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PubMed1996

Conserved sequence motifs, alignment, and secondary structure for the third domain of animal 12S rRNA.

Secondary structure models are an important step for aligning sequences, understanding probabilities of nucleotide substitutions, and evaluating the reliability of phylogenetic reconstructions. A set of conserved sequence motifs is derived from comparative sequence analysis of 184 invertebrate and vertebrate taxa (including many taxa from the same genera, families, and orders) with reference to a secondary structure model for domain III of animal mitochondrial small subunit (12S) ribosomal RNA. A template is presented to assist with secondary structure drawing. Our model is similar to previous models but is more specific to mitochondrial DNA, fitting both invertebrate and vertebrate groups, including taxa with markedly different nucleotide compositions. The second half of the domain III sequence can be difficult to align precisely, even when secondary structure information is considered. This is especially true for comparisons of anciently diverged taxa, but well-conserved motifs assist in determining biologically meaningful alignments. Patterns of conservation and variability in both paired and unpaired regions make differential phylogenetic weighting in terms of "stems" and "loops" unsatisfactory. We emphasize looking carefully at the sequence data before and during analyses, and advocate the use of conserved motifs and other secondary structure information for assessing sequencing fidelity.

Animals↗

PubMed2002

The crocodilian mitochondrial control region: general structure, conserved sequences, and evolutionary implications.

We present the first comprehensive analysis of the crocodilian control region. We have analyzed sequences from all three families of Crocodylia (Crocodylidae, Gavialidae, Alligatoridae), incorporating all genera except Paleosuchus and Melanosuchus. Within the control region of other vertebrates, several sequence motifs and their order appear to be conserved. Herein, we compare aligned crocodilian D-loop sequences to homologous sequences from other vertebrates ranging from fish to birds. Among other findings, we have discovered that while domain I tends to be shorter than the same region in mammals and birds, it contains sequences similar in structure to both the goose-hairpin and termination associated sequences (TAS). Domain II is highly conservative with regard to size among the taxa examined and contains several of the conserved sequence boxes characterized in other vertebrates. Domain III contains several interesting sequence motifs including tandemly repeated sequences, a long poly-A region in the Crocodylidae, and possible bidirection promoter sequences.

Alligators and Crocodiles↗

PubMed1989

An NTP-binding motif is the most conserved sequence in a highly diverged monophyletic group of proteins involved in positive strand RNA viral replication.

NTP-motif, a consensus sequence previously shown to be characteristic of numerous NTP-utilizing enzymes, was identified in nonstructural proteins of several groups of positive-strand RNA viruses. These groups include picorna-, alpha-, and coronaviruses infecting animals and como-, poty-, tobamo-, tricorna-, hordei-, and furoviruses of plants, totalling 21 viruses. It has been demonstrated that the viral NTP-motif-containing proteins constitute three distinct families, the sequences within each family being similar to each other at a statistically highly significant level. A lower, but still valid similarity has also been revealed between the families. An overall alignment has been generated, which includes several highly conserved sequence stretches. The two most prominent of the latter contain the socalled "A" and "B" sites of the NTP-motif, with four of the five invariant amino acid residues observed within these sequences. These observations, taken together with the results of comparative analysis of the positions occupied by respective proteins (domains) in viral multidomain proteins, suggest that all the NTP-motif-containing proteins of positive-strand RNA viruses are homologous, constituting a highly diverged monophyletic group. In this group the "A" and "B" sites of the NTP-motif are the most conserved sequences and, by inference, should play the principal role in the functioning of the proteins. A hypothesis is proposed that all these proteins possess NTP-binding capacity and possibly NTPase activity, performing some NTP-dependent function in viral RNA replication. The importance of phylogenetic analysis for the assessment of the significance of the occurrence of the NTP-motif (and of sequence motifs of this sort in general) in proteins is emphasized.

Amino Acid Sequence↗

PubMed2000

A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing.

