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PubMed2003

Replication labeling patterns and chromosome territories typical of mammalian nuclei are conserved in the early metazoan Hydra.

To investigate the evolutionary conservation of higher order nuclear architecture previously described for mammalian cells we have analyzed the nuclear architecture of the simple polyp Hydra. These diploblastic organisms have large nuclei (8-10 microm) containing about 3x10(9) bp of DNA organized in 15 chromosome pairs. They belong to the earliest metazoan phylum and are separated from mammals by at least 600 million years. Single and double pulse labeling with halogenated nucleotides (bromodeoxyuridine, iododeoxyuridine and chlorodeoxyuridine) revealed striking similarities to the known sequence of replication labeling patterns in mammalian nuclei. These patterns reflect a persistent nuclear arrangement of early, mid-, and late replicating chromatin foci that could be identified during all stages of interphase over at least 5-10 cell generations. Segregation of labeled chromatids led after several cell divisions to nuclei with single or a few labeled chromosome territories. In such nuclei distinct clusters of labeled chromatin foci were separated by extended nuclear areas with non-labeled chromatin, which is typical of a territorial arrangement of interphase chromosomes. Our results indicate the conservation of fundamental features of higher order chromatin arrangements throughout the evolution of metazoan animals and suggest the existence of conserved mechanism(s) controlling this architecture.

Animals↗
PubMed1998

Paradoxical enhancement of the activity of a bacterial multidrug transporter caused by substitutions of a conserved residue.

Substitution of threonine or serine for the evolutionary conserved intramembrane proline P347 of the Bacillus subtilis multidrug transporter Bmr significantly increases the toxin-effluxing activity of Bmr without affecting its abundance in the cell. In cocultivation experiments, we demonstrate that although the mutant T347 Bmr is advantageous to cells growing in the presence of a toxin, the wild-type P347 Bmr is advantageous under the conditions of nutritional limitation. This may explain why Bmr has evolved the way it did, that is, with proline at position 347. These observations provide a basis for speculating that the evolution of Bmr has been determined by its presently unidentified natural function rather than by its ability to expel diverse toxins from the cell.

Acriflavine↗
PubMed2001

Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins.

Bacterial heat shock proteins (hsp) are evolutionary conserved immunodominant proteins that manifest amino acid homologies with hsp present in mammalian cells. Preimmunization with mycobacterial hsp65 has been found to protect against various forms of experimental arthritis. As these protective effects have previously been attributed to induction of self homologue cross-reactive T cell responses, the question was raised as to whether this protective effect could be extended to other highly conserved and immunodominant microbial Ags with mammalian homologues. Therefore, we immunized Lewis rats with conserved bacterial Ags (superoxide dismutase, aldolase, GAPDH, and hsp70). Although all Ags appeared highly immunogenic, we only found a protective effect in experimental arthritis after immunization with bacterial hsp70. The protective effect of hsp70 was accompanied with a switch in the subclasses of hsp70-specific Abs, suggesting the induction of Th2-like response. The most striking difference between immunization with hsp70 and all other immunodominant Ags was the expression of IL-10 found after immunization with hsp70. Even more, while immunization with hsp70 led to Ag-induced production of IL-10 and IL-4, immunization with aldolase led to increased production of IFN-gamma and TNF-alpha. Thus, the protective effect of conserved immunodominant proteins in experimental arthritis seems to be a specific feature of hsp. Therefore, hsp may offer unique possibilities for immunological intervention in inflammatory diseases.

Adoptive Transfer↗
PubMed2004

The evolving roles of alternative splicing.

Alternative splicing is now commonly thought to affect more than half of all human genes. Recent studies have investigated not only the scope but also the biological impact of alternative splicing on a large scale, revealing that its role in generating proteome diversity may be augmented by a role in regulation. For instance, protein function can be regulated by the removal of interaction or localization domains by alternative splicing. Alternative splicing can also regulate gene expression by splicing transcripts into unproductive mRNAs targeted for degradation. To fully understand the scope of alternative splicing, we must also determine how many of the predicted splice variants represent functional forms. Comparisons of alternative splicing between human and mouse genes show that predominant splice variants are usually conserved, but rare variants are less commonly shared. Evolutionary conservation of splicing patterns suggests functional importance and provides insight into the evolutionary history of alternative splicing.

