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At least 613 records · Page 34Linked to original sources
PubMed2006

A synthetic phage lambda regulatory circuit.

Analysis of synthetic gene regulatory circuits can provide insight into circuit behavior and evolution. An alternative approach is to modify a naturally occurring circuit, by using genetic methods to select functional circuits and evolve their properties. We have applied this approach to the circuitry of phage lambda. This phage grows lytically, forms stable lysogens, and can switch from this regulatory state to lytic growth. Genetic selections are available for each behavior. We previously replaced lambda Cro in the intact phage with a module including Lac repressor, whose function is tunable with small molecules, and several cis-acting sites. Here, we have in addition replaced lambda CI repressor with another tunable module, Tet repressor and several cis-acting sites. Tet repressor lacks several important properties of CI, including positive autoregulation and cooperative DNA binding. Using a combinatorial approach, we isolated phage variants with behavior similar to that of WT lambda. These variants grew lytically and formed stable lysogens. Lysogens underwent prophage induction upon addition of a ligand that weakens binding by the Tet repressor. Strikingly, however, addition of a ligand that weakens binding by Lac repressor also induced lysogens. This finding indicates that Lac repressor was present in the lysogens and was necessary for stable lysogeny. Therefore, these isolates had an altered wiring diagram from that of lambda. We speculate that this complexity is needed to compensate for the missing features. Our method is generally useful for making customized gene regulatory circuits whose activity is regulated by small molecules or protein cofactors.

Amino Acid Sequence↗
PubMed1992

Natural genetic engineering in evolution.

The results of molecular genetics have frequently been difficult to explain by conventional evolutionary theory. New findings about the genetic conservation of protein structure and function across very broad taxonomic boundaries, the mosaic structure of genomes and genetic loci, and the molecular mechanisms of genetic change all point to a view of evolution as involving the rearrangement of basic genetic motifs. A more detailed examination of how living cells restructure their genomes reveals a wide variety of sophisticated biochemical systems responsive to elaborate regulatory networks. In some cases, we know that cells are able to accomplish extensive genome reorganization within one or a few cell generations. The emergence of bacterial antibiotic resistance is a contemporary example of evolutionary change; molecular analysis of this phenomenon has shown that it occurs by the addition rearrangement of resistance determinants and genetic mobility systems rather than by gradual modification of pre-existing cellular genomes. In addition, bacteria and other organisms have intricate repair systems to prevent genetic change by sporadic physicochemical damage or errors of the replication machinery. In their ensemble, these results show that living cells have (and use) the biochemical apparatus to evolve by a genetic engineering process. Future research will reveal how well the regulatory systems integrate genomic change into basic life processes during evolution.

Animals↗
PubMed1997

Molecular evolution of the vertebrate troponin I gene family.

In the higher vertebrates troponin I (TnI) is encoded by three related genes, each of which is expressed specifically in one of the three major sarcomeric muscle cell classes, i.e. cardiomyocytes or fast or slow skeletal muscle fibers. The TnIcardiac isoform contains an "extra" block of proline-rich protein sequence near the N-terminus encoded by an exon that has no counterpart in the TnIfast and TnIslow genes. All three TnI isoforms appear to be orthologously related between birds and mammals, indicating that the TnI gene family was already established in its modern form in the early reptile common ancestor to birds and mammals. Analysis of ascidian TnI suggests that early vertebrate ancestors contained a single TnI gene and that the gene duplications that established the family occurred after the ascidian/vertebrate divergence. Evidence from organisms representing evolutionary intermediates between ascidians and reptiles is incomplete and does not yet delineate the exact order and timing of the TnI gene duplication events. However it does appear that early tetrapods already contained specialized TnI genes encoding long and short isoforms and that multiple differentially expressed TnI genes were present in the vertebrate lineage before the teleost/tetrapod divergence. Ascidians and the protostome invertebrate Drosophila produce long and short TnI isoforms (the longer isoforms containing a proline-rich block of extra sequence near the N-terminus) by an alternative RNA splicing mechanism from a single gene. It is likely that the alternative splicing mechanism is an ancestral feature, and that during vertebrate evolution this mechanism was abandoned in favor of transcriptional regulatory mechanisms directing tissue-specific expression of multiple genes separately encoding long and short TnI isoforms.

