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Results for “regulatory evolution”

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PubMed2003

Regulatory roles of conserved intergenic domains in vertebrate Dlx bigene clusters.

Dlx homeobox genes of vertebrates are generally arranged as three bigene clusters on distinct chromosomes. The Dlx1/Dlx2, Dlx5/Dlx6, and Dlx3/Dlx7 clusters likely originate from duplications of an ancestral Dlx gene pair. Overlaps in expression are often observed between genes from the different clusters. To determine if the overlaps are a result of the conservation of enhancer sequences between paralogous clusters, we compared the Dlx1/2 and the Dlx5/Dlx6 intergenic regions from human, mouse, zebrafish, and from two pufferfish, Spheroides nephelus and Takifugu rubripes. Conservation between all five vertebrates is limited to four sequences, two in Dlx1/Dlx2 and two in Dlx5/Dlx6. These noncoding sequences are >75% identical over a few hundred base pairs, even in distant vertebrates. However, when compared to each other, the four intergenic sequences show a much more limited similarity. Each intergenic sequence acts as an enhancer when tested in transgenic animals. Three of them are active in the forebrain with overlapping patterns despite their limited sequence similarity. The lack of sequence similarity between paralogous intergenic regions and the high degree of sequence conservation of orthologous enhancers suggest a rapid divergence of Dlx intergenic regions early in chordate/vertebrate evolution followed by fixation of cis-acting regulatory elements.

Animals↗

PubMed2025

Analysis of Duplication and Potential Functional Divergence of Wing Gene Network Components in Pea Aphids.

A fundamental focus of evolutionary developmental biology is uncovering the genetic mechanisms responsible for the gain and loss of characters. One approach to this question is to investigate changes in the coordinated expression of a group of genes important for the development of a character of interest (a gene regulatory network). Here we consider the possibility that modifications to the wing gene regulatory network (wGRN), as defined by work primarily done in Drosophila melanogaster, were involved in the evolution of wing dimorphisms of the pea aphid (Acyrthosiphon pisum). We hypothesize that this may have occurred via changes in expression levels or by duplication followed by divergence of wGRN components. To test this, we annotated members of the wGRN in the pea aphid genome and assessed their expression levels in first and third nymphal instars of winged and wingless morphs of males and asexual females. We find that only 2 of the 32 assessed genes exhibit morph-biased expression. We also find that three wing genes (apterous (ap), warts (wts), and decapentaplegic (dpp)) have undergone gene duplication. In each case, the resulting paralogs show signs consistent with functional divergence, exhibiting either sex-, morph-, or stage-specific expression. Two gene duplicates, wts2 and dpp3, are of particular interest with respect to wing dimorphism, as they exhibit male morph-specific isoforms and wingless male-biased expression, respectively. These gene expression results provide an important first step toward identifying members of the pea aphid wGRN that may play a causative role in differentiating winged from wingless morphs. These findings supplement our understanding of trends in developmental gene network evolution, such as side-stepping pleiotropic constraint via duplication and sub-functionalization, underlying the emergence of novel phenotypes.

Animals↗

PubMed1992

Conservation and evolution of transcriptional mechanisms in eukaryotes.

Eukaryotic transcriptional activators play key roles in controlling cell growth and specifying embryonic development. These activators can stimulate promoters from distances up to tens of kilobases by a mechanism that is remarkably conserved in eukaryotes ranging from yeast to humans. Although the primary sequence of certain activators has also been conserved in widely divergent organisms, the regulatory roles that these factors play have been altered over evolution to fit the specific needs of the host.

Amino Acid Sequence↗

PubMed2000

Conservation and elaboration of Hox gene regulation during evolution of the vertebrate head.

The comparison of Hox genes between vertebrates and their closest invertebrate relatives (amphioxus and ascidia) highlights two derived features of Hox genes in vertebrates: duplication of the Hox gene cluster, and an elaboration of Hox expression patterns and roles compared with non-vertebrate chordates. We have investigated how new expression domains and their associated developmental functions evolved, by testing the cis-regulatory activity of genomic DNA fragments from the cephalochordate amphioxus Hox cluster in transgenic mouse and chick embryos. Here we present evidence for the conservation of cis-regulatory mechanisms controlling gene expression in the neural tube for half a billion years of evolution, including a dependence on retinoic acid signalling. We also identify amphioxus Hox gene regulatory elements that drive spatially localized expression in vertebrate neural crest cells, in derivatives of neurogenic placodes and in branchial arches, despite the fact that cephalochordates lack both neural crest and neurogenic placodes. This implies an elaboration of cis-regulatory elements in the Hox gene cluster of vertebrate ancestors during the evolution of craniofacial patterning.