Alternative Splicing↗
PubMed1997

A conserved cluster of homeodomain binding sites in the mouse Hoxa-4 intron functions in Drosophila embryos as an enhancer that is directly regulated by Ultrabithorax.

The evolutionary conservation of the homeodomains suggests that their in vivo DNA binding sites may also be conserved between vertebrates and invertebrates. The regulatory function of the mouse Hoxa-4 and Hoxb-4 introns were analyzed in Drosophila since they both contain a cluster of three homeodomain binding sites, the HB1 element, which was also found in the introns of other Hox genes ranging from fish to humans as well as in the Ultrabithorax (Ubx) and decapentaplegic (dpp) genes of Drosophila. The enhancer of the Hoxa-4 intron was found to respond to several homeobox genes activating a lacZ reporter gene in particular cells of the epidermis in Drosophila embryos. The enhancer activity was found to be similar to previously described autoregulatory elements of Deformed (Dfd), the Drosophila homolog of Hoxa-4, but additional expression was observed in more posterior segments activated by Ubx and repressed by abdominal-A (abd-A). Point mutations in the homeodomain binding sites in HB1 abolished the enhancer activity. A second site suppression experiment showed that UBX interacts directly with the HB1 element. When the HB1 element in the Hoxa-4 intron was replaced by that of the mesodermal enhancer of dpp, which was previously shown to be directly controlled by Ubx, Ubx-dependent activation was retained, but repression by abd-A was lost. The same result was obtained when the third binding site of HB1 was altered, suggesting that this site is responsible for abd-A-dependent repression. Finally, deletion of potential cofactor binding sites flanking the HB1 element that are also conserved in the medaka, chicken, and mouse genes revealed that they are important for enhancer function in Drosophila and that the Dfd-dependent and the Ubx-dependent expression requires different sites. The evolutionary and functional conservation of the HB1 elements indicates that not only the homeodomains but also some of their in vivo binding sites are conserved between vertebrates and invertebrates.

Animals↗
PubMed1990

Carbohydrate epitopes involved in neural cell recognition are conserved between vertebrates and leech.

We are reporting on the evolutionary conservation of carbohydrate epitope families from vertebrate to leech. 1) The sulfated L2/HNK-1 carbohydrate epitope (Abo T, Balch CM (1981): J Immunol 127:1024-1029; Kruse J, Mailhammer R, Wernecke H, Faissner A, Timpl R, Schachner M (1984): Nature 311:153-155) is detected on glycoproteins of leech neurons using monoclonal antibodies (mAbs) L2 (336) and HNK-1. 2) Three rat mAbs, L3, L4, and L5, bind to leech nerve and muscle. The L3, L4, and L5 epitopes are localized to a group of mannosidic leech glycoproteins originally identified through mAbs Lan3-2 (Hogg N, Flaster M, Zipser B (1983): J Neurosci Res 9:445-457 and Laz6-189 (McRorie JW III, Zipser B (1988): "Cell Culture Approaches to Invertebrate Neuroscience." London: Academie Press, pp 33-52. MAb Lan3-2, which binds to a mannosidic epitope of the 130 kD sensory protein, has recently been shown to perturb the penetration of sensory afferents into the synaptic area of the central neuropile (Zipser B, Morell R, Bajt ML (1989): Neuron 3:621-630). The L3, L4, and L5 mAbs have been described to recognize different mannosidic epitopes on glycoproteins, some of which have been identified as neural cell adhesion molecules, and on astrocyte-specific proteoglycan from mouse brain (Kücherer A, Faissner A, Schachner M (1987): J Cell Biol 104:1597-1602; Fahrig T, Schmitz B, Weber D, Kücherer-Ehret A, Faissner A, Schachner M (1990): Eur J Neurosci 2:153-161; Streit A, Faissner A, Gehrig B, Schachner M (1990): J Neurochem In Press). The superposition of five different mannosidic epitopes on the axons of sensory afferents suggests complex, concerted participation of mannosidic epitopes in neuronal pathfinding and target recognition.