Adenosine deaminases that act on RNA (ADARs) are RNA editing enzymes that convert adenosines to inosines within cellular and viral RNAs. Certain glutamate receptor (gluR) pre-mRNAs are substrates for the enzymes in vivo. For example, at the R/G editing site of gluR-B, -C, and -D RNAs, ADARs change an arginine codon (AGA) to a glycine codon (IGA) so that two protein isoforms can be synthesized from a single encoded mRNA; the highly related gluR-A sequence is not edited at this site. To gain insight into what features of an RNA substrate are important for accurate and efficient editing by an ADAR, we performed a phylogenetic analysis of sequences required for editing at the R/G site. We observed highly conserved sequences that were shared by gluR-B, -C, and -D, but absent from gluR-A. Surprisingly, in contrast to results obtained in phylogenetic analyses of tRNA and rRNA, it was the bases in paired, helical regions whose identity was conserved, whereas bases in nonhelical regions varied, but maintained their nonhelical state. We speculate this pattern in part reflects constraints imposed by ADAR's unique specificity and gained support for our hypotheses with mutagenesis studies. Unexpectedly, we observed that some of the gluR introns were conserved beyond the sequences required for editing. The approximately 600-nt intron 13 of gluR-C was particularly remarkable, showing >94% nucleotide identity between human and chicken, organisms estimated to have diverged 310 million years ago.

Adenosine Deaminase↗

PubMed1989

Bacteriophage Mu late promoters: four late transcripts initiate near a conserved sequence.

Late transcription of bacteriophage Mu, which results in the expression of phage morphogenetic functions, is dependent on Mu C protein. Earlier experiments indicated that Mu late RNAs originate from four promoters, including the previously characterized mom promoter. S1 nuclease protection experiments were used to map RNA 5' ends in the three new regions. Transcripts were initiated at these points only in the presence of C and were synthesized in a rightward direction on the Mu genome. Amber mutant marker rescue analysis of plasmid clones and limited DNA sequencing demonstrated that these new promoters are located between C and lys, upstream of I, and upstream of P within the N gene. A comparison of the promoter sequences upstream from the four RNA 5' ends yielded two conserved sequences: the first (tA . . cT, where capital and lowercase letters indicate 100 and 75% base conservation, respectively), at approximately -10, shares some similarity with the consensus Escherichia coli sigma 70 -10 region, while the second (ccATAAc CcCPuG/Cac, where Pu indicates a purine), in the -35 region, bears no resemblance to the E. coli -35 consensus. We propose that these conserved Mu late promoter consensus sequences are important for C-dependent promoter activity. Plasmids containing transcription fusions of these late promoters to lacZ exhibited C-dependent beta-galactosidase synthesis in vivo, and C was the only Mu product needed for this transactivation. As expected, the late promoter-lacZ fusions were activated only at late times after induction of a Mu prophage. The C-dependent activation of lacZ fusions containing only a few bases of the 5' end of Mu late RNA and the presence of altered promoter sequences imply that C acts at the level of transcription initiation.

Bacteriophage mu↗

PubMed2002

Conserved sequences in a tissue-specific regulatory region of the pdx-1 gene mediate transcription in Pancreatic beta cells: role for hepatocyte nuclear factor 3 beta and Pax6.

Pancreas duodenum homeobox 1 (PDX-1) is absolutely required for pancreas development and the maintenance of islet beta-cell function. Temporal and cell-type-specific transcription of the pdx-1 gene is controlled by factors acting upon sequences found within its 5'-flanking region. Critical cis-acting transcriptional control elements are located within a nuclease hypersensitive site that contains three conserved subdomains, termed areas I, II, and III. We show that area II acts as a tissue-specific regulatory region of the pdx-1 gene, directing transgene expression to a subpopulation of islet cells. Mutation of the area II hepatocyte nuclear factor 3 (HNF3) binding element in the larger area I- and area II- containing PstBst fragment also decreases PB(hsplacZ) transgene penetrance. These two results indicate possible ontogenetic and/or functional heterogeneity of the beta-cell population. Several other potential positive- and negative-acting control elements were identified in area II after mutation of the highly conserved sequence blocks within this subdomain. Pax6, a factor essential for islet alpha-cell development and islet hormone gene expression, was shown to bind in area II in vitro. Pax6 and HNF3 beta were also found to bind to this region in vivo by using the chromatin immunoprecipitation assay. Collectively, these data suggest an important role for both HNF3 beta and Pax6 in regulating pdx-1 expression in beta cells.