Amino Acid Sequence↗
PubMed2002

Arthropod Hox genes: insights on the evolutionary forces that shape gene functions.

Comparative studies suggest that gene duplication, changes in cis-regulatory elements and changes in protein sequence all contribute to the evolution of Hox gene functions, but the evolutionary dynamics of these changes are probably different. It seems likely that gene duplications arise as neutral changes and acquire an adaptive significance later on. By contrast, some changes in regulatory and protein-coding sequences can have immediate consequences in morphological evolution.

Animals↗
PubMed2006

Heterotachy in mammalian promoter evolution.

We have surveyed the evolutionary trends of mammalian promoters and upstream sequences, utilising large sets of experimentally supported transcription start sites (TSSs). With 30,969 well-defined TSSs from mouse and 26,341 from human, there are sufficient numbers to draw statistically meaningful conclusions and to consider differences between promoter types. Unlike previous smaller studies, we have considered the effects of insertions, deletions, and transposable elements as well as nucleotide substitutions. The rate of promoter evolution relative to that of control sequences has not been consistent between lineages nor within lineages over time. The most pronounced manifestation of this heterotachy is the increased rate of evolution in primate promoters. This increase is seen across different classes of mutation, including substitutions and micro-indel events. We investigated the relationship between promoter and coding sequence selective constraint and suggest that they are generally uncorrelated. This analysis also identified a small number of mouse promoters associated with the immune response that are under positive selection in rodents. We demonstrate significant differences in divergence between functional promoter categories and identify a category of promoters, not associated with conventional protein-coding genes, that has the highest rates of divergence across mammals. We find that evolutionary rates vary both on a fine scale within mammalian promoters and also between different functional classes of promoters. The discovery of heterotachy in promoter evolution, in particular the accelerated evolution of primate promoters, has important implications for our understanding of human evolution and for strategies to detect primate-specific regulatory elements.

Animals↗
PubMed2005

Chromosomal fragility, structural rearrangements and mobile element activity may reflect dynamic epigenetic mechanisms of importance in neurobehavioural genetics.

Advances in human genome analyses have not yet allowed identification of specific genetic mechanisms underlying the expression of human neurobehavioural disorders. There is an increasing awareness that several genes may contribute to behavioural phenotypes and these genes appear to interact in as yet undetermined ways. It has been suggested that the problem needs elucidation from an epigenetic, gene expression perspective. Cytogenetic instability manifesting as chromosomal fragile sites, translocations, duplications, deletions and inversions, when co-occurring with neurobehavioural disorders, may offer a doorway to the investigation of such chromatin level, regulatory region, epigenetic processes. Due to earlier indications of non-specificity of chromosomal aberrations, poor phenotype:genotype correlations and a shift to analysing candidate coding regions on high resolution map level, the only utility of chromosomal breakpoints came to be seen as harbouring possible candidate genes of interest when segregating together with particular neurobehavioural disorders. More recent findings of the expression of highly specific subsets of fragile sites in association with Tourette and Rett syndromes need to be extended to other neurobehavioural disorders to ascertain whether observed patterns can be considered representative of 'chromatin endophenotypes' correlating with discrete sets of neurobehavioural symptoms. Environmental/epigenetic factors could affect the chromatin characteristics of the genome arising through DNA strand breakage, mobile element activity and retroinsertion, establishing new architectural features of regulatory control networks very rapidly in comparison to coding region evolution rates. Microarray-based techniques for the genome-wide mapping of in vivo protein-DNA interactions offer increasingly comprehensive views of genetic and epigenetic regulatory networks. It may be informative to include functionally significant chromatin structural variation analyses when considering candidate genes for neurobehavioural disorders.

Cell Cycle↗
PubMed1991

Detection of homeobox genes in development and evolution.

The homeobox genes encode a family of DNA-binding regulatory proteins whose function and genomic organization make them an important model system for the study of development and differentiation. Oligonucleotide primers corresponding to highly conserved regions of Antennapediaclass homeodomains were designed to detect and identify homeobox sequences in populations of DNA or RNA by means of the polymerase chain reaction (PCR). Here we present a survey of sequences detected by PCR using an initial set of primers (HoxA and HoxB) based on an early nucleotide consensus for vertebrate Antennapedia-class homeodomains. Several novel sequences are reported from both mouse genomic DNA and RNA from the developing mouse telencephalon. Forebrain-derived clones are similar to the chicken CHox7, Drosophila H2.0, and mouse Hlx genes. PCR also proved to be a rapid method for identifying homeobox sequences from diverse metazoan species. Cloning of three Antennapedia-related sequences from cnidarians provides evidence of ancient roles for homeobox genes early in metazoan evolution.

