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PubMed2005

Comparative genomics using fugu: a tool for the identification of conserved vertebrate cis-regulatory elements.

With the imminent completion of the whole genome sequence of humans, increasing attention is being focused on the annotation of cis-regulatory elements in the human genome. Comparative genomics approaches based on evolutionary conservation have proved useful in the detection of conserved cis-regulatory elements. The pufferfish, Fugu rubripes, is an attractive vertebrate model for comparative genomics, by virtue of its compact genome and maximal phylogenetic distance from mammals. Fugu has lost a large proportion of nonessential DNA, and retained single orthologs for many duplicate genes that arose in the fish lineage. Non-coding sequences conserved between fugu and mammals have been shown to be functional cis-regulatory elements. Thus, fugu is a model fish genome of choice for discovering evolutionarily conserved regulatory elements in the human genome. Such evolutionarily conserved elements are likely to be shared by all vertebrates, and related to regulatory interactions fundamental to all vertebrates. The functions of these conserved vertebrate elements can be rapidly assayed in mammalian cell lines or in transgenic systems such as zebrafish/medaka and Xenopus, followed by validation of crucial elements in transgenic rodents.

Animals↗
PubMed1996

Conservation of minor histocompatibility antigens between human and non-human primates.

It is well accepted that minor histocompatibility antigens (mHag) can function as transplantation barriers between HLA-matched individuals. Little is known about the molecular nature and evolutionary conservation of mHag. It is only very recently that the first human mHag were identified. The HLA-A2.1-restricted mHag HA-2 and the HLA-B7-restricted mHag H-Y appeared to be peptides derived from polymorphic self proteins. Here we show that the HLA-A2.1-restricted mHag HA-1, HA-2, and the H-Y peptides are conserved between man, chimpanzees and rhesus macaques. Human cytotoxic T cell clones specific for the HLA-A2.1-restricted mHag HA-1, HA-2, and H-Y recognized HLA-A2.1 gene-transfected chimpanzee and rhesus macaque cells. High-pressure liquid chromatography fractionation of HLA-A2.1-bound peptides isolated from the HLA-A2.1-transfected chimpanzee cells revealed that the chimpanzee HA-1 and HA-2 co-eluted with the human HA-1 and HA-2. Subsequent amino acid sequencing showed that the chimpanzee HA-2 peptide is identical to the human HA-2 peptide. Our functional and biochemical results demonstrate that mHag peptides are conserved for over 35 million years.

Amino Acid Sequence↗
PubMed1974

Three flies and three islands: parallel evolution in Drosophila.

Most organisms are evolutionary conservatives; they may subdivide their niches but tend to remain within them. Yet the fossil record shows many cases of breakthrough to a new mode of life. How may such evolutionary innovation be recognized at this time level? Three species of Drosophila have accomplished an innovation in that they breed as obligate commensals on tropical land crabs. This could be dismissed as a curious aberration were it not for the fact that the three flies concerned represent three different phyletic lines of the family. Although Drosophila is abundant on the continents, these three parallel innovative evolutions have occurred on islands. The proposal is made that the genetic systems of many conservative groups of organisms carry variability that would permit them to evolve in a novel direction. The realization of this capacity, however, is possible only under special environmental conditions.

Adaptation, Biological↗
PubMed1998

Comparative molecular analysis of Na+/H+ exchangers: a unified model for Na+/H+ antiport?

Despite 30 years of study on Na+/H+ exchange, the molecular mechanisms of antiport remain obscure. Most challenging, the identity of amino acids involved in binding transported cations is still unknown. We review data examining the identity of residues that are involved in cation binding and translocation of prokaryotic and eukaryotic Na+/H+ antiporters. Several polar residues specifically distributed within or immediately adjacent to membrane spanning regions are implicated as being important. These key amino acids are conserved in prokaryotes and in some lower eukaryotic forms of the Na+/ H+ antiporter, despite their being dispersed throughout the protein and despite an overall low similarity in the linear sequence of these Na+/H+ antiporters. We suggest that this conservation of isolated residues (together with distances between them) reflects a general physicochemical mechanism of cation binding by exchangers. The binding could be based on coordination of the substrate cation by a crown ether-like cluster of polar atomic groups amino acids, as has been hypothesized by Boyer. Traditional screening for the extended, highly conserved linear protein sequences might not be applicable when searching for functional domains of ion transporters. Three-dimensional constellations of polar residues (3D-motifs) may be evolutionary conserved rather than linear primary sequence.