Animals↗
PubMed2001

Regulation of neural determination by evolutionarily conserved signals: anti-BMP factors and what next?

The evolutionary conservation of Chordin/bone morphogenetic protein (BMP) signaling supports the hypothesis of dorsal-ventral axis inversion of vertebrates and invertebrates, and implies that the invention of a central nervous system occurred only once during animal evolution. This hypothesis is further strengthened by recent findings of the conservation of downstream genes and modifier genes of neural induction. On the other hand, in contrast with such gross conservation, recent data suggest that the requirement for some signals in neural determination may differ even within the vertebrate subphylum.

Amphibians↗
PubMed2003

Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1.

The evolutionary conservation of T lymphocyte subsets bearing T-cell receptors (TCRs) using invariant alpha-chains is indicative of unique functions. CD1d-restricted natural killer T (NK-T) cells that express an invariant Valpha14 TCRalpha chain have been implicated in microbial and tumour responses, as well as in auto-immunity. Here we show that T cells that express the canonical hValpha7.2-Jalpha33 or mValpha19-Jalpha33 TCR rearrangement are preferentially located in the gut lamina propria of humans and mice, respectively, and are therefore genuine mucosal-associated invariant T (MAIT) cells. Selection and/or expansion of this population requires B lymphocytes, as MAIT cells are absent in B-cell-deficient patients and mice. In addition, we show that MAIT cells are selected and/or restricted by MR1, a monomorphic major histocompatibility complex class I-related molecule that is markedly conserved in diverse mammalian species. MAIT cells are not present in germ-free mice, indicating that commensal flora is required for their expansion in the gut lamina propria. This indicates that MAIT cells are probably involved in the host response at the site of pathogen entry, and may regulate intestinal B-cell activity.

Amino Acid Sequence↗
PubMed1988

An evolutionarily conserved protein binding sequence upstream of a plant light-regulated gene.

A protein factor, identified in nuclear extracts obtained from tomato (Lycopersicon esculentum, Solanaceae) and Arabidopsis thaliana (Brassicaceae) seedlings, specifically binds upstream sequences from the plant light-regulated gene family encoding the small subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (RBCS). RBCS upstream sequences from tomato, pea (Pisum sativum, Leguminosae), and Arabidopsis are recognized by the factor. The factor recognition occurs via a short conserved sequence (G box) whose consensus sequence is 5'-TCTTACACGTGGCAYY-3' (where Y is pyrimidine). This sequence is distinct from the GT motif described previously in RBCS promoters. Two other conserved sequences, showing a lesser degree of evolutionary conservation, are found upstream of the G box but do not bind to the G box binding factor (GBF). Twelve nucleotides within the G box are sufficient for the formation of a stable DNA-GBF complex. GBF is found in both light-grown and dark-adapted tomato leaf extracts, but it is present in greatly reduced amounts in root extracts.

Base Sequence↗
PubMed1998

Conservation of eukaryotic DNA repair mechanisms.

PURPOSE: To discuss the evolutionary conservation of different DNA repair processes. The proteins that carry out base excision repair show a varying degree of structural conservation, but a high level of functional complementation between species, as might be expected for a sequential pathway. In nucleotide excision repair there is a high degree of structural conservation, but few examples of functional complementation because the process involves multiprotein complexes. Repair by homologous recombination involves proteins that are highly conserved structurally. The process of repair of DNA breaks by non-homologous end-joining is conserved in eukaryotes, but the level of sequence identity of several of the proteins is fairly low and some components involved in man do not appear to have sequence homologues in yeast. CONCLUSIONS: All DNA repair processes are highly conserved. The degree of structural and functional conservation varies between the different processes.

Animals↗
PubMed2005

Conserved sequences and the evolution of gene regulatory signals.

Studies of evolutionary conservation of gene regulatory signals have led to a paradox: extensive sequence similarity implies functional conservation in non-coding regions across mammalian species; however, this stands in contrast to our understanding of transcriptional regulatory sites composed of degenerate recognition sequences for transcription factors that can maintain functional equivalence despite considerable sequence divergence. The latter observation provides an explanation for the rapid evolution of new traits through the gain and loss of transcription factor binding sites that bring new genes under the control of an existing genetic regulatory network. The former observation might point to novel mechanisms of gene regulation and/or chromosome function that are currently unappreciated. Recent comparative genome analysis has highlighted extensive conserved sequences in mammalian genomes that are beginning to be functionally characterized.

