. Human HOXA 11 fetal kidney antisense cDNAs were identified and sequenced, demonstrating the evolutionary conservation of Hoxa 11 antisense transcription. As for the mouse, the human antisense RNAs were polyadenylated and showed several alternative processing patterns, but shared the sequences of a common 3' exon. The evolutionary conservation of the opposite strand transcripts strongly suggests function. A significantly long open reading frame was observed, but mouse-human comparisons argued against true coding function. Murine kidney Hoxa 11 antisense transcription and processing was also examined, revealing tissue-specific differences between limb and kidney. A novel procedure, designated Race in Circles, was devised and used to define mouse limb antisense transcription start sites. Furthermore, comparisons of human, mouse, and chicken sense transcript Hoxa 11 homeobox nucleotide sequences and their respective encoded homeodomains indicate a very strong selective pressure in vertebrates against mutations that result in coding changes. Given the significant differences in amino acid sequences of the homeodomains of different Hox genes, this observation argues for individual homeodomain functional specificity.

5' Untranslated Regions↗

PubMed2000

Evolutionary conservation of kinetochore protein sequences in plants.

The evolutionary conservation of structural/functional kinetochore proteins has been studied on isolated nuclei and pro-/metaphase chromosomes of mono- and dicot plants. The cross-reactivities of antibodies against human CENPC, CENPE and CENPF, and against maize CENPCa with the centromeric regions of mitotic chromosomes of Vicia faba and/or Hordeum vulgare are shown. Putative homologs of the kinetochore protein SKP1 (suppressor of kinetochore protein 1p of yeast) were found in both species and of CBF5p (centromere binding factor 5 of yeast) in barley. Antibodies against synthetic peptides derived from partial sequences encoding these proteins were produced and recognized the centromeric regions on mitotic chromosomes as detected by indirect immunofluorescence.

Amino Acid Sequence↗

PubMed1996

Evolutionary conservation and molecular characteristics of repetitive sequences of Drosophila koepferae.

Thirteen middle repetitive DNA clones obtained from the genome of Drosophila koepferae have been tested for their evolutionary conservation in the other seven species of the buzzatii and martensis clusters (repleta group). All but two of these clones exhibit qualitatively similar patterns of hybridization in the eight species. The average interspecific hybridization signal is 85 per cent of that found intraspecifically, ranging from 73 to 93 per cent. Partial sequencing of six of these clones has shown sequences related to the retrotransposon Gypsy, first characterized in D. melanogaster, as well as to the Anopheles gambiae LINE elements T1Ag and Q. A fragment of a hitherto unknown, short inverted repeat transposable element has also been found. The evolutionary conservation of repetitive D. koepferae sequences seems to be related to the high proportion of simple DNA and inactive mobile elements in the genome of this species.

Amino Acid Sequence↗

PubMed2005

ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures.

Key amino acid positions that are important for maintaining the 3D structure of a protein and/or its function(s), e.g. catalytic activity, binding to ligand, DNA or other proteins, are often under strong evolutionary constraints. Thus, the biological importance of a residue often correlates with its level of evolutionary conservation within the protein family. ConSurf (http://consurf.tau.ac.il/) is a web-based tool that automatically calculates evolutionary conservation scores and maps them on protein structures via a user-friendly interface. Structurally and functionally important regions in the protein typically appear as patches of evolutionarily conserved residues that are spatially close to each other. We present here version 3.0 of ConSurf. This new version includes an empirical Bayesian method for scoring conservation, which is more accurate than the maximum-likelihood method that was used in the earlier release. Various additional steps in the calculation can now be controlled by a number of advanced options, thus further improving the accuracy of the calculation. Moreover, ConSurf version 3.0 also includes a measure of confidence for the inferred amino acid conservation scores.

Amino Acid Substitution↗

PubMed1985

Evolutionary conservation of ribosomal protein mRNA sequences: application for expansion of corresponding cDNA and gene libraries.