Amino Acid Sequence↗
PubMed1987

Primary structure of rat cardiac beta-adrenergic and muscarinic cholinergic receptors obtained by automated DNA sequence analysis: further evidence for a multigene family.

Two cDNA clones, lambda RHM-MF and lambda RHB-DAR, encoding the muscarinic cholinergic receptor and the beta-adrenergic receptor, respectively, have been isolated from a rat heart cDNA library. The cDNA clones were characterized by restriction mapping and automated DNA sequence analysis utilizing fluorescent dye primers. The rat heart muscarinic receptor consists of 466 amino acids and has a calculated molecular weight of 51,543. The rat heart beta-adrenergic receptor consists of 418 amino acids and has a calculated molecular weight of 46,890. The two cardiac receptors have substantial amino acid homology (27.2% identity, 50.6% with favored substitutions). The rat cardiac beta receptor has 88.0% homology (92.5% with favored substitutions) with the human brain beta receptor and the rat cardiac muscarinic receptor has 94.6% homology (97.6% with favored substitutions) with the porcine cardiac muscarinic receptor. The muscarinic cholinergic and beta-adrenergic receptors appear to be as conserved as hemoglobin and cytochrome c but less conserved than histones and are clearly members of a multigene family. These data support our hypothesis, based upon biochemical and immunological evidence, that suggests considerable structural homology and evolutionary conservation between adrenergic and muscarinic cholinergic receptors. To our knowledge, this is the first report utilizing automated DNA sequence analysis to determine the structure of a gene.

Amino Acid Sequence↗
PubMed1998

Archaeal binding protein-dependent ABC transporter: molecular and biochemical analysis of the trehalose/maltose transport system of the hyperthermophilic archaeon Thermococcus litoralis.

We report the cloning and sequencing of a gene cluster encoding a maltose/trehalose transport system of the hyperthermophilic archaeon Thermococcus litoralis that is homologous to the malEFG cluster encoding the Escherichia coli maltose transport system. The deduced amino acid sequence of the malE product, the trehalose/maltose-binding protein (TMBP), shows at its N terminus a signal sequence typical for bacterial secreted proteins containing a glyceride lipid modification at the N-terminal cysteine. The T. litoralis malE gene was expressed in E. coli under control of an inducible promoter with and without its natural signal sequence. In addition, in one construct the endogenous signal sequence was replaced by the E. coli MalE signal sequence. The secreted, soluble recombinant protein was analyzed for its binding activity towards trehalose and maltose. The protein bound both sugars at 85 degrees C with a Kd of 0.16 microM. Antibodies raised against the recombinant soluble TMBP recognized the detergent-soluble TMBP isolated from T. litoralis membranes as well as the products from all other DNA constructs expressed in E. coli. Transmembrane segments 1 and 2 as well as the N-terminal portion of the large periplasmic loop of the E. coli MalF protein are missing in the T. litoralis MalF. MalG is homologous throughout the entire sequence, including the six transmembrane segments. The conserved EAA loop is present in both proteins. The strong homology found between the components of this archaeal transport system and the bacterial systems is evidence for the evolutionary conservation of the binding protein-dependent ABC transport systems in these two phylogenetic branches.

ATP-Binding Cassette Transporters↗
PubMed2005

REVCOM: a robust Bayesian method for evolutionary rate estimation.