Animals↗
PubMed1995

Differential subsequence conservation of interspersed repetitive Streptococcus pneumoniae BOX elements in diverse bacteria.

Evolutionary conservation of an interspersed repetitive DNA sequence, BOX, from Streptococcus pneumoniae was investigated to explore the mosaic nature of these elements. BOX elements consist of various combinations of three subunits, boxA, boxB, and boxC. Eight oligonucleotide probes were designed based on consensus DNA sequences of boxA, boxB, and boxC subunits. DNA hybridization studies and PCR using these probes/primers demonstrate that oligonucleotide sequences within the boxA subunit appear to be conserved among diverse bacterial species. The boxB and boxC subunits show only limited, if any, sequence conservation in bacteria other than S. pneumoniae. Intact BOX elements with boxA, boxB, and boxC subunits were only present in high copy number in pneumococcal strains. This pattern of differential conservation lends support to the modular nature of BOX repetitive elements in that boxA-like subsequences are effectively independent of boxB-like or boxC-like subunits in bacteria other than S. pneumoniae. Furthermore, dendrograms derived from repetitive sequence-based PCR (rep-PCR) fingerprints of S. pneumoniae isolates using the BOXA1R primer yielded clustering patterns that were similar to those obtained previously by other methods, suggesting that these repetitive sequence-based DNA fingerprints represent intrinsic properties of an S. pneumoniae strain's genome. Our results indicate widespread conservation of boxA-like subsequences in the bacterial kingdom, lend support to the mosaic nature of BOX in S. pneumoniae, and demonstrate the utility of boxA-based primers for rep-PCR fingerprinting of many microorganisms.

Bacteria↗
PubMed2002

Evolution of placentally expressed cathepsins.

Species and strain variants of a family of placentally expressed cathepsins (PECs) were cloned and sequenced in order to identify evolutionary conserved structural characteristics of this large family of cysteine proteases. Cathepsins M, P, Q, and R, are conserved in mice and rats but homologs of these genes are not found in human or rabbit placenta, showing that this family of proteases are probably restricted to rodents. Species-specific gene duplications have given rise to variants of cathepsin M in mice, and cathepsin Q in rats. Although the PECs have diverged at a greater rate than the other lysosomal cathepsins, residues around the specificity sub-sites of the individual enzymes are conserved. Strain-specific polymorphisms show that the evolutionary rate of divergence of cathepsins M and 3, the most recently duplicated pair of mouse genes, is even higher than the other PECs. In human placenta, critical functions of the PECs are probably performed by broader specificity proteases such as cathepsins B and L.

Amino Acid Sequence↗
PubMed2003

Conservation in the CYP51 family. Role of the B' helix/BC loop and helices F and G in enzymatic function.

CYP51 (sterol 14 alpha-demethylase) is an essential enzyme in sterol biosynthetic pathways and the only P450 gene family having catalytically identical orthologues in different biological kingdoms. The proteins have low sequence similarity across phyla, and the whole family contains about 40 completely conserved amino acid residues. Fifteen of these residues lie in the secondary structural elements predicted to form potential substrate recognition sites within the P450 structural fold. The role of 10 of these residues, in the B' helix/BC loop, helices F and G, has been studied by site-directed mutagenesis using as a template the soluble sterol 14 alpha-demethylase of known structure, CYP51 from Mycobacterium tuberculosis (MT) and the human orthologue. Single amino acid substitutions of seven residues (Y76, F83, G84, D90, L172, G175, and R194) result in loss of the ability of the mutant MTCYP51 to metabolize lanosterol. Residual activity of D195A is very low, V87A is not expressed as a P450, and A197G has almost 1 order of magnitude increased activity. After purification, all of the mutants show normal spectral properties, heme incorporation, and the ability to be reduced enzymatically and to interact with azole inhibitors. Profound influence on the catalytic activity correlates well with the spectral response to substrate binding, effect of substrate stabilization on the reduced state of the P450, and substrate-enhanced efficiency of enzymatic reduction. Mutagenesis of corresponding residues in human CYP51 implies that the conserved amino acids might be essential for the evolutionary conservation of sterol 14 alpha-demethylation from bacteria to mammals.