Amino Acid Sequence↗
PubMed1999

Molecular domestication--more than a sporadic episode in evolution.

Transposable elements are short but complex pieces of DNA or RNA containing a streamlined minimal-genome with the capacity for its selfish replication in a foreign genomic environment. Cis-regulatory sections within the elements orchestrate tempo and mode of TE expression. Proteins encoded by TEs mainly direct their own propagation within the genome by recruitment of host-encoded factors. On the other hand, TE-encoded proteins harbor a very attractive repertoire of functional abilities for a cell. These proteins mediate excision, replication and integration of defined DNA fragments. Furthermore, some of these proteins are able to manipulate important host factors by altering their original function. Thus, if the host genome succeeds in domesticating such TE-encoded proteins by taming their 'anarchistic behavior,' such an event can be considered as an important evolutionary innovation for its own benefit. In fact, the domestication of TE-derived cis-regulatory modules and protein coding sections took place repeatedly in the course of genome evolution. We will present prominent cases that impressively demonstrate the beneficial impact of TEs on host biology over evolutionary time. Furthermore, we will propose that molecular domestication might be considered as a resumption of the same evolutionary process that drove the transition from 'primitive genomes' to 'modern' ones at the early dawn of life, that is, the adaptive integration of a short piece of autonomous DNA into a complex regulatory network.

Amino Acid Sequence↗
PubMed1998

Highly conserved RNA sequences that are sensors of environmental stress.

The putative function of highly conserved regions (HCRs) within 3' untranslated regions (3'UTRs) as regulatory RNA sequences was efficiently and quantitatively assessed by using modular retroviral vectors. This strategy led to the identification of HCRs that alter gene expression in response to oxidative or mitogenic stress. Databases were screened for UTR sequences of >100 nucleotides that had retained 70% identity over more than 300 million years of evolution. The effects of 10 such HCRs on a standard reporter mRNA or protein were studied. To this end, we developed a modular retroviral vector that can allow for a direct comparison of the effects of different HCRs on gene expression independent of their gene-intrinsic 5'UTR, promoter, protein coding region, or poly(A) sequence. Five of the HCRs tested decreased mRNA steady-state levels 2- to 10-fold relative to controls, presumably by altering mRNA stability. One HCR increased translation, and one decreased translation. Elevated mitogen levels caused four HCRs to increase protein levels twofold. One HCR increased protein levels fourfold in response to hypoxia. Although nonconserved UTR sequences may also have a role, these results provide evidence that sequences that are highly conserved during evolution are good candidates for RNA motifs with posttranscriptional regulatory functions in gene expression.

3' Untranslated Regions↗
PubMed2006

A WNT of things to come: evolution of Wnt signaling and polarity in cnidarians.

The conserved family of Wnt signaling molecules mediates various developmental processes including governing cell fate, proliferation, and polarity. The diverse developmental functions of the Wnt genes in bilaterians have obscured the evolutionary origin of this important signaling pathway. Recent work in the Cnidaria has shown the diversity of Wnt genes, and regulatory components of Wnt signaling, evolved early in metazoan evolution, prior to the divergence of cnidarians and bilaterians. Evidence from Hydra and the sea anemone, Nematostella, demonstrates a role for Wnt signaling in axis formation and patterning, as well as gastrulation and germ-layer specification. In this review, we examine what is currently known about Wnt signaling in cnidarians, and discuss what this group of "simple" animals may reveal about the evolution of Wnt signaling and polarity.

Animals↗
PubMed1996

Budding yeast SKP1 encodes an evolutionarily conserved kinetochore protein required for cell cycle progression.