MOTIVATION: Evolutionary conservation estimated from a multiple sequence alignment is a powerful indicator of the functional significance of a residue and helps to predict active sites, ligand binding sites, and protein interaction interfaces. Many algorithms that calculate conservation work well, provided an accurate and balanced alignment is used. However, such a strong dependence on the alignment makes the results highly variable. We attempted to improve the conservation prediction algorithm by making it more robust and less sensitive to (1) local alignment errors, (2) overrepresentation of sequences in some branches and (3) occasional presence of unrelated sequences. RESULTS: A novel method is presented for robust constrained Bayesian estimation of evolutionary rates that avoids overfitting independent rates and satisfies the above requirements. The method is evaluated and compared with an entropy-based conservation measure on a set of 1494 protein interfaces. We demonstrated that approximately 62% of the analyzed protein interfaces are more conserved than the remaining surface at the 5% significance level. A consistent method to incorporate alignment reliability is proposed and demonstrated to reduce arbitrary variation of calculated rates upon inclusion of distantly related or unrelated sequences into the alignment.

Algorithms↗
PubMed2000

Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice.

Mouse genetic models can be used to dissect molecular mechanisms that result in human disease. This approach requires detection and demonstration of compelling parallels between phenotypes in mouse and human. Ts65Dn mice are at dosage imbalance for many of the same genes duplicated in trisomy 21 or Down syndrome (DS), the most common live-born human aneuploidy. Analysis of the craniofacial skeleton of Ts65Dn mice using three-dimensional morphometric methods demonstrates an absolute correspondence between Ts65Dn and DS craniofacial dysmorphology, a distinctive and completely penetrant DS phenotype. The genes at dosage imbalance in Ts65Dn are localized to a small region of mouse chromosome 16 and, by comparative mapping, to the corresponding region of human Chromosome 21, providing independent experimental data supporting the contribution of genes in this region to this characteristic DS phenotype. This analysis establishes precise parallels in human and mouse skull phenotypes resulting from dosage imbalance for the same genes, revealing strong conservation of the evolved developmental genetic program that underlies mammalian skull morphology and validating the use of this mouse model in the analysis of this important DS phenotype. This evolutionary conservation further establishes the mouse as a valid model for a wide range of syndromes producing craniofacial maldevelopment.

Animals↗
PubMed1998

Cloning and characterization of a new type of mouse chemokine.

We report here the identification and characterization of the mouse homologue of a human CX3C chemokine described by F. Bazan et al. (1997, Nature 385, 640-644). Termed fractalkine, this molecule constitutes a fourth or delta chemokine structural type that displays a novel CX3C sequence fingerprint. Distinct from the alpha, beta, or gamma chemokine families, the polypeptide chain of CX3C predicts a 373-amino-acid type I transmembrane glycoprotein with the chemokine domain resting on top of an extended mucin-like stalk. Comparison of the mouse and human protein chains shows a high degree of conservation in all the globular segments with the exception of the stalk portion. The striking identity of an amino acid stretch encompassing a putative juxtamembrane cleavage site suggests the evolutionary conservation of both membrane-bound and processed CX3C forms. Northern analysis reveals the presence of mouse CX3C mRNA in heart, brain, lung, kidney, skeletal muscle, and testis tissues. The mouse CX3C gene was further localized to the central region of chromosome 8 by interspecific backcross mapping; a related locus was detected on chromosome 11. The novel location of this gene from other chemokine gene clusters adds to the notion that CX3C is a fundamentally new class of chemokine.

Amino Acid Sequence↗
PubMed1985

Isolation and characterization of the measles virus F1 polypeptide: comparison with other paramyxovirus fusion proteins.

Measles virus fusion (F) protein has been isolated by immunoadsorption to a complex of monoclonal antibodies bound to protein A-Sepharose. The 41-kDa F1 component of the fusion protein was obtained pure in high yield by preparative SDS-polyacrylamide gel electrophoresis. The amino acid composition of the F1 chain was determined and the N-terminal sequence was analyzed for 40 residues. The structure determined is largely hydrophobic, with 24 residues of Val, Ile, Leu, Met, Phe, or Ala. Comparison with previously published data on the F1 polypeptide of Sendai virus showed considerable similarity in amino acid composition. Extensive N-terminal sequence homologies with F1 polypeptides of different paramyxoviruses are also noticed, including a nine-residue segment strictly conserved among four F1 polypeptides studied, as well as a weaker but distinct and Gly-rich sequence homology with the influenza A and B virus HA2 polypeptides. The evolutionary conservation of the N-terminal region at the site of cleavage of surface glycoproteins of the two families of myxoviruses highlights its specialized function in membrane fusion.