Animals↗
PubMed1997

Identification of an essential Caulobacter crescentus gene encoding a member of the Obg family of GTP-binding proteins.

We have identified an essential Caulobacter crescentus gene (cgtA) that encodes a member of a recently identified subfamily of GTPases (the Obg family) conserved from Bacteria to Archaea to humans. This evolutionary conservation between distantly related species suggests that this family of GTP-binding proteins possesses a fundamental, yet unknown, cellular role. In this report, we describe the isolation and sequence of the cgtA gene. The predicted CgtA protein displays striking similarity to the Obg family of small, monomeric GTP-binding proteins, both in the conserved guanine nucleotide-binding domains and throughout the N-terminal glycine-rich domain that is found in many members of the Obg family. Disruption of the cgtA gene was lethal, demonstrating that this gene is essential for cell growth. Immunoblot analysis revealed that CgtA protein levels remained constant throughout the C. crescentus cell cycle.

Alleles↗
PubMed2004

Comparison of diverse protein sequences of the nuclear-encoded subunits of cytochrome C oxidase suggests conservation of structure underlies evolving functional sites.

Interspecific comparisons of protein sequences can reveal regions of evolutionary conservation that are under purifying selection because of functional constraints. Interpreting these constraints requires combining evolutionary information with structural, biochemical, and physiological data to understand the biological function of conserved regions. We take this integrative approach to investigate the evolution and function of the nuclear-encoded subunits of cytochrome c oxidase (COX). We find that the nuclear-encoded subunits evolved subsequent to the origin of mitochondria and the subunit composition of the holoenzyme varies across diverse taxa that include animals, yeasts, and plants. By mapping conserved amino acids onto the crystal structure of bovine COX, we show that conserved residues are structurally organized into functional domains. These domains correspond to some known functional sites as well as to other uncharacterized regions. We find that amino acids that are important for structural stability are conserved at frequencies higher than expected within each taxon, and groups of conserved residues cluster together at distances of less than 5 A more frequently than do randomly selected residues. We, therefore, suggest that selection is acting to maintain the structural foundation of COX across taxa, whereas active sites vary or coevolve within lineages.

Animals↗
PubMed1985

Tubulin evolution: ciliate-specific epitopes are conserved in the ciliary tubulin of Metazoa.

In spite of their overall evolutionary conservation, the tubulins of ciliates display electrophoretic and structural particularities. We show here that antibodies raised against Paramecium and Tetrahymena ciliary tubulins fail to recognize the cytoplasmic tubulins of all the metazoans tested. Immunoblotting of peptide maps of ciliate tubulins reveals that these antibodies react with one or very few ciliate-specific epitopes, in contrast to polyclonal antibodies against vertebrate tubulins, which are equivalent to autoantibodies and recognize several epitopes in both ciliate and vertebrate tubulins. Furthermore, we show that the anti-ciliate antibodies recognize ciliary and flagellar tubulins of metazoans ranging from sea urchin to mammals (with the exception of humans). The results support the conclusion that although duplication and specialization of tubulin genes in metazoans may have led to distinct types of tubulins, the axonemal one has remained highly conserved.

Animals↗
PubMed1993

Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments.

To identify evolutionary conserved domains and facilitate the recognition of potentially significant mutations in NF1 patients or tumors, we have determined the complete approximately 12 kb sequence of mouse neurofibromatosis type 1 mRNA. The sequence predicts a 2841 amino acid protein that is more than 98% identical to human neurofibromin. All but 9 of the 45 amino acid differences between mouse and human neurofibromin occur in the N-terminal half of the protein, with 16 changes clustered just upstream of the IRA-related segment. Given the high degree of sequence identity, virtually any sequence alteration in NF1 patients or tumors is potentially significant. We have also found that the 3' untranslated segment of NF1 mRNA is highly conserved, suggesting that this region may also be a target for mutations in NF1 patients.

Amino Acid Sequence↗