Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “functional divergence”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources
PubMed2005

Cardiac nitric oxide: emerging role for nNOS in regulating physiological function.

Emerging evidence shows that neuronal nitric oxide synthase (nNOS) plays several diverging roles in modulating cardiac function. This review examines the nitric oxide (NO) pathway and the regulatory mechanisms to which nNOS signalling is sensitive. These mechanisms are diverse and include regulation of gene expression, posttranscriptional regulation, protein trafficking, allosteric modulation of nNOS and redox modification to alter NO bioavailability once synthesised. Functionally, alteration in nNOS-NO signalling in the heart may correlate with different cardiac regulatory states. The idea of this being associated with exercise-trained states and myocardial disease is discussed.

Allosteric Regulation↗
PubMed2001

A simple algorithm to infer gene duplication and speciation events on a gene tree.

MOTIVATION: When analyzing protein sequences using sequence similarity searches, orthologous sequences (that diverged by speciation) are more reliable predictors of a new protein's function than paralogous sequences (that diverged by gene duplication), because duplication enables functional diversification. The utility of phylogenetic information in high-throughput genome annotation ('phylogenomics') is widely recognized, but existing approaches are either manual or indirect (e.g. not based on phylogenetic trees). Our goal is to automate phylogenomics using explicit phylogenetic inference. A necessary component is an algorithm to infer speciation and duplication events in a given gene tree. RESULTS: We give an algorithm to infer speciation and duplication events on a gene tree by comparison to a trusted species tree. This algorithm has a worst-case running time of O(n(2)) which is inferior to two previous algorithms that are approximately O(n) for a gene tree of sequences. However, our algorithm is extremely simple, and its asymptotic worst case behavior is only realized on pathological data sets. We show empirically, using 1750 gene trees constructed from the Pfam protein family database, that it appears to be a practical (and often superior) algorithm for analyzing real gene trees. AVAILABILITY: http://www.genetics.wustl.edu/eddy/forester.

Algorithms↗
PubMed2005

Qualitative evaluation of divergent thinking in patients with schizophrenia.

Patients with schizophrenia show deficits across a broad spectrum of neurocognitive domains. In particular, deficits in verbal fluency are common. Verbal fluency tests are neuropsychological tests that assess frontal lobe function or executive function but also assess divergent thinking. However, few studies have considered the impairment of verbal fluency from the viewpoint of divergent thinking. To consider the structure of divergent thinking, not only verbal assessments but also non-verbal assessments are indispensable. We administered several fluency tests, the idea fluency test, the design fluency test, and word (letter and category) fluency tests to 26 patients with schizophrenia and 26 healthy control subjects to evaluate divergent thinking in both groups and assessed their responses qualitatively. An acceptable minimal level of intelligence was maintained in the patient group. Although attention and executive functioning were relatively preserved in the subjects with schizophrenia, they demonstrated significant deficits in divergent thinking and had particular difficulty in producing ideas and designs requiring concept flexibility, a conversion of viewpoint, originality, or novelty. Research on deficits in divergent thinking in patients with schizophrenia may contribute to the development of cognitive and behavioral rehabilitation programs.

Adult↗
PubMed2002

Identification of essential amino acid changes in paired domain evolution using a novel combination of evolutionary analysis and in vitro and in vivo studies.

Pax genes are defined by the presence of a paired box that encodes a DNA-binding domain of 128 amino acids. They are involved in the development of the central nervous system, organogenesis, and oncogenesis. The known Pax genes are divided into five groups within two supergroups. By means of a novel combination of evolutionary analysis, in vitro binding assays and in vivo functional analyses, we have identified the key residues that determine the differing DNA-binding properties of the two supergroups and of the Pax-2, 5, 8 and Pax-6 subgroups within supergroup I. The differences in binding properties between the two supergroups are largely caused by amino acid changes at residues 20 and 121 of the paired domain. Although the paired domains of the Pax-2, 5, 8 and the Pax-6 group differ by >19 amino acids, their distinct DNA-binding properties are determined almost completely by a single amino acid change. Thus, a small number of amino acid changes can account in large part for the divergence in binding properties among the known paired domains. Our approach for selecting candidate sites responsible for the functional divergence between genes should also be useful for studying other gene families.

