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Results for “regulatory evolution”

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PubMed2002

mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.

mTOR/RAFT1/FRAP is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. We report that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway. Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression. The association of raptor with mTOR also negatively regulates the mTOR kinase activity. Conditions that repress the pathway, such as nutrient deprivation and mitochondrial uncoupling, stabilize the mTOR-raptor association and inhibit mTOR kinase activity. We propose that raptor is a missing component of the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Sex and the single worm: sex determination in the nematode C. elegans.

The study of sex determination in model organisms has been especially fruitful in increasing our understanding of developmental biology, gene regulation and evolutionary mechanisms. The free living nematode, Caenorhabditis elegans, can develop as one of two sexes; male or self-fertilizing hermaphrodite. Here we discuss the progress toward a genetic and molecular understanding of that decision. Numerous genetic loci have been identified that affect sexual fate, and epistasis analysis of these genes has led to a model of a regulatory hierarchy with stepwise negative interactions. It is becoming evident that many of the genes have numerous levels of regulation. We also discuss the apparent rapid rate of evolution that many of the sex determination proteins have undergone. Protein sequences of homologues from closely related species are more divergent than homologues of proteins involved in other developmental processes. Rapid evolution of sex determination genes may be a common theme throughout the animal kingdom.

Animals↗
PubMed1994

Redundant genes?

Explore the source record for details and available documents.

Alleles↗
PubMed1998

The extended protein kinase C superfamily.

Members of the mammalian protein kinase C (PKC) superfamily play key regulatory roles in a multitude of cellular processes, ranging from control of fundamental cell autonomous activities, such as proliferation, to more organismal functions, such as memory. However, understanding of mammalian PKC signalling systems is complicated by the large number of family members. Significant progress has been made through studies based on comparative analysis, which have defined a number of regulatory elements in PKCs which confer specific location and activation signals to each isotype. Further studies on simple organisms have shown that PKC signalling paradigms are conserved through evolution from yeast to humans, underscoring the importance of this family in cellular signalling and giving novel insights into PKC function in complex mammalian systems.

Amino Acid Sequence↗
PubMed2003

A bacterial conjugation machinery recruited for pathogenesis.

Type IV secretion systems (T4SS) are multicomponent transporters of Gram-negative bacteria adapted to functions as diverse as DNA transfer in bacterial conjugation or the delivery of effector proteins into eukaryotic target cells in pathogenesis. The generally modest sequence conservation between T4SS may reflect their evolutionary distance and/or functional divergence. Here, we show that the establishment of intraerythrocytic parasitism by Bartonella tribocorum requires a putative T4SS, which shares an unprecedented level of sequence identity with the Trw conjugation machinery of the broad-host-range antibiotic resistance plasmid R388 (up to 80% amino acid identity for individual T4SS components). The highly conserved T4SS loci are collinear except for the presence of numerous tandem gene duplications in B. tribocorum, which mostly encode variant forms of presumed surface-exposed pilus subunits. Conservation is not only structural, but also functional: R388 mutated in either trwD or trwH encoding essential T4SS components could be trans-complemented for conjugation by the homologues of the B. tribocorum system. Conservation also includes the transcription regulatory circuit: both T4SS loci encode a highly homologous and interchangeable KorA/KorB repressor system that negatively regulates the expression of all T4SS components. This striking example of adaptive evolution reveals the capacity of T4SS to assume dedicated functions in either DNA transfer or pathogenesis over rather short evolutionary distance and implies a novel role for the conjugation systems of widespread broad-host-range plasmids in the evolution of bacterial pathogens.

Bartonella↗
PubMed2002

Inferring the phylogeny of disjunct populations of the azure-winged magpie Cyanopica cyanus from mitochondrial control region sequences.

The azure-winged magpie (AWM), Cyanopica cyanus, is found in Asia and Iberia. This remarkable disjunct distribution has been variously explained by either the sixteenth-century introduction of birds into Iberia from the Far East, or by the loss of individuals from the central part of their range as a result of Pleistocene glaciations. We have used the mitochondrial control region to undertake a molecular phylogenetic analysis of the AWM, with sequences examined from individuals collected from across the current distribution range and incorporating representatives of all currently defined subspecies. The Western birds are genetically distinct from their Asian congeners and their divergence is basal in the phylogenetic tree. This indicates that the AWM is native to Iberia and not the result of a recent introduction from Asia. In Asia, two major mitochondrial DNA lineages were identified. These correspond to an Inland Asia group and a Pacific Seaboard group, and are separated topographically by the Da Hingan Ling mountains and the Yellow Sea. Molecular clock estimates suggest that these divergences are associated with Pleistocene glaciations. Furthermore, our data do not support the current classification of the AWM into 10 subspecies, as defined based on morphology and geographical distribution.