Animals↗

PubMed2006

The active evolutionary lives of echinoderm larvae.

Echinoderms represent a researchable subset of a dynamic larval evolutionary cosmos. Evolution of echinoderm larvae has taken place over widely varying time scales from the origins of larvae of living classes in the early Palaeozoic, approximately 500 million years ago, to recent, rapid and large-scale changes that have occurred within living genera within a span of less than a million years to a few million years. It is these recent evolutionary events that offer a window into processes of larval evolution operating at a micro-evolutionary level of evolution of discrete developmental mechanisms. We review the evolution of the diverse larval forms of living echinoderms to outline the origins of echinoderm larval forms, their diversity among living echinoderms, molecular clocks and rates of larval evolution, and finally current studies on the roles of developmental regulatory mechanisms in the rapid and radical evolutionary changes observed between closely related congeneric species.

Animals↗

PubMed2026

Flexible use of conserved motifs constrains genome access in cell type evolution.

Cell types can be organized into related families, but the regulatory mechanisms that define and maintain these families across deep evolutionary time remain unknown. Here, combining single-nucleus multi-omic sequencing with deep learning to analyse the accessible genomes of two groups of vastly divergent animals including flatworms and vertebrates, we find that hundreds of accessibility-dictating sequence motifs partition into distinct yet conserved sets, or 'vocabularies', each associated with a specific cell type family. However, combinatorial relationships among these motifs preferred by individual cell types are largely species specific. Deep-learning models trained on one species accurately predict family-level chromatin accessibility in distantly related species, albeit frequently rely on different motifs from shared vocabularies to reach convergent predictions. By contrast, models trained on individual cell types within a family lose cross-species predictive power, indicating that the regulatory syntax governing cell type-level identity evolves rapidly. We propose a 'collective maintenance' model in which motif vocabularies defining cell type families are evolutionarily stable, while recombination of these motifs generates cell type-specific regulatory programmes. This suggests that family identity is maintained collectively by large, conserved pools of regulatory factors, analogous to the logic of developmental homology, where character identity persists through network-level conservation despite extensive rewiring.

Journal Article↗

PubMed1998

Association of developmental regulatory genes with the development of different molar tooth shapes in two species of rodents.

While the evolutionary history of mammalian tooth shapes is well documented in the fossil record, the developmental basis of their tooth shape evolution is unknown. We investigated the expression patterns of eight developmental regulatory genes in two species of rodents with different molar morphologies (mouse, Mus musculus and sibling vole, Microtus rossiaemeridionalis). The genes Bmp-2, Bmp-4, Fgf-4 and Shh encode signal molecules, Lef-1, Msx-1 and Msx-2, are transcription factors and p21CIP1/WAF1 participates in the regulation of cell cycle. These genes are all known to be associated with developmental regulation in mouse molars. In this paper we show that the antisense mRNA probes made from mouse cDNA cross-hybridized with vole tissue. The comparisons of gene expression patterns and morphologies suggest that similar molecular cascades are used in the early budding of tooth germs, in the initiation of tooth crown base formation, and in the initiation of each cusp's development. Furthermore, the co-localization of several genes indicate that epithelial signalling centres function at the three stages of morphogenesis. The earliest signalling centre in the early budding epithelium has not been reported before, but the latter signalling centres, the primary and the secondary enamel knots, have been studied in mouse. The appearance of species-specific tooth shapes was manifested by the regulatory molecules expressed in the secondary enamel knots at the areas of future cusp tips, whilst the mesenchymal gene expression patterns had a buccal bias without similar species-specific associations.

Animals↗

PubMed2000

Iron-sulfur proteins: ancient structures, still full of surprises.

This article is a survey of the properties and functions of Fe-S proteins under the following headings: sulfur and iron; iron-sulfur clusters; evolution of cofactor use; early observations; complex and extended clusters; sulfur exchange and core interconversions; synthesis and biosynthesis of Fe-S clusters; functions of Fe-S clusters: electron transfer, electron delocalization, spin states and magnetism, covalency of sulfur bonds; non-electron transfer functions of Fe-S clusters: substrate binding and catalysis, regulatory and sensing functions.

Evolution, Molecular↗

PubMed2006

Optimization of the Tet-On system for regulated gene expression through viral evolution.