Amino Acid Sequence↗
PubMed2006

The latent promiscuity of newly identified microbial lactonases is linked to a recently diverged phosphotriesterase.

In essence, evolutionary processes occur gradually, while maintaining fitness throughout. Along this line, it has been proposed that the ability of a progenitor to promiscuously catalyze a low level of the evolving activity could facilitate the divergence of a new function by providing an immediate selective advantage. To directly establish a role for promiscuity in the divergence of natural enzymes, we attempted to trace the origins of a bacterial phosphotriesterase (PTE), an enzyme thought to have evolved for the purpose of degradation of a synthetic insecticide introduced in the 20th century. We surmised that PTE's promiscuous lactonase activity may be a vestige of its progenitor and tested homologues annotated as "putative PTEs" for lactonase and phosphotriesterase activity. We identified three genes that define a new group of microbial lactonases dubbed PTE-like lactonases (PLLs). These enzymes proficiently hydrolyze various lactones, and in particular quorum-sensing N-acyl homoserine lactones (AHLs), and exhibit much lower promiscuous phosphotriesterase activities. PLLs share key sequence and active site features with PTE and differ primarily by an insertion in one surface loop. Given their biochemical and biological function, PLLs are likely to have existed for many millions of years. PTE could have therefore evolved from a member of the PLL family while utilizing its latent promiscuous paraoxonase activity as an essential starting point.

Amino Acid Sequence↗
PubMed2004

Patterns of diversifying selection in the phytotoxin-like scr74 gene family of Phytophthora infestans.

Phytophthora infestans, the organism responsible for the Irish famine, causes late blight, a re-emerging disease of potato and tomato. Little is known about the molecular evolution of P. infestans genes. To identify candidate effector genes (virulence or avirulence genes) that may have co-evolved with the host, we mined expressed sequence tag (EST) data from infection stages of P. infestans for secreted and potentially polymorphic genes. This led to the identification of scr74, a gene that encodes a predicted 74-amino acid secreted cysteine-rich protein with similarity to the Phytophthora cactorum phytotoxin PcF. The expression of scr74 was upregulated approximately 60-fold 2 to 4 days after inoculation of tomato and was also significantly induced during early stages of colonization of potato. The scr74 gene was found to belong to a highly polymorphic gene family within P. infestans with 21 different sequences identified. Using the approximate and maximum likelihood (ML) methods, we found that diversifying selection likely caused the extensive polymorphism observed within the scr74 gene family. Pairwise comparisons of 17 scr74 sequences revealed elevated ratios of nonsynonymous to synonymous nucleotide-substitution rates, particularly in the mature region of the proteins. Using ML, all 21 polymorphic amino acid sites were identified to be under diversifying selection. Of these 21 amino acids, 19 are located in the mature protein region, suggesting that selection may have acted on the functional portions of the proteins. Further investigation of gene copy number and organization revealed that the scr74 gene family comprises at least three copies located in a region of no more than 300 kb of the P. infestans genome. We found evidence that recombination contributed to sequence divergence within at least one gene locus. These results led us to propose an evolutionary model that involves gene duplication and recombination, followed by functional divergence of scr74 genes. This study provides support for using diversifying selection as a criterion for identifying candidate effector genes from sequence databases.

Algal Proteins↗
PubMed2004

ETR-3 and CELF4 protein domains required for RNA binding and splicing activity in vivo.

Members of the CUG-BP and ETR-3 like factor (CELF) protein family bind within conserved intronic elements (called MSEs) flanking the cardiac troponin T (cTNT) alternative exon 5 and promote exon inclusion in vivo and in vitro. Here we use a comparative deletion analysis of two family members (ETR-3 and CELF4) to identify separate domains required for RNA binding and splicing activity in vivo. CELF proteins contain two adjacent RNA binding domains (RRM1 and RRM2) near the N-terminus and one RRM (RRM3) near the C-terminus, which are separated by a 160-230 residue divergent domain of unknown function. Either RRM1 or RRM2 of CELF4 are necessary and sufficient for binding MSE RNA and RRM2 plus an additional 66 amino acids of the divergent domain are as effective as full-length protein in activating MSE-dependent splicing in vivo. Non-overlapping N- and C-terminal regions of ETR-3 containing either RRM1 and RRM2 or RRM3 plus segments of the adjacent divergent domain activate MSE-dependent exon inclusion demonstrating an unusual functional redundancy of the N- and C-termini of the protein. These results identify specific regions of ETR-3 and CELF4 that are likely targets of protein-protein interactions required for splicing activation.