The budding yeast SKP1 gene, identified as a dosage suppressor of a known kinetochore protein mutant, encodes an intrinsic 22.3 kDa subunit of CBF3, a multiprotein complex that binds centromere DNA in vitro. Temperature-sensitive mutations in SKP1 define two distinct phenotypic classes. skp1-4 mutants arrest predominantly as large budded cells with a G2 DNA content and short mitotic spindle, consistent with a role in kinetochore function. skp1-3 mutants, however, arrest predominantly as multiply budded cells with a G1 DNA content, suggesting an additional role during the G1/S phase. Identification of Skp1p homologs from C. elegans, A. thaliana, and H. sapiens indicates that SKP1 is evolutionarily highly conserved. Skp1p therefore represents an intrinsic kinetochore protein conserved throughout eukaryotic evolution and may be directly involved in linking kinetochore function with the cell cycle-regulatory machinery.

Alleles↗
PubMed2000

Genetic basis of tooth development and dental defects.

Tooth development is under strict genetic control, and during recent years an increasing number of genes have been identified that are involved in the regulation of tooth morphogenesis. One of the organs in which development is now beginning to be understood at the gene level, the tooth is an example of a typical vertebrate organ starting as an epithelial bud and undergoing complex morphogenesis, regulated by interactions between epithelial and mesenchymal tissue layers. It has become evident that developmental regulatory genes have been conserved to a high degree during evolution and that similar gene networks regulate the development of teeth as of other vertebrate organs. So far, all genes that have been linked with early tooth morphogenesis have developmental regulatory functions in other organs, too. The majority of these genes are associated with the signaling pathways transmitting interactions between cells and tissues. They include genes encoding the actual signals as well as their receptors, mediators of signaling in the cytoplasm and transcription factors regulating gene expression in the nucleus. Deletion of the function of many of these genes in transgenic mice results in arrested tooth development, but all these mutants also show defects in many other tissues. Mutations in several of these genes in humans have been identified as causes of dental defects, mainly hypodontia.

Animals↗
PubMed1996

The impact of oxidative stress on eukaryotic iron metabolism.

The processes of iron uptake and distribution are highly regulated in mammalian cells. Expression of the transferrin receptor is increased when cells are iron-depleted, while expression of the iron sequestration protein ferritin is increased in cells that are iron-replete. Regulation of expression of proteins of iron uptake (transferrin receptor) and iron sequestration (ferritin) presumably ensures that levels of reactive free iron are not high in cells. Formation of reactive oxygen species occurs when free iron reacts with oxygen, and tight regulation of iron metabolism may enable cells to avoid engaging in destructive chemical reactions. Levels of intracellular iron are directly sensed by two iron sensing proteins. Iron regulatory protein 1 (IRP1) is a bifunctional protein; in cells that are iron-replete, IRP1 contains an iron-sulfur cluster and functions as cytosolic aconitase. In cells that are iron-depleted, IRP1 binds stem-loop structures in RNA transcripts known as iron responsive elements (IREs). Iron regulatory protein 2 (IRP2) binds similar stem-loop structures, but the mode of regulation of IRP2 is different in that IRP2 is rapidly degraded in iron-replete cells. The post-transcriptional regulation of genes of iron metabolism in mammalian cells ensures that cells have an adequate supply of iron, and also ensures that cells do not generate excess reactive oxygen species through the interaction of free iron and oxygen.

Aconitate Hydratase↗
PubMed2001

Otx genes in the development and evolution of the vertebrate brain.

Most of the gene candidates for the control of developmental programmes that underlie brain morphogenesis in vertebrates are the orthologues of Drosophila genes coding for signalling molecules or transcription factors. Among these, the orthodenticle group, including the Drosophila orthodenticle (otd) and the vertebrate Otx1 and Otx2 genes, is mostly involved in fundamental processes of anterior neural patterning. In mouse, Drosophila and intermediate species otd/Otx genes have shown a remarkable similarity in expression pattern suggesting that they could be part of a conserved control system operating in the brain and different from that coded by the HOX complexes controlling the hindbrain and spinal cord. In order to verify this hypothesis, a series of mouse models have been generated in which the functions of the murine Otx genes were: (i) fully inactivated, (ii) replaced with each other, and (iii) replaced with the Drosophila otd gene. The data obtained highlight a crucial role for the Otx genes in specification, regionalization and terminal differentiation of rostral central nervous system and lead to hypothesize that modification of their regulatory control may have influenced the morphogenesis and evolution of the brain.

Alleles↗
PubMed2006

The life-cycle of operons.