The ability to control (trans)gene expression is important both for basic biological research and applications such as gene therapy. In vivo use of the inducible tetracycline (Tc)-regulated gene expression system (Tet-On system) is limited by its low sensitivity for the effector doxycycline (dox). We used viral evolution to optimize this Escherichia coli-derived regulatory system for its function in mammalian cells. The components of the Tet-On system (the transcriptional activator rtTA and its tetO DNA binding site) were incorporated into the human immunodeficiency virus (HIV)-1 genome to control viral replication. Prolonged culturing of this HIV-rtTA virus resulted in virus variants that acquired mutations in the rtTA gene. Some of these mutations enhance the transcriptional activity and dox-sensitivity of the rtTA protein. This improvement was observed with different tetO-containing promoters and was independent of the episomal or chromosomal status of the target gene. Combination of these beneficial mutations resulted in greatly improved rtTA variants that are seven-fold more active and 100-fold more dox-sensitive than the original Tet-On system. Furthermore, some of the new Tet-On systems are responsive to Tc and minocycline. Importantly, these rtTA variants show no activity in the absence of dox. The optimized rtTA variants are particularly useful for in vivo applications that require a more sensitive or more active Tet-On system.

Anti-Bacterial Agents↗

PubMed2005

Patterns of evolution of genes disrupted in expression in Drosophila species hybrids.

Divergence between species in regulatory pathways may contribute to hybrid incompatibilities such as sterility. Consistent with this idea, genes involved in male fertility often evolve faster than most other genes both in amino acid sequence and in expression. Previously, we identified a panel of male-specific genes under-expressed in sterile male hybrids of Drosophila simulans and D. mauritiana relative to pure species, and we showed that this under-expression is associated with infertility. In a preliminary effort to assess the generalities in the patterns of evolution of these genes, I examined patterns of mRNA expression in three of these genes in sterile F 1 hybrid males of D. pseudoobscura and D. persimilis . F 1 hybrid males bearing D. persimilis X chromosomes under-expressed all these genes relative to the parental species, while hybrids bearing D. pseudoobscura X chromosomes under-expressed two of these three genes. Interestingly, the third gene, CG5762 , has undergone extensive amino acid evolution within the D. pseudoobscura species group, possibly driven by positive natural selection. We conclude that some of the same genes exhibit disruptions in expression within each of the two species groups, which could suggest commonalities in the regulatory architecture of sterility in these groups. Alternative explanations are also considered.

Animals↗

PubMed2000

Evolution of C4 phosphoenolpyruvate carboxylase in Flaveria, a conserved serine residue in the carboxyl-terminal part of the enzyme is a major determinant for C4-specific characteristics.

C4 phosphoenolpyruvate carboxylases have evolved from ancestral C3 isoforms during the evolution of angiosperms and gained distinct kinetic and regulatory properties compared with the C3 isozymes. To identify amino acid residues and/or domains responsible for these C4-specific properties the C4 phosphoenolpyruvate carboxylase of Flaveria trinervia (C4) was compared with its orthologue in the closely related C3 plant Flaveria pringlei. Reciprocal enzyme chimera were constructed and the kinetic constants, K(0.5) and k(cat), as well as the Hill coefficient, h, were determined for the substrate phosphoenolpyruvate both in the presence and absence of the activator glucose 6-phosphate. By this approach two regions were identified which determined most of the kinetic differences of the C4 and C3 ppcA phosphoenolpyruvate carboxylases with respect to the substrate PEP. In addition, the experiments suggest that the two regions do not act additively but interact with each other. The region between amino acids 296 and 437 is essential for activation by glucose 6-phosphate. The carboxyl-terminal segment between amino acids 645 and 966 contains a C4 conserved serine or a C3 invariant alanine at position 774 in the respective enzyme isoform. Site-directed mutagenesis shows that this position is a key determinant for the kinetic properties of the two isozymes.

Alanine↗

PubMed1998

A single base change altered the regulation of the Waxy gene at the posttranscriptional level during the domestication of rice.