Animals↗
PubMed2006

Origins and impact of constraints in evolution of gene families.

Recent investigations of high-throughput genomic and phenomic data have uncovered a variety of significant but relatively weak correlations between a gene's functional and evolutionary characteristics. In particular, essential genes and genes with paralogs have a slight propensity to evolve more slowly than nonessential genes and singletons, respectively. However, given the weakness and multiplicity of these associations, their biological relevance remains uncertain. Here, we show that existence of an essential paralog can be used as a specific and strong gauge of selection. We partition gene families in several genomes into two classes: those that include at least one essential gene (E-families) and those without essential genes (N-families). We find that weaker purifying selection causes N-families to evolve in a more dynamic regime with higher rates both of duplicate fixation and pseudogenization. Because genes in E-families are subject to significantly stronger purifying selection than those in N-families, they survive longer and exhibit greater sequence divergence. Longer average survival time also allows for divergence of upstream regulatory regions, resulting in change of transcriptional context among paralogs in E-families. These findings are compatible with differential division of ancestral functions (subfunctionalization) or emergence of novel functions (neofunctionalization) being the prevalent modes of evolution of paralogs in E-families as opposed to pseudogenization (nonfunctionalization), which is the typical fate of paralogs in N-families. Unlike other characteristics of genes, such as essentiality, existence of paralogs, or expression level, membership in an E-family or an N-family strongly correlates with the level of selection and appears to be a major determinant of a gene's evolutionary fate.

Animals↗
PubMed1995

Participation of the human beta-globin locus control region in initiation of DNA replication.

The human beta-globin locus control region (LCR) controls the transcription, chromatin structure, and replication timing of the entire locus. DNA replication was found to initiate in a transcription-independent manner within a region located 50 kilobases downstream of the LCR in human, mouse, and chicken cells containing the entire human beta-globin locus. However, DNA replication did not initiate within a deletion mutant locus lacking the sequences that encompass the LCR. This mutant locus replicated in the 3' to 5' direction. Thus, interactions between distantly separated sequences can be required for replication initiation, and factors mediating this interaction appear to be conserved in evolution.

Animals↗
PubMed1986

Complete nucleotide sequence and transcription of ermF, a macrolide-lincosamide-streptogramin B resistance determinant from Bacteroides fragilis.

DNA sequence analysis of a portion of an EcoRI fragment of the Bacteroides fragilis R plasmid pBF4 has allowed us to identify the macrolide-lincosamide-streptogramin B resistance (MLSr) gene, ermF. ermF had a relative moles percent G + C of 32, was 798 base pairs in length, and encoded a protein of approximately 30,360 daltons. Comparison between the deduced amino acid sequence of ermF and six other erm genes from gram-positive bacteria revealed striking homologies among all of these determinants, suggesting a common origin. Based on these and other data, we believe that ermF codes for an rRNA methylase. Analysis of the nucleotide sequences upstream and downstream from the ermF gene revealed the presence of directly repeated sequences, now identified as two copies of the insertion element IS4351. One of these insertion elements was only 26 base pairs from the start codon of ermF and contained the transcriptional start signal for this gene as judged by S1 nuclease mapping experiments. Additional sequence analysis of the 26 base pairs separating ermF and IS4351 disclosed strong similarities between this region and the upstream regulatory control sequences of ermC and ermA (determinants of staphylococcal origin). These results suggested that ermF was not of Bacteroides origin and are discussed in terms of the evolution of ermF and the expression of drug resistance in heterologous hosts.

Amino Acid Sequence↗
PubMed1992

The cDNA of UL15, a highly conserved herpes simplex virus 1 gene, effectively replaces the two exons of the wild-type virus.

The UL15 gene of herpes simplex virus 1 (HSV-1) is encoded by two or more exons in all herpesvirus genomes sequenced to date. The UL15 coding region is highly conserved, and the intron invariably encodes other genes transcribed antisense to the UL15 coding region. Previously we reported that we deleted the intron domain encoding UL16 but were unable to delete UL15 (J. D. Baines and B. Roizman, J. Virol. 65:938-944, 1991). Here we report that we replaced exon I of UL15 with an unspliced cDNA copy of UL15 in HSV-1 DNA and deleted 58% of the carboxyl-terminal sequences of the natural copy of exon II, including the polyadenylation signal. The yields of infectious virus obtained upon infection with viruses containing the cDNA copy of UL15 were similar to those of an isogenic virus with a wild-type UL15 gene. We therefore conclude that the separation of the two exons of UL15 by an intron encoding two genes is not essential for the replication of HSV, at least in cell culture.