Operons are a major feature of all prokaryotic genomes, but how and why operon structures vary is not well understood. To elucidate the life-cycle of operons, we compared gene order between Escherichia coli K12 and its relatives and identified the recently formed and destroyed operons in E. coli. This allowed us to determine how operons form, how they become closely spaced, and how they die. Our findings suggest that operon evolution may be driven by selection on gene expression patterns. First, both operon creation and operon destruction lead to large changes in gene expression patterns. For example, the removal of lysA and ruvA from ancestral operons that contained essential genes allowed their expression to respond to lysine levels and DNA damage, respectively. Second, some operons have undergone accelerated evolution, with multiple new genes being added during a brief period. Third, although genes within operons are usually closely spaced because of a neutral bias toward deletion and because of selection against large overlaps, genes in highly expressed operons tend to be widely spaced because of regulatory fine-tuning by intervening sequences. Although operon evolution may be adaptive, it need not be optimal: new operons often comprise functionally unrelated genes that were already in proximity before the operon formed.

Bacillus subtilis↗
PubMed2003

Evolutionary convergence in Otx expression in the pentameral adult rudiment in direct-developing sea urchins.

Convergence is a significant evolutionary phenomenon. Arrival at similar morphologies from different starting points indicates a strong role for natural selection in shaping morphological phenotypes. There is no evidence yet of convergence in the developmental mechanisms that underlie the evolution of convergent developmental phenotypes. Here we report the expression domains in sea urchins of two important developmental regulatory genes ( Orthodenticle and Runt), and show evidence of molecular convergence in the evolution of direct-developing sea urchins. Indirect development is ancestral in sea urchins. Evolutionary loss of the feeding pluteus stage and precocious formation of the radially symmetric juvenile has evolved independently in numerous sea urchin lineages, thus direct development is an evolutionary convergence. Indirect-developing species do not express Otx during the formation of their five primordial tube feet, the ancestral condition. However, each direct-developing urchin examined does express Otx in the tube feet. Otx expression in the radial arms of direct-developing sea urchins is thus convergent, and may indicate a specific need for Otx use in direct development, a constraint that would make direct development less able to evolve than if there were multiple molecular means for it to evolve. In contrast, Runt is expressed in tube feet in both direct- and indirect-developing species. Because echinoderms are closely related to chordates and postdate the protostome/deuterostome divergence, they must have evolved from bilaterally symmetrical ancestors. Arthropods and chordates use Otx in patterning their anterior axis, and Runt has multiple roles including embryonic patterning in arthropods, and blood and bone cell differentiation in vertebrates. Runt has apparently been co-opted in echinoderms for patterning of pentamery, and Otx in pentameral patterning among direct-developing echinoids. The surprisingly dynamic nature of Otx evolution reinvigorates debate on the role of natural selection vs shared ancestry in the evolution of novel features.

Animals↗
PubMed2006

Across-tissue expression and evolution of genes controlled by the Aire transcription factor.

Aire (autoimmune regulatory protein) enhances expression of certain genes in thymic medullary epithelial cells (MECs). Using publicly available data, we examined expression patterns, across 82 distinct tissue types, of genes previously identified as Aire-activated, Aire-repressed, and Aire-independent. Consistent with the hypothesis that the effect of Aire in MECs is to increase expression of tissue-specific genes, Aire-activated genes had a low overall level of expression but a large range between the lowest and the highest levels of expression in different tissues. By contrast, Aire-repressed genes tended to have a high overall level of expression and less marked differences between the highest and the lowest levels of expression. Nonetheless, the expression scores of Aire-repressed genes showed broader ranges of values than those of Aire-independent genes. Phylogenetic analyses of members of two gene families that included two Aire-activated genes illustrated two contrasting patterns of the relationship of Aire-activated genes within the same family. The two Aire-activated members of the major urinary protein family arose through a recent gene duplication (after the rat-mouse divergence), whereas the most recent common ancestor of the two Aire-activated members of cytochrome p450 family 2 duplicated prior to the radiation of the eutherian orders. In the latter family, the Aire-activated Cyp2a4 gene and the Aire-independent Cyp2a5 gene arose through a recent duplication, after the rat-mouse divergence. Thus the set of Aire-activated genes is subject to change over evolutionary time and includes genes of recent origin.

Animals↗