Amino Acid Sequence↗
PubMed1997

Evolutionary diversity of symbiotically induced nodule MADS box genes: characterization of nmhC5, a member of a novel subfamily.

Unique organs called nodules form on legume roots in response to intracellular infection by soil bacteria in the genus Rhizobium. This study describes a new MADS box gene, nmhC5, which along with nmh7 (J. Heard and K. Dunn, Proc. Natl. Acad. Sci. USA 92:5273-5277, 1995), is expressed in alfalfa (Medicago sativa) root nodules. Together, these genes represent the first putative transcription factors identified in nodules. Expression in a root-derived structure supports the growing sentiment that MADS box proteins have diverse roles in plant development. Comparison of the putative translation product of nmhC5 with those of other reported members of the MADS box family suggests that the overall structure of nmhC5 is conserved. Evolutionary analysis among the MADS box family showed that nmhC5 is orthologous to a root-expressed clone in Arabidopsis thaliana, agl17, and that nmh7 is similar to the floral subfamily with AP3 (DefA)/PI (Glo). Consistent with a prediction of homodimer formation, NMHC5 was shown to bind a CArG consensus sequence in vitro. In contrast, NMH7, which shows structural similarity to MADS box proteins that form heterodimers, did not bind the CArG element in an in vitro DNA-binding assay, suggesting the existence of an unknown dimer partner. The root-derived MADS box genes constitute a novel subfamily of vegetatively expressed MADS box genes. The evolutionary diversity between nmh7 and nmhC5 could represent an overall mechanistic conservation between plant developmental processes or could mean that nmh7 and nmhC5 make fundamentally different contributions to the development of the nodule.

Amino Acid Sequence↗
PubMed1980

Dictyostelium small nuclear RNA D2 is homologous to rat nucleolar RNA U3 and is encoded by a dispersed multigene family.

We have cloned and partially sequenced a 3.9 kb Bgl II restriction fragment from the genome of the cellular slime mold Dictyostelium discoideum which encodes D2, the most abundant small nuclear RNA (snRNA) in vegetative amoebae. The D2 gene is colinear with the mature snRNA and is surrounded by extremely A + T rich DNA for at least 61 nucleotides 5' to the coding region and 218 nucleotides in the 3' direction. D2 is the only small stable RNA encoded by the cloned DNA fragment. Although D2 RNA is homogeneous in length, a comparison of the RNA and DNA sequencing data indicates that C/U or A/G heterogeneity is present in at least three positions within the D2 RNA sequence. Such minor heterogeneity implies that D2 is encoded by multiple genes, and indeed five different restriction fragments complementary to D2 RNA can be detected when genomic blots are probed with labeled fragments derived from the cloned D2 coding region. Further hybridizaton experiments using the cloned flanking sequences as probes suggest that sequences outside the RNA coding region are not detectably conserved between the five dispersed loci. The D2 RNA sequence is more tha 40% homologous to the small nucleolar RNA U3B from rat Novikoff hepatoma, and the implications of this evolutionary conservation are discussed.

Animals↗
PubMed2005

Cloning and functional characterization of the Xenopus orthologue of the Treacher Collins syndrome (TCOF1) gene product.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development caused by mutations in the TCOF1 gene, which encodes the nucleolar phosphoprotein treacle. We previously reported a function for mammalian treacle in ribosomal DNA gene transcription by its interaction with upstream binding factor. As an initial step in the development of a TCS model for frog the cDNA that encodes the Xenopus laevis treacle was cloned. Although the derived amino acid sequence shows a poor homology with its mammalian orthologues, Xenopus treacle has 11 highly homologous direct repeats near the center of the protein molecule similar to those present in its human, dog and mouse orthologues. Comparison of their amino acid compositions indicates conservation of predominant specific amino acid residues. Antisense-mediated down-regulation of treacle expression in X. laevis oocytes resulted in inhibition of rDNA gene transcription. The results suggest evolutionary conservation of the function of treacle in ribosomal RNA biogenesis in higher eukaryotes.