Animals↗

PubMed1986

Sequence conservation in the protein coding and intron regions of the engrailed transcription unit.

Engrailed (en) is a gene involved in proper segmentation of the Drosophila embryo. The predicted en protein contains a homeodomain and regions rich in polyalanine, polyglutamine, polyglutamate/aspartate and serine. We have taken an evolutionary approach to define which regions may be of fundamental importance by examining the D. virilis genomic sequence homologous to the D. melanogaster en primary transcription unit. Sequence homology begins at the first ATG of a long open reading frame yielding proteins of 584 and 552 amino acids for the D. virilis and D. melanogaster proteins, respectively. The predicted amino acid sequence can be divided into conserved and non-conserved domains. The C-terminal 30% of the protein (which includes the homeodomain) is completely conserved. In the N-terminal 70% of the protein, the overall conservation is 71%, but non-conservative amino acid changes occur in clusters and there are short stretches of highly conserved sequence. A region rich in glutamate and aspartate is conserved and has homology to an 18-amino acid sequence present in members of the myc family of proteins. Major differences in the size of the two proteins occur in regions of non-conserved repeated sequences. In the introns of the engrailed transcription units there are long stretches of conservation, suggesting this DNA may be of functional importance.

Amino Acid Sequence↗

PubMed1996

Cloning of a cDNA encoding a mouse transcriptional repressor displaying striking sequence conservation across vertebrates.

The nucleotide sequence encoding an approx. 120-kDa transcriptional repressor (MEB1) was determined from a cDNA which was cloned from a mouse brain library. An alignment of the deduced amino-acid sequences of the putative functional domains of MEB1 with those from the human, hamster and chicken homologues reveals a dramatic degree of conservation.

Amino Acid Sequence↗

PubMed1995

The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif.

Ran/TC4 is an essential, nuclear GTPase implicated in the initiation of DNA replication, entry into and exit from mitosis, and in nuclear RNA and protein transport through the nuclear pore complex. This diversity of functions suggests that Ran interacts with a large number of down-stream targets. Using an overlay assay, we detected a family of putative target proteins that associate with GTP-bound Ran. The sequence of only one such protein, HTF9a/RanBP1, is known. We have now cloned two additional Ran-binding proteins, allowing identification of a distinctive, highly conserved sequence motif of approximately 150 residues. This motif represents a minimal Ran-binding domain that stabilizes the GTP-bound state of Ran. The isolated domain also functions as a coactivator of Ran-GTPase-activating protein. Mutation of a conserved residue within the Ran-binding domain of HTF9a protein drastically reduced Ran binding. Ran-binding proteins coimmunoprecipitated with epitope-tagged Ran from cell lysates, suggesting that these proteins may associate in vivo. A previously uncharacterized Caenorhabditis elegans gene could encode a protein (96 kDa) possessing two Ran-binding domains. This open reading frame also contains similarities to nucleoporins, suggesting a functional link between Ran and nuclear pore complexes.

Amino Acid Sequence↗

PubMed1992

Conserved sequence blocks 5' to start codons of plant mitochondrial genes.