Base Sequence↗
PubMedDate not supplied

The evidence for G-protein-coupled receptors and heterotrimeric G proteins in protozoa and ancestral metazoa.

In higher eukaryotes G-protein-coupled signal transduction pathways are a common mechanism used to detect an extracellular message and transmit a signal, via a membrane-bound receptor and a heterotrimeric G protein, to second messenger producing enzymes and effector proteins. The techniques used to identify components of these pathways are increasingly being applied to protozoa and ancestral metazoa. Many of the organisms studied do seem to express functional homologues of those found in higher eukaryotes and increasingly genes encoding these proteins are being cloned. Sequence analysis of the isolated alpha-subunits of heterotrimeric G proteins shows that these proteins have extensive homology to their mammalian counterparts, and often show absolute sequence identity in functionally significant regions. The receptor clones isolated clearly establish that protozoa and early metazoa express proteins with seven transmembrane spanning domains. Comparisons with mammalian receptors indicate that these proteins are likely to be regulated by phosphorylation and dephosphorylation events, although the pathways which control these are yet to be identified. The postulated regulatory mechanisms and the number of homologous clones isolated from some protozoa suggest that a highly regulated system of transmembrane signalling appeared at a relatively early stage in evolution.

Animals↗
PubMed1994

Specific binding of 12-O-tetradecanoylphorbol-13-acetate to histone H1.

12-O-Tetradecanoylphorbol-13-acetate (TPA) binds specifically to histone H1 prepared from HeLa cells and to calf histone H1 with dissociation constants of 4.3 x 10(-7) and 9.3 x 10(-7) M, respectively. The TPA-binding to histone H1 was confirmed immunologically using a monoclonal antibody directed against an evolutionally conserved epitope of histone H1. This binding would influence DNA structure and the basal level of transcription, and may, in turn, account for the cell growth-regulatory activity of TPA.

Amino Acid Sequence↗
PubMed2026

Outbreaks of fluconazole-resistant Candida parapsilosis are driven by low-biofilm-producing isolates that emerge under host selection.

Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by fluconazole-resistant (FLCR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbial traits enabling persistence of these outbreak lineages remain poorly defined. Here, we show that FLCR-Cp isolates responsible for prolonged, multi-country outbreaks consistently exhibit a striking low-biofilm-producing (LBP) phenotype. Contrary to the prevailing view that robust biofilm formation promotes persistence, LBP strains displayed enhanced stress tolerance, increased cell wall masking, and reduced immune recognition. These traits conferred resistance to neutrophil and macrophage killing and enhanced survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains. Whole-genome sequencing (WGS) of a global isolate collection further demonstrated that the LBP phenotype has emerged independently multiple times, supporting convergent evolution under host selection. Functional genomic analyses suggest that biofilm attenuation arises through multigenic changes, and disruption of key biofilm-associated transcriptional regulators enhanced fitness during immune interactions. Together, our findings overturn the assumption that robust biofilm formation drives outbreak persistence and instead identify biofilm attenuation as an adaptive tradeoff that promotes immune evasion and long-term survival. These results redefine our understanding of C. parapsilosis adaptation during healthcare-associated outbreaks and shift attention toward host-driven evolutionary processes than environmental persistence alone.

Biofilms↗
PubMed2005

Natural antisense RNAs in the nervous system.

Natural antisense RNAs are endogenous molecules that are complementary to RNA transcripts of already established function. They were discovered first in prokaryotes in which they are now recognised as an important component of molecular mechanisms involved in the regulation of gene expression. Recently, through the cumulative efforts of molecular biologists and bioinformaticians, natural antisense RNAs have been demonstrated in significant numbers in eukaryotic systems also. Probably the most exciting outcome of these studies is that natural antisense RNAs are particularly prevalent in the nervous system. Here we discuss the major known types of natural antisense RNAs in eukaryotic systems and focus on their potential roles in the regulation of gene expression in the brain.

Animals↗
PubMed2002

Molecular phylogeography of the red deer (Cervus elaphus) populations in Xinjiang of China: comparison with other Asian, European, and North American populations.