The rice waxy (wx) locus has two functional alleles, Wxa and Wxb, which are defined by a large difference in the amount of the gene product, called Wx protein, that accumulates in mature seeds. To elucidate the molecular mechanism underlying this difference and to identify the base change causing the alteration of the regulation of the Wx gene during rice evolution, we determined the nucleotide sequences of the regulatory region of Wx alleles and analyzed their function in a transient assay system using rice protoplasts. All Wxa alleles from Oryza sativa Indica, O. rufipogon, and O. glaberrima have a normal sequence of GT at the 5' splice junction of the first intron, representing a high expression level of the Wx transcripts in the endosperm and a high beta-glucuronidase (GUS) activity in protoplasts. On the other hand, Wxb alleles from two strains of O. sativa Japonica have TT at the 5' splice junction, representing a low expression level of the mature transcripts and a low GUS activity. Northern blot analysis also indicated that a larger transcript, consisting of the unspliced first intron, is closely correlated with the function of the Wxb allele. These results suggest that a single base change at the 5' splice junction causes inefficient splicing and, as a result, reduces the level of mature transcript and the GUS activity in the Wxb allele. The Wxb allele in O. saativa Japonica may have been differentiated from the Wxa allele of O. rufipogon, its wild progenitor, by this mutation, and, therefore, a single base change that has altered the regulation of the Wx gene at the posttranscriptional level probably occurred during the domestication of rice.

Alleles↗

PubMed2005

Molecular evolution of FLORICAULA/LEAFY orthologs in the Andropogoneae (Poaceae).

Members of the grass family (Poaceae) exhibit a broad range of inflorescence structures and other morphologies, making the grasses an interesting model system for studying the evolution of development. Here we present an analysis of the molecular evolution of FLORICAULA/LEAFY-like genes, which are important developmental regulatory loci known to affect inflorescence development in a wide range of flowering plant species. We have focused on sequences from the Andropogoneae, a tribe within the grass family that includes maize (Zea mays ssp. mays) and Sorghum (Sorghum bicolor). The FLORICAULA/LEAFY gene phylogeny we generated largely agrees with previously published phylogenies for the Andropogoneae using other nuclear genes but is unique in that it includes both members of one of the many duplicate gene sets present in maize. The placement of these sequences in the phylogeny suggests that the duplication of the maize FLORICAULA/LEAFY orthologs, zfl1 and zfl2, is a consequence of a proposed tetraploidy event that occurred in the common ancestor of Zea and a closely related genus, Tripsacum. Our data are consistent with the hypothesis that the transcribed regions of the FLORICAULA/LEAFY-like genes in the Andropogoneae are functionally constrained at both nonsynonymous and synonymous sites and show no evidence of directional selection. We also examined conservation of short noncoding sequences in the first intron, which may play a role in gene regulation. Finally, we investigated the genetic diversity of one of the two maize FLORICAULA/LEAFY orthologs, zfl2, in maize and its wild ancestor, teosinte (Z. mays ssp. parviglumis), and found no evidence for selection pressure resulting from maize domestication within the zfl2-coding region.

Base Sequence↗

PubMed2000

Adaptive variation in lactate dehydrogenase-B gene expression: role of a stress-responsive regulatory element.

Although changes in gene regulation may play an important role in adaptive evolution, there have been few attempts to investigate the molecular mechanisms responsible for adaptively significant variation in gene expression. Here we describe the mechanism underlying an adaptive difference in the expression of the lactate dehydrogenase-B gene (Ldh-B) between northern and southern populations of the fish Fundulus heteroclitus. Ldh-B regulatory sequences from northern and southern individuals, coupled to a luciferase reporter gene, were introduced into the livers of live fish. Deletion studies indicated that sequence changes between 400 and 500 bp upstream of the transcription start site resulted in a 2-fold difference in reporter gene transcription. These sequence changes can account for the previously observed 2-fold difference in Ldh-B transcription between populations. Variation in transcription factors did not play an important role. Sequences within the functionally important region resemble a mammary tumor virus glucocorticoid responsive element (MTV-GRE) in southern alleles, whereas northern alleles differ from the consensus by 1 bp. To test the hypothesis that this element is involved in the variation between populations of F. heteroclitus, we exposed transiently transgenic fish containing Ldh-B regulatory sequence/reporter gene constructs to handling stress or injected cortisol. Both treatments increased reporter gene transcription driven by southern alleles but not northern alleles, as expected if an MTV-GRE sequence were involved. This finding suggests that sequence variation in a GRE is the cause of the adaptive differences in Ldh-B gene expression between populations and demonstrates that small changes in gene regulatory sequences can have important evolutionary consequences.

Adaptation, Physiological↗

PubMed1999

Molecular cloning of mouse glycolate oxidase. High evolutionary conservation and presence of an iron-responsive element-like sequence in the mRNA.