Three sequence blocks of 10-12 bp are conserved in sequence and order 5' to putative start codons of several higher-plant mitochondrial genes. At least 25 examples were found, primarily associated with coxII, atp6, and orf25, in monocotyledons and dicotyledons. The proximal block can be 9 bp from start codons, and the three blocks generally occur within 100 bp 5' of start codons. In three examples 5' termini of the blocks represent recombination breakpoints, resulting in conservation of the blocks in resultant configurations. The two proximal blocks can form a secondary structure motif. The occurrence of the blocks near start codons, and conserved sequence and order, is consistent with a possible role in translation initiation or regulation.

Base Sequence↗

PubMed2005

CREDO: a web-based tool for computational detection of conserved sequence motifs in noncoding sequences.

SUMMARY: CREDO is a user-friendly, web-based tool that integrates the analysis and results of different algorithms widely used for the computational detection of conserved sequence motifs in noncoding sequences. It enables easy comparison of the individual results. CREDO offers intuitive interfaces for easy and rapid configuration of the applied algorithms and convenient views on the results in graphical and tabular formats. AVAILABILITY: http://mips.gsf.de/proj/regulomips/credo.htm.

Algorithms↗

PubMed1994

Conserved sequences in a class of rare eukaryotic nuclear introns with non-consensus splice sites.

Eukaryotic nuclear genomes contain a rare class of pre-mRNA introns with consensus sequence features that differ markedly from most pre-mRNA introns. Four genes have so far been identified that contain one copy each of this rare intron class in addition to several standard introns. These introns and homologous introns from several species were compared to identify conserved sequence elements and to establish consensus sequences for these elements. The only well-conserved elements are found at the 5' and 3' ends of the introns. The 5' splice site sequence is ATATCCTT beginning with the first nucleotide of the intron and is invariant in the introns examined to date. The 3' splice site consensus sequence is YCCAC ending at the last nucleotide of the intron. An almost invariant sequence of TCCTTAAC is also found near the 3' end of the intron (the 3' upstream element). The length of the introns varies between 95 and 2940 nucleotides. The sequence organization of these introns suggests that they represent a variant class of pre-mRNA introns that might be spliced via a spliceosome mechanism employing factors distinct from those used by other pre-mRNA introns. A search of small nuclear RNA (snRNA) sequences for regions complementary to the conserved elements of this rare class of introns found a strong match between U12 snRNA and the 3' upstream element and a weaker match between U11 snRNA and the 5' splice site sequence.

Animals↗

PubMed1986

Sequence conservation and region shuffling in an endoglucanase and an exoglucanase from Cellulomonas fimi.

Cellulomonas fimi produces an endoglucanase and an exoglucanase which bind strongly to cellulose. Each enzyme contains three distinct regions: a short sequence of about 20 amino acids containing only proline and threonine (the Pro-Thr box); an irregular region, rich in hydroxyamino acids, of low charge density, and which is predicted to have little secondary structure; and an ordered region of higher charge density which contains a potential active site, and which is predicted to have secondary structure. The Pro-Thr box is conserved almost perfectly in the two enzymes. The irregular regions are 50% conserved, and the conserved sequences include four Asn-Xaa-Ser/Thr sites. The ordered regions appear not to be conserved, but the potential active sites both have the sequence Glu-Xaa7-Asn-Xaa6-Thr; they occur at widely separated sites in the two regions. The order of the regions is reversed in the two enzymes: irregular-Pro-Thr box-ordered in the endoglucanase; ordered-Pro-Thr box-irregular in the exoglucanase. The genes for the two enzymes appear to have arisen by shuffling of two conserved sequences and either one or two other sequences.

Actinomycetales↗

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↗

PubMed2006

A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia.

Exposure to atypical antipsychotic drugs such as valproate increases the expression of chaperones that assist in the folding of proteins in the endoplasmic reticulum (ER) including calreticulin, GRP78/BiP, GRP94, and PD1. This neuroprotective role may be involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia and bipolar disorder. The 5'-flanking region of the human calreticulin gene was screened in 100 cases of schizophrenia by PCR/SSCA between -485 and +1 basepair (bp) relative to the transcription start site. A G > C point mutation was detected at -48 in a case of paranoid schizophrenia, which was not detected in 280 unrelated control subjects (560 chromosomes). This is the first report of mutation in relation with the calreticulin gene. The -48G > C mutation creates a CpG site at the core promoter region of the gene. The role of this mutation remains to be clarified in the pathophysiology of the disease.