To illustrate phylogeography of red deer (Cervus elaphus) populations of Xinjiang, we determined their mitochondrial DNA (mtDNA) control region sequences, and then investigated geographic variations and phylogenetic relationships between Xinjiang populations and other populations from Asia, Europe, and North America. The C. elaphus mtDNA control region shared different copy numbers of tandem repeats of 38 to 43-bp motifs which clearly distinguished the Western lineage from the Eastern lineage of this species in Eurasia. The western lineage comprised the Tarim populations from southern Xinjiang and the European populations, all of which had four copies of the motifs. By contrast, the Eastern lineage consisted of populations from northern Xinjiang (Tianshan and Altai Mountains), other Asian areas (Alashan, Gansu, Tibet, Mongolia, and northeastern China), and North America, all of which shared six copies of the motifs. MtDNA phylogenetic trees showed that there are two major clusters of haplotypes which referred to the Western and Eastern lineages, and that subgroupings of haplotypes in each cluster were congruent with their geographic distributions. The present study revealed that a boundary separating the Western lineage from the Eastern lineage occurs between Tarim Basin and Tianshan Mountains in Xinjiang. Meanwhile, North American populations were genetically closer to those of northern Xinjiang, northeastern China, and Mongolia, supporting that C. elaphus immigrated from northeastern Eurasia to North America through the glacier-induced land-bridge (Beringia) which had formed between the two continents after Late Pleistocene.

Animals↗
PubMed2004

Homologs of CD83 from elasmobranch and teleost fish.

Dendritic cells are one of the most important cell types connecting innate and adaptive immunity, but very little is known about their evolutionary origins. To begin to study dendritic cells from lower vertebrates, we isolated and characterized CD83 from the nurse shark (Ginglymostoma cirratum (Gici)) and rainbow trout (Oncorhynchus mykiss (Onmy)). The open reading frames for Gici-CD83 (194 aa) and Onmy-CD83 (218 aa) display approximately 28-32% identity to mammalian CD83 with the presence of two conserved N-linked glycosylation sites. Identical with mammalian CD83 genes, Gici-CD83 is composed of five exons including conservation of phase for the splice sites. Mammalian CD83 genes contain a split Ig superfamily V domain that represents a unique sequence feature for CD83 genes, a feature conserved in both Gici- and Onmy-CD83. Gici-CD83 and Onmy-CD83 are not linked to the MHC, an attribute shared with mouse but not human CD83. Gici-CD83 is expressed rather ubiquitously with highest levels in the epigonal tissue, a primary site for lymphopoiesis in the nurse shark, whereas Onmy-CD83 mRNA expression largely paralleled that of MHC class II but at lower levels. Finally, Onmy-CD83 gene expression is up-regulated in virus-infected trout, and the promoter is responsive to trout IFN regulatory factor-1. These results suggest that the role of CD83, an adhesion molecule for cell-mediated immunity, has been conserved over 450 million years of vertebrate evolution.

Amino Acid Sequence↗
PubMed2005

The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function.

Atg6/Beclin 1 is an evolutionarily conserved protein family that has been shown to function in vacuolar protein sorting (VPS) in yeast; in autophagy in yeast, Drosophila, Dictyostelium, C.elegans, and mammals; and in tumor suppression in mice. Atg6/Beclin 1 is thought to function as a VPS and autophagy protein as part of a complex with Class III phosphatidylinositol 3'-kinase (PI3K)/Vps34. However, nothing is known about which domains of Atg6/Beclin 1 are required for its functional activity and binding to Vps34. We hypothesized that the most highly conserved region of human Beclin 1 spanning from amino acids 244-337 is essential for Vps34 binding, autophagy, and tumor suppressor function. To investigate this hypothesis, we evaluated the effects of wild-type and mutant beclin 1 gene transfer in autophagy-deficient MCF7 human breast carcinoma cells. We found that, unlike wild-type Beclin 1, a Beclin 1 mutant lacking aa 244-337 (Beclin 1DeltaECD), is unable to enhance starvation-induced autophagy in low Beclin 1-expressing MCF7 human breast carcinoma cells. In contrast to wild-type Beclin 1, mutant Beclin 1DeltaECD is unable to immunoprecipitate Vps34, has no Beclin 1-associated Vps34 kinase activity, and lacks tumor suppressor function in an MCF7 scid mouse xenograft tumor model. The maturation of cathepsin D, which requires intact Vps34-dependent VPS function, is comparable in autophagy-deficient low-Beclin 1 expressing MCF7 cells, autophagy-deficient MCF7 cells transfected with Beclin 1DeltaECD, and autophagy-competent MCF7 cells transfected with wild-type Beclin 1. These findings identify an evolutionarily conserved domain of Beclin 1 that is essential for Vps34 interaction, autophagy function, and tumor suppressor function. Furthermore, they suggest a connection between Beclin 1-associated Class III PI3K/Vps34-dependent autophagy, but not VPS, function and the mechanism of Beclin 1 tumor suppressor action in human breast cancer cells.

Amino Acid Sequence↗