Animals↗
PubMed1996

Functional conservation of yeast mtTFB despite extensive sequence divergence.

Transcription of mtDNA in the yeast S. cerevisiae depends on recognition of a consensus nonanucleotide promoter sequence by mtRNA polymerase acting with a 40-kDa dissociable factor known as mtTFB or Mtflp. mtTFB has been cloned and characterized in S. cerevisiae, but has not been studied in similar detail in any other organism. Although it is known that mitochondrial transcription in the dairy yeast, Kluyveromyces lactis, initiates within the same consensus promoter sequence used in S. cerevisiae, no previous studies have focused on the proteins involved in transcription initiation in K. lactis. In this article, we report the cloning of mtTFB from K. lactis and from a yeast more closely related to S. cerevisiae, S. kluyveri. Both novel mtTFB genes were able to substitute for the MTF1 gene in S. cerevisiae. Both proteins purified following expression in E. coli were able to support specific transcription initiation in vitro with the S. cerevisiae mtRNA polymerase. The S. kluyveri and K. lactis mtTFB proteins share only 56% and 40% identity with S. cerevisiae mtTFB, respectively. Alignments of the three mtTFB sequences did not reveal any regions larger than 30 amino acids with greater than 60% amino acid identity. In particular, regions proposed to show sequence similarity to bacterial sigma factors were not more highly conserved than other regions of the mtTFB proteins. All three yeast mtTFB genes lack conventional amino-terminal mitochondrial targeting sequences, suggesting that all three proteins may be imported into mitochondria by the same unusual mechanism reported for S. cerevisiae mtTFB.

Amino Acid Sequence↗
PubMed2006

TESOTf-induced rearrangement of quinols. Efficient construction of the fully functionalized carbon skeleton of the griseusins by a divergent-reconvergent approach.

[reaction: see text] The "reverse polarity" or "umpolung" strategy for the total synthesis of aryl C-glycosides was developed in the context of the antibiotic (-)-griseusin B. Although a key reaction in a model sequence for the total synthesis produced two structurally divergent products, both were converted to the same advanced model intermediate that contains the complete carbon skeleton and (except for the extraneous oxygen substituent in the model series) the functional group pattern of the griseusins.

Glycosides↗
PubMed2005

Functionally layered dendrimers: a new building block and its application to the synthesis of multichromophoric light-harvesting systems.

[reaction: see text] A divergent synthesis of internally functionalized dendrimers based on a modular functional monomer has been developed. This strategy was applied to the construction of a light-harvesting dendrimer containing one set of naphthopyranone dyes located at the interior and another set of coumarin chromophores located in the adjacent outer layer surrounding a porphyrin acceptor. Quantitative energy transfer from both donor pigments is observed, giving rise to exclusive emission from the porphyrin core over all excitation wavelengths.

Dendrimers↗
PubMed1998

Regulation of protein topology by trans-acting factors at the endoplasmic reticulum.

In mammalian cells, the Sec61 complex and translocating chain-associated membrane protein (TRAM) are necessary and sufficient to direct the biogenesis, in the appropriate topology, of all secretory and membrane proteins examined thus far. We demonstrate here that the proper translocation of the prion protein (PrP), a substrate that can be synthesized in more than one topologic form, requires additional factors. In the absence of these additional factors, PrP is synthesized exclusively in the transmembrane topology (termed the CtmPrP form) associated with the development of neurodegenerative disease. Thus, translocation accessory factors, acting on some but not other substrates, can function as molecular switches to redirect nascent proteins toward divergent topologic fates with different functional consequences.