Amino Acid Sequence↗
PubMed1999

AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant.

The accumulation of reactive oxygen species (ROS) in response to extracellular signals or intracellular biochemical processes can be regulated by the coordinate action of many antioxidant proteins. Because moderate levels of ROS can act as intracellular messengers in many of these processes, this modulation is critical for the transduction of specific signals. The thiol-specific antioxidant (TSA) family is a highly conserved group of enzymes that can reduce hydroperoxides in the presence of a thiol-containing electron donor. AOP2 (antioxidant protein 2) is a newly described member that shows significant evolutionary conservation between many different organisms. The protein contains three motifs that are highly conserved within the TSA family, including a cysteine residue that is the active site of oxidation for this class of proteins. Although AOP2 possesses TSA activity, it has several unique characteristics, including the absence of a second cysteine residue that is conserved in all other TSA proteins, the presence of a unique carboxy-terminal domain, and a demonstrated phospholipase activity. Furthermore, AOP2 shows conservation of several amino acids important in dimer formation and active site configuration that are not found in the other family members. Together, these data strongly suggest that AOP2 is a novel thiol-dependent antioxidant that functions to scavenge particular hydroperoxides in the cell and mediate specific signals. There is also evidence supporting a role for AOP2 in certain disease processes including atherosclerosis. Further evaluation of this protein and its substrate specificity will likely shed light on its precise role in cellular oxidant defense, signal transduction and pathogenesis.

Amino Acid Motifs↗
PubMed2000

Evidence for evolutionarily conserved secondary structure in the H19 tumor suppressor RNA.

The molecular basis for function of the mammalian H19 as a tumor suppressor is poorly understood. Large, conserved open reading frames (ORFs) are absent from both the human and mouse cDNAs, suggesting that it may act as an RNA. Contradicting earlier reports, however, recent studies have shown that the H19 transcript exists in polysomal form and is likely translated. To distinguish between possible functional roles for the gene product, we have characterized the sequence requirements for H19-mediated in vitro suppression of tumor cell clonogenicity and analyzed the sequence of the gene cloned from a range of mammals. A cDNA version of the human gene, lacking the unusually short introns characteristic of imprinted genes, is as effective as a genomic copy in blocking anchorage-independent growth by G401 cells. The first 710 nucleotides of the gene can be deleted with no effect on in vitro activity. Further truncations from either the 5'- or 3'-end, however, cause a loss of suppression of clonogenicity. Using conserved sequences within the H19 gene as PCR primers, genomic DNA fragments were amplified from a range of mammalian species that span the functional domain defined by deletion analysis. Sequences from cat, lynx, elephant, gopher and orangutan complement the previous database of sequences from human, mouse, rat and rabbit. Hypothetical translation of the resulting sequences shows an absence of conserved ORFs of any size. Free energy and covariational analysis of the RNA sequences was used to identify potential helical pairings within the H19 transcript. A set of 16 helices are supported by covariation (i.e. conservation of base pairing potential in the absence of primary sequence conservation). The predicted RNA pairings consist largely of local hairpins but also include several long range interactions that bridge the 5'- and 3'-ends of the functional domain. Given the evolutionary conservation of structure at the RNA level and the absence of conservation at the protein level, we presume that the functional product of the H19 gene is a structured RNA.

Animals↗
PubMed2006

Mechanism of ribosome shunting in Rice tungro bacilliform pararetrovirus.