Cloned cDNAs, containing ribosomal protein sequences from mouse (five cDNAs) or Xenopus laevis (six cDNAs), were used to estimate the evolutionary conservation, from insects to mammals, of the corresponding mRNA sequences. Northern blot analysis reveals a variable degree of homology between these sequences in different eukaryotes. Thus, among the ribosomal protein cDNA clones utilized, some exhibit complete, others partial, and a few no interphyla cross-hybridization. Melting profile analysis was employed to quantitate this homology. It is proposed that for expansion of eukaryotic ribosomal cDNA and gene libraries, one can exploit the interspecies homology of the corresponding sequences. However, the diverse evolutionary conservation of individual ribosomal protein gene sequences should be taken into account.

Animals↗

PubMed2006

Differential evolutionary conservation of motif modes in the yeast protein interaction network.

BACKGROUND: The importance of a network motif (a recurring interconnected pattern of special topology which is over-represented in a biological network) lies in its position in the hierarchy between the protein molecule and the module in a protein-protein interaction network. Until now, however, the methods available have greatly restricted the scope of research. While they have focused on the analysis in the resolution of a motif topology, they have not been able to distinguish particular motifs of the same topology in a protein-protein interaction network. RESULTS: We have been able to assign the molecular function annotations of Gene Ontology to each protein in the protein-protein interactions of Saccharomyces cerevisiae. For various motif topologies, we have developed an algorithm, enabling us to unveil one million "motif modes", each of which features a unique topological combination of molecular functions. To our surprise, the conservation ratio, i.e., the extent of the evolutionary constraints upon the motif modes of the same motif topology, varies significantly, clearly indicative of distinct differences in the evolutionary constraints upon motifs of the same motif topology. Equally important, for all motif modes, we have found a power-law distribution of the motif counts on each motif mode. We postulate that motif modes may very well represent the evolutionary-conserved topological units of a protein interaction network. CONCLUSION: For the first time, the motifs of a protein interaction network have been investigated beyond the scope of motif topology. The motif modes determined in this study have not only enabled us to differentiate among different evolutionary constraints on motifs of the same topology but have also opened up new avenues through which protein interaction networks can be analyzed.

Algorithms↗

PubMed2000

Evolutionary conservation of C-terminal domains of primary sigma(70)-type transcription factors between plants and bacteria.

Three different cDNAs coding for putative plant plastid sigma(70)-type transcription initiation factors have recently been cloned and sequenced from Arabidopsis thaliana. We have analyzed the evolutionary conservation of function(s) of the N-terminal and C-terminal halves of these three sigma factors by in vitro transcription studies using heterologous transcription systems and by complementation assays using Escherichia coli thermosensitive rpoD mutants. Our results indicate differences and similarities of the three plant factors and their prokaryotic ancestors. The functions of the N-terminal parts of the plant sigma factors are considerably different from the function of the N-terminal part of the principal sigma(70) factor of E. coli. On the other hand, the C-terminal parts have kept at least two characteristics when compared with their prokaryotic ancestors: 1) they can distinguish between different promoter structures, and 2) one of them is capable of fully complementing E. coli rpoD mutants, i.e. recognizing all essential E. coli promoters that are used by the E. coli principal sigma(70) factor. This shows for the first time in vivo a strong evolutionary conservation of cis- and trans-acting elements between the prokaryotic and the plant plastid transcriptional machinery.

Amino Acid Sequence↗

PubMed2005

Identification of an evolutionary conserved SURF-6 domain in a family of nucleolar proteins extending from human to yeast.

The mammalian SURF-6 protein is localized in the nucleolus, yet its function remains elusive in the recently characterized nucleolar proteome. We discovered by searching the Protein families database that a unique evolutionary conserved SURF-6 domain is present in the carboxy-terminal of a novel family of eukaryotic proteins extending from human to yeast. By using the enhanced green fluorescent protein as a fusion protein marker in mammalian cells, we show that proteins from distantly related taxonomic groups containing the SURF-6 domain are localized in the nucleolus. Deletion sequence analysis shows that multiple regions of the SURF-6 protein are capable of nucleolar targeting independently of the evolutionary conserved domain. We identified that the Saccharomyces cerevisiae member of the SURF-6 family, named rrp14 or ykl082c, has been categorized in yeast databases to interact with proteins involved in ribosomal biogenesis and cell polarity. These results classify SURF-6 as a new family of nucleolar proteins in the eukaryotic kingdom and point out that SURF-6 has a distinct domain within the known nucleolar proteome that may mediate complex protein-protein interactions for analogous processes between yeast and mammalian cells.