Animals↗
PubMed1997

Mitochondrial DNA sequence divergence in weevils of the Pissodes strobi species complex (Coleoptera:Curculionidae).

Mitochondrial DNA sequence divergence is unusually high between several species of the Pissodes strobi complex, in contrast to low allozyme and morphological divergences, and the ability to hybridize in the laboratory. We sequenced an 810 bp segment in seven individuals, representing four species in the P. strobi complex and one outgroup species, P. affinis Randall. The 810 bp segment covered the 3' half of the cytochrome oxidase subunit I (COI) gene. We also sequenced one specimen of P. strobi (Peck) over a 2301 bp region of mtDNA, extending from the 5' end of COI to the 3' end of COII. Uncorrected sequence divergences were below 1.1% among three specimens of P. schwarzi Hopkins, and between P. terminalis Hopping and P. nemorensis Germar. All other interspecific combinations in the P. strobi complex showed divergences of 6.0-7.5%. The outgroup species, P. affinis, had an average divergence of 12.8% from members of the P. strobi group. As in most other insects, A + T content in Pissodes mtDNA was high; transition:transversion ratio was high among lineages exhibiting low divergences, but declined with increasing sequence divergence; and inferred amino acid sequence divergences were low. The degree of sequence divergence differs markedly across different functional regions of the COI gene. The high mtDNA divergences within the P. strobi complex calculated from direct sequencing support earlier reports based on restriction site surveys; however, cladograms based on mtDNA sequence differ from those based on earlier work.

Amino Acids↗
PubMed1991

Fibre divergence in the distal optic radiation: possible basis of functional plasticity in adult primate visual cortex.

The precision of retinotopy in primate visual cortex is commonly thought to result from highly ordered arrangement of fibres in the visual pathways. However, rigid point-to-point representation is hardly compatible with findings of a substantial reorganization of visual cortical maps after peripheral and central lesions. Such observations could be accounted for by divergence in the optic radiation. To explore the hypothesis of fibre divergence, we made small knife cuts in the distal optic radiation of macaca fascicularis. After subsequent axonal tracing by injecting WGA-HRP into lateral geniculate nucleus, we studied the course of distal fibres in white matter. The amount of divergence was assessed by measuring, relative to the prevailing fibre course, length and orientation of labelled fibres between lesion and entry into cortex. Lesion sizes between 1 mm to 3 mm did not result in any detectable diminution of terminal labelling in layer IVC of striate cortex. Individual labelled fibres were found to diverge symmetrically from both sides into the gap distal to the lesion. Divergence starts at a distance of about 3 mm before cortex. At the white matter boundary, less than 10% of all fibres still retain the original direction, with the remaining fibres taking any other orientation without preference. We estimate that this corresponds to a divergence of visual afferents encompassing about 6-10 mm of cortical distance, if intracortical arborization of terminal fibres is taken into account. Possible consequences for functional plasticity in the adult primate visual cortex are discussed.

Animals↗
PubMed2006

Born to bind: the BTB protein-protein interaction domain.

The BTB domain is a protein-protein interaction motif that is found throughout eukaryotes. It determines a unique tri-dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB-containing proteins are numerous and control cellular processes that range from actin dynamics to cell-cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the high variability of the BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB-containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein-protein interaction domain.

Amino Acid Sequence↗
PubMed1983

Timed effects of an oral adrenergic bronchodilator on pulmonary function and measurements of plasma and leukocyte cyclic AMP: divergence in duration of drug action and development of tolerance.

The time course of response to initiation and withdrawal of treatment with terbutaline (5 mg orally, three times daily) was examined in eight normal subjects and 14 asthmatic patients. The various indices of response, examined simultaneously, yielded divergent estimates of the duration of drug action and the development of tolerance during continuous treatment. Bronchodilator responses were observed after each dose of terbutaline, but within 8 hr after a dose, pulmonary functions were similar to those observed in the absence of treatment. There was a suggestion of moderate tolerance to the bronchodilator effects of medication in that areas under the curve for increments in pulmonary function after terbutaline were lower during treatment than after the initial doses of medication; but the variations in magnitude of pulmonary response on different study days did not achieve statistical significance. Measurements of plasma cyclic AMP concentration suggested a much longer duration of drug action, with elevated levels observed 24 hr after a treatment dose; there was a progressive decrease in the plasma cyclic AMP responses to medication during the course of treatment. Conversely, leukocyte cyclic AMP responses to adrenergic stimulation were suppressed within 4 hr after the first dose of medication; the suppression persisted throughout treatment and for 1 to 3 days thereafter. These observations indicated that duration of drug action and induction of tolerance vary in different organ systems.