Adult↗

PubMed1992

Polymorphic variation within "conserved" sequences at the 3' end of the human RDS gene which results in amino acid substitutions.

The human RDS gene, previously mapped to chromosome 6p, encodes a protein found in the outer disc membrane of the photoreceptor cells of the retina. The cDNA sequence of the human gene shows 85% identity with the bovine peripherin gene and the rds (retinal degeneration slow) genes from mouse and rat. Mutations in the RDS gene have recently been implicated in autosomal dominant retinitis pigmentosa (adRP) in some families. Here we present evidence that the third exon of this gene is subject to polymorphic variation in humans. The three sequence alterations described in this paper give rise to amino acid substitutions. However, as these missense mutations also occur in the normal population they are not implicated as causing adRP. Interestingly such sequence variation is not found within other species examined including mouse and bovine. These intragenic polymorphisms will be of future potential value in studies to locate further disease causing mutations in adRP patients in the RDS gene.

Amino Acid Sequence↗

PubMed1992

Chromatin structure and conserved sequence elements in genes encoding ribosomal proteins in Tetrahymena thermophila.

The chromatin structure of the macronuclear genes encoding ribosomal proteins S25 and L1 in the ciliated protozoan Tetrahymena thermophila was analyzed. Using the indirect end-labelling technique, DNase-I-hypersensitive regions were located in the promoter regions as well as in the 3' regions of the genes. The DNase-I-hypersensitive regions were present in chromatin of exponentially growing cells, where the rate of ribosomal-protein gene transcription is high, and in chromatin from starved cells, where transcription of ribosomal-protein genes is severely depressed. Micrococcalnuclease-digestion experiments revealed that the promoter regions of the S25 gene and the L1 gene are devoid of nucleosomes in exponentially growing cells. In starved cells, no nucleosomal organisation of the promoter region of the L1 gene could be detected, whereas nucleosomal structures were discernible in the promoter region of the S25 gene. A conspicuous polypurine sequence motif, AARGGGAAA, is present within or adjacent to the DNase-I-hypersensitive regions in the promoter of the S25 and the L1 gene, and interestingly, the same motif is found also in the promoter regions of the genes encoding ribosomal proteins L21 and L37.

Animals↗

PubMed1999

The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation.

G protein-coupled receptor kinases (GRKs) desensitize G protein-coupled receptors by phosphorylating activated receptors. The six known GRKs have been classified into three subfamilies based on sequence and functional similarities. Examination of the mouse GRK4 subfamily (GRKs 4, 5, and 6) suggests that mouse GRK4 is not alternatively spliced in a manner analogous to human or rat GRK4, whereas GRK6 undergoes extensive alternative splicing to generate three variants with distinct carboxyl termini. Characterization of the mouse GRK 5 and 6 genes reveals that all members of the GRK4 subfamily share an identical gene structure, in which 15 introns interrupt the coding sequence at equivalent positions in all three genes. Surprisingly, none of the three GRK subgroups (GRK1, GRK2/3, and GRK4/5/6) shares even a single intron in common, indicating that these three subfamilies are distinct gene lineages that have been maintained since their divergence over 1 billion years ago. Comparison of the amino acid sequences of GRKs from various mammalian species indicates that GRK2, GRK5, and GRK6 exhibit a remarkably high degree of sequence conservation, whereas GRK1 and particularly GRK4 have accumulated amino acid changes at extremely rapid rates over the past 100 million years. The divergence of individual GRKs at vastly different rates reveals that strikingly different evolutionary pressures apply to the function of the individual GRKs.

Alternative Splicing↗