In plant pararetroviruses, pregenomic RNA serves both as a template for replication through reverse transcription and a polysictronic mRNA. This RNA has a complex leader sequence preceding the first large ORF. The leader contains multiple short ORFs and strong secondary structure, both inhibiting ribosome scanning. Translation on this RNA is initiated by shunting, in which scanning ribosomes bypass a large portion of the leader with the inhibitory secondary structure and short ORFs. In Cauliflower mosaic virus (CaMV), the ribosome shunting mechanism involves translation of the 5'-proximal short ORF terminating in front of the secondary structure that appears to force ribosomes to take off and resume scanning at a landing site downstream of the structure. Using two plant protoplast systems and shunt-competent wheat-germ extracts, we demonstrate that in Rice tungro bacilliform virus (RTBV) shunting also depends on the first short ORF followed by strong secondary structure. Swapping of the conserved shunt elements between CaMV and RTBV revealed the importance of nucleotide composition of the landing sequence for efficient shunting. The results suggest that the mechanism of ribosome shunting is evolutionary conserved in plant pararetroviruses.

5' Untranslated Regions↗
PubMed1990

Conserved enzymes mediate the early reactions of carotenoid biosynthesis in nonphotosynthetic and photosynthetic prokaryotes.

Carotenoids comprise one of the most widespread classes of pigments found in nature. The first reactions of C40 carotenoid biosynthesis proceed through common intermediates in all organisms, suggesting the evolutionary conservation of early enzymes from this pathway. We report here the nucleotide sequence of three genes from the carotenoid biosynthesis gene cluster of Erwinia herbicola, a nonphotosynthetic epiphytic bacterium, which encode homologs of the CrtB, CrtE, and CrtI proteins of Rhodobacter capsulatus, a purple nonsulfur photosynthetic bacterium. CrtB (prephytoene pyrophosphate synthase), CrtE (phytoene synthase), and CrtI (phytoene dehydrogenase) are required for the first three reactions specific to the carotenoid branch of general isoprenoid metabolism. The homologous proteins from E. herbicola and R. capsulatus show sequence identities of 41.7% for CrtI, 33.7% for CrtB, and 30.8% for CrtE. E. herbicola and R. capsulatus CrtI also display 27.2% and 27.9% sequence identity, respectively, with R. capsulatus CrtD (methoxyneurosporene dehydrogenase). All three dehydrogenases possess a hydrophobic N-terminal domain containing a putative ADP-binding beta alpha beta fold characteristic of enzymes known to bind FAD or NAD(P) cofactors. In addition, E. herbicola and R. capsulatus CrtB show 25.2% and 23.3% respective sequence identities with the protein product of pTOM5, a tomato cDNA of unknown function that is differentially expressed during fruit ripening. These data indicate the structural conservation of early carotenoid biosynthesis enzymes in evolutionarily diverse organisms.

Amino Acid Sequence↗
PubMed1999

Conservation of histone binding and transcriptional repressor functions in a Schizosaccharomyces pombe Tup1p homolog.

The Ssn6p-Tup1p corepressor complex is important to the regulation of several diverse genes in Saccharomyces cerevisiae and serves as a model for corepressor functions. To investigate the evolutionary conservation of these functions, sequences homologous to the S. cerevisiae TUP1 gene were cloned from Kluyveromyces lactis (TUP1) and Schizosaccharomyces pombe (tup11(+)). Interestingly, while the K. lactis TUP1 gene complemented an S. cerevisiae tup1 null mutation, the S. pombe tup11(+) gene did not, even when expressed under the control of the S. cerevisiae TUP1 promoter. However, an S. pombe Tup11p-LexA fusion protein repressed transcription of a corresponding reporter gene, indicating that this Tup1p homolog has intrinsic repressor activity. Moreover, a chimeric protein containing the amino-terminal Ssn6p-binding domain of S. cerevisiae Tup1p and 544 amino acids from the C-terminal region of S. pombe Tup11p complemented the S. cerevisiae tup1 mutation. The failure of native S. pombe Tup11p to complement loss of Tup1p functions in S. cerevisiae corresponds to an inability to bind to S. cerevisiae Ssn6p in vitro. Disruption of tup11(+) in combination with a disruption of tup12(+), another TUP1 homolog gene in S. pombe, causes a defect in glucose repression of fbp1(+), suggesting that S. pombe Tup1p homologs function as repressors in S. pombe. Furthermore, Tup11p binds specifically to histones H3 and H4 in vitro, indicating that both the repression and histone binding functions of Tup1p-related proteins are conserved across species.

Amino Acid Sequence↗