Administration, Oral↗
PubMed1987

Alcohol and aldehyde dehydrogenases: structures of the human liver enzymes, functional properties and evolutionary aspects.

All three types of subunit of class I human alcohol dehydrogenase have been analyzed both at the protein and cDNA levels, and the structures of alpha, beta 1, beta 2, gamma 1, and gamma 2 subunits are known. The same applies to class II pi subunits. Extensive protein data are also available for class III chi subunits. In the class I human isozymes, amino acid exchanges occur at 35 positions in total, with 21-28 replacements between any pair of the alpha/beta/gamma chains. These values, compared with those from species differences between the corresponding human and horse enzymes, suggest that isozyme developments in the class I enzyme resulted from separate gene duplications after the divergence of the human and equine evolutionary lines. All subunits exhibit some unique properties, with slightly closer similarity between the human gamma and horse enzyme subunits and somewhat greater deviations towards the human alpha subunit. Differences are large also in segments close to the active site zinc ligands and other functionally important positions. Species differences are distributed roughly equally between the two types of domain in the subunit, whereas isozyme differences are considerably more common in the catalytic than in the coenzyme-binding domain. These facts illustrate a functional divergence among the isozymes but otherwise similar changes during evolution. Polymorphic forms of beta and gamma subunits are characterized by single replacements at one and two positions, respectively, explaining known deviating properties. Class II and class III subunits are considerably more divergent. Their homology with class I isozymes exhibits only 60-65% positional identity. Hence, they reflect further steps towards the development of new enzymes, with variations well above the horse/human species levels, in contrast to the class I forms. Again, functionally important residues are affected, and patterns resembling those previously established for the divergently related polyol dehydrogenases are encountered. The two isozymes of human aldehyde dehydrogenase also exhibit considerable differences, with only 68% structural identity. The results show an early divergence into isozymes before the man/horse species radiation. Cys-302 is a functionally important residue and is located in one of the regions with conserved hydrophobic properties. Other regions with large differences in hydropathic properties may explain the absence of cross-hybridizing isozyme forms of human liver aldehyde dehydrogenase.

Alcohol Dehydrogenase↗
PubMed1996

Evolution of the src-related protein tyrosine kinases.

A phylogenetic analysis of src-related protein tyrosine kinases (PTKs) showed that one group of these genes is quite ancient in the animals, its divergence predating the divergence of the diploblast and triploblast phyla. Three other major groupings of genes were found to predate the divergence of protostome and deuterostome phyla. Most known src-related PTKs of mammals were found to belong to five well-differentiated families: srcA, srcB, abl, csk, and tec. One srcA gene (fyn) has an alternatively spliced seventh exon which shows a different pattern of relationship from the remainder of the gene; this suggests that this exon may have been derived by a recombinational event with another gene, perhaps one related to fgr. The recently published claim that mammalian members of this family expressed in the nervous system evolve more slowly at nonsynonymous nucleotide sites than do those expressed in the immune system was not supported by an analysis of 13 pairs of human and mouse orthologues. Rather, T-cell-specific src-related PTKs were found to have higher rates of nonsynonymous substitution than were those having broader expression. This effect was particularly marked in the peptide binding site of the SH2 domain. While the SH2 binding site was highly conserved among paralogous mammalian members of the srcA and srcB subfamilies, no such effect was seen in the comparison of paralogous members of the csk and tec subfamilies. This suggests that, while the peptide binding function of SH2 is conserved within both srcA and srcB subfamilies, paralogous members of the csk and tec subfamilies have diverged functionally with respect to peptide recognition by SH2.

Alternative Splicing↗