Amino Acid Sequence↗

PubMed1998

Consequence of the removal of evolutionary conserved disulfide bridges on the structure and function of charybdotoxin and evidence that particular cysteine spacings govern specific disulfide bond formation.

Scorpion toxins are miniglobular proteins containing a common structural motif formed by an alpha-helix on one face, an antiparallel beta-sheet on the opposite face, and three disulfide bonds making up most of its internal volume. We have investigated the role of these evolutionary conserved bonds by replacing each couple of bridged cysteine residues of the scorpion charybdotoxin by a pair of nonbridging L-alpha-aminobutyric acid (Aba) residues. Three analogues were obtained by solid-phase synthesis, Chab I, Chab II, and Chab III, containing the Aba residues in positions 7 and 28, 13 and 33, 17 and 35, respectively. Circular dichroism analysis showed that the purified Chab II acquired a conformation similar to that of charybdotoxin, while the Chab I and Chab III possess decreased nativelike characteristics. All analogues block single high-conductance Ca(2+)-activated K+ channels from rat skeletal muscle inserted into planar lipid bilayers, but with different potencies. Chab II is the most active analogue (KD = 8.0 x 10(-8) M), with a 9-fold lower affinity as compared to native charybdotoxin. Chab I and Chab III have, respectively, 180- and 580-fold lower affinity. Therefore, the removal of evolutionary conserved disulfide bridges does not prevent the toxin to adopt a functional and presumably nativelike structure. However, removal of one disulfide bond affects the yields of formation of correct pairing between the remaining cysteine residues, and only Chab I preserves the ability to form the native disulfide pairings with high efficiency. This is the only analogue to preserve particular spacings of three and one residue between the cysteines, which have been described to thermodynamically disfavor disulfide bond formation between the cysteines [Zhang R., and Snyder, G. H. (1989) J. Biol. Chem. 264, 18472-18479]. Therefore, we conclude that the position of the cysteine residues in the sequence of charybdotoxin, by disfavoring specific pairings and favoring others, may govern selective formation of specific disulfide bonds, thus, explaining the efficient folding properties of Chab I and of native charybdotoxin. The structural properties of the Chab analogues and the discovered role of the cysteine spacings have interesting implications in protein design and engineering.

Amino Acid Sequence↗

PubMed1999

Evolutionary conservation of circulating soluble low density lipoprotein receptor-related protein-like ("LRP-like") molecules.

Low density lipoprotein receptor family members characteristically bind 39-kDa receptor associated protein (RAP). Soluble forms of these receptors have been described in humans including the 515/85-kDa dimeric receptor, low density lipoprotein receptor-related protein (LRP/alpha2MR), which is involved in multiple processes including lipoprotein and protease metabolism. Here we demonstrate evolutionary conservation in the generation of these soluble RAP-binding proteins of high molecular weight, by identifying their presence in mammalian, avian, and reptilian sera as well as in the circulating haemolymph of a mollusc. Sera extracted on immobilized RAP, produced bands at approximately 500 kDa in radiolabeled ligand blots by using the LRP/alpha2MR-specific ligand, Pseudomonas exotoxin A (PEA). These findings suggest that circulating RAP-binding proteins with high molecular weight in vertebrates share features of LRP/alpha2MR (LRP-like molecules). RAP-binding molecules in the mammalian serum extracts were further characterized as LRP/alpha2MR homologues in Western blots by using antibodies against the 515-kDa alpha-chain of LRP/alpha2MR. Western blots of mammalian serum extracts using two monoclonal antibodies recognizing the 85-kDa transmembrane beta-chain suggested that a portion of the beta-chain's ectodomain remains associated with the alpha-chain, but the beta-chain's intracellular carboxy terminus is absent. These results are consistent with evolutionary conservation in the generation, composition, and ligand-binding ability of soluble LRP-like receptors and suggest that their presence is a necessary aspect of the receptor's function.

Animal Population Groups↗