Iron regulatory proteins (IRPs) control the synthesis of several proteins in iron metabolism by binding to iron-responsive elements (IREs), a hairpin structure in the untranslated region (UTR) of corresponding mRNAs. Binding of IRPs to IREs in the 5' UTR inhibits translation of ferritin heavy and light chain, erythroid aminolevulinic acid synthase, mitochondrial aconitase, and Drosophila succinate dehydrogenase b, whereas IRP binding to IREs in the 3' UTR of transferrin receptor mRNA prolongs mRNA half-life. To identify new targets of IRPs, we devised a method to enrich IRE-containing mRNAs by using recombinant IRP-1 as an affinity matrix. A cDNA library established from enriched mRNA was screened by an RNA-protein band shift assay. This revealed a novel IRE-like sequence in the 3' UTR of a liver-specific mouse mRNA. The newly identified cDNA codes for a protein with high homology to plant glycolate oxidase (GOX). Recombinant protein expressed in bacteria displayed enzymatic GOX activity. Therefore, this cDNA represents the first vertebrate GOX homologue. The IRE-like sequence in mouse GOX exhibited strong binding to IRPs at room temperature. However, it differs from functional IREs by a mismatch in the middle of its upper stem and did not confer iron-dependent regulation in cells.

Alcohol Oxidoreductases↗

PubMed2003

Muscle-specific expression of myogenin in zebrafish embryos is controlled by multiple regulatory elements in the promoter.

Myogenin is a member of the basic Helix-Loop-Helix transcription factor family that play key roles in myoblast specification and differentiation. Myogenin is specifically expressed in developing somite and skeletal muscles in zebrafish embryos. To determine the regulation of myogenin expression, we reported here the characterization of zebrafish myogenin gene and analysis of its promoter activity in zebrafish embryos. Our data showed that a 0.8-kb myogenin promoter was sufficient to direct correct temporal and spatial muscle-specific green fluorescence protein expression in zebrafish embryos. Sequence analysis identified two putative E box sites in the myogenin gene promoter. In addition, a MEF2 recognition site and a MEF3 binding site were also found in the promoter. Mutation of the E boxes, MEF2 or MEF3 binding site individually had little effect on the muscle-specificity and activity of the myogenin promoter. However, mutating these sites in various combinations, e.g. E boxes and MEF2 binding site, or MEF2 and MEF3 sites significantly reduced the activity of the promoter. Moreover, mutating the E boxes, MEF2 and MEF3 sites together almost abolished the activity of the promoter. These data indicate that muscle-specific expression of myogenin in zebrafish embryos is controlled by multiple regulatory elements in the promoter. In addition, because these regulatory elements control myogenin expression in mouse and human embryos, these data suggest that the regulatory mechanism controlling myogenin expression might be conserved during evolution.

Animals↗

PubMed2004

Gene regulation by tetracyclines.

Gene regulation by tetracyclines has become a widely-used tool to study gene functions in pro- and eukaryotes. This regulatory system originates from Gram-negative bacteria, in which it fine-tunes expression of a tetracycline-specific export protein mediating resistance against this antibiotic. This review attempts to describe briefly the selective pressures governing the evolution of tetracycline regulation, which have led to the unique regulatory properties underlying its success in manifold applications. After discussing the basic mechanisms we will present the large variety of designed alterations of activities which have contributed to the still growing tool-box of components available for adjusting the regulatory properties to study gene functions in different organisms or tissues. Finally, we provide an overview of the various experimental setups available for pro- and eukaryotes, and touch upon some highlights discovered by the use of tetracycline-dependent gene regulation.

Allosteric Regulation↗

PubMed2005

Functional diversity in the gene network controlled by the master regulator p53 in humans.

Individual differences in susceptibility to exposure induced diseases are likely due to variation in the DNA sequences of "environmental response" genes, many of which are arranged in complex regulatory networks. Among approximately 10 million inherited DNA variations, called single nucleotide polymorphisms (SNPs), perhaps only a few thousand, will actually influence human disease risk. We have combined bioinformatics and laboratory approaches to investigate genetic variation within the p53 stress response network. p53, a prominent tumor suppressor protein, is a master regulator that targets over a hundred genes for transcriptional upregulation or repression through sequence-specific interactions with DNA response elements (REs). We identified many human genes in the network that contain SNPs in REs that can be transactivated by p53. The discovery of these individual differences has implications for variation in human responses to environmental stresses, risk of disease, and responsiveness to drug therapies. The findings also provide insight into the evolution of complex networks and the role of master regulatory genes, such as p53, in such networks.

Alleles↗