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Results for “regulatory evolution”

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PubMed2002

Speciation despite gene flow when developmental pathways evolve.

Evolutionary biologists assume that species formation requires a drastic reduction in gene exchange between populations, but the rate sufficient to prevent speciation is unknown. To study speciation, we use a new class of population genetic models that incorporate simple developmental genetic rules, likely present in all organisms, to construct the phenotype. When we allow replicate populations to evolve in parallel to a new, shared optimal phenotype, often their hybrids acquire poorly regulated phenotypes: Dobzhansky-Muller incompatibilities arise and postzygotic reproductive isolation evolves. Here we show that, although gene exchange does inhibit this process, it is the proportion of migrants exchanged (m) rather than the number of migrants (Nm) that is critical, and rates as high as 16 individuals exchanged per generation still permit the evolution of postzygotic isolation. Stronger directional selection counters the inhibitory effect of gene flow, increasing the speciation probability. We see similar results when populations in a standard two-locus, two-allele Dobzhansky-Muller model are subject to simultaneous directional selection and gene flow. However, in developmental pathway models with more than two loci, gene flow is more able to impede speciation. Genetic incompatibilities arise as frequent by-products of adaptive evolution of traits determined by regulatory pathways, something that does not occur when phenotypes are modeled using the standard, additive genetic framework. Development therefore not only constrains the microevolutionary process, it also facilitates the interactions among genes and gene products that make speciation more likely-even in the face of strong gene flow.

Animals↗

PubMed2000

Osteopoiesis: the early development of bone cells.

An understanding of the disorders of bone formation clearly requires insights into the complex regulatory events occurring during the evolution of bone precursor cells into osteoblasts. Moreover, a rational approach to therapeutic interventions that might alter the clinical course of bone disorders must take into consideration the exact nature of the developmental control mechanism(s) being affected during the disease process. The process of osteopoiesis involves the proliferation and maturation of primitive precursor cells into functional osteoblasts. The bone cell lineage originates from mesenchymal stem cells that commit to the osteogenic cell lineage becoming osteoprogenitor cells, preosteoblasts, osteoblasts, and osteocytes. In order to understand how different regulatory signals coordinate bone cell development, it is important to study the responses of bone progenitor cells to different microenviromental signals. This requires that lineage markers be identified for the various populations of bone cells and their precursors, that cell separation techniques be established so that cells of the osteogenic lineage can be purified at different stages of differentiation, and that these isolated cells are studied under serum-free, chemically defined conditions. This review focuses on the current understanding of bone progenitor cell development, examining the various types of precursor cells, their responses to cytokines and other extracellular influences, and recent observations on the biochemical and molecular control of lineage-specific gene expression. Although the emphasis is on human cells, the importance of work using rodent cells goes without saying, and is addressed where relevant.

Bone Development↗

PubMed2004

Adaptive evolution of transcription factor binding sites.

BACKGROUND: The regulation of a gene depends on the binding of transcription factors to specific sites located in the regulatory region of the gene. The generation of these binding sites and of cooperativity between them are essential building blocks in the evolution of complex regulatory networks. We study a theoretical model for the sequence evolution of binding sites by point mutations. The approach is based on biophysical models for the binding of transcription factors to DNA. Hence we derive empirically grounded fitness landscapes, which enter a population genetics model including mutations, genetic drift, and selection. RESULTS: We show that the selection for factor binding generically leads to specific correlations between nucleotide frequencies at different positions of a binding site. We demonstrate the possibility of rapid adaptive evolution generating a new binding site for a given transcription factor by point mutations. The evolutionary time required is estimated in terms of the neutral (background) mutation rate, the selection coefficient, and the effective population size. CONCLUSIONS: The efficiency of binding site formation is seen to depend on two joint conditions: the binding site motif must be short enough and the promoter region must be long enough. These constraints on promoter architecture are indeed seen in eukaryotic systems. Furthermore, we analyse the adaptive evolution of genetic switches and of signal integration through binding cooperativity between different sites. Experimental tests of this picture involving the statistics of polymorphisms and phylogenies of sites are discussed.

Animals↗

PubMed2002

scute expression in Calliphora vicina reveals an ancestral pattern of longitudinal stripes on the thorax of higher Diptera.

In Drosophila the stereotyped arrangement of sensory bristles on the notum is determined by the tightly regulated control of transcription of the achaete-scute (ac-sc) genes which are expressed in small proneural clusters of cells at the sites of each future bristle. Expression relies on a series of discrete cis-regulatory elements present in the ac-sc gene complex that are the target of the transcriptional activators pannier (pnr) and the genes of the iroquois complex. Stereotyped bristle patterns are common among species of acalyptrate Schizophora such as Drosophila, and are thought to have derived from an ancestral pattern of four longitudinal rows extending the length of the scutum, through secondary loss of bristles. To investigate evolutionary changes in bristle patterns and ac-sc regulation by pnr, we have isolated homologues of these genes from Calliphora vicina, a species of calyptrate Schizophora separated from Drosophila by at least 100 million years. Calliphora vicina displays a pattern of four rows of bristles on the scutum resembling the postulated ancestral one. We find that sc in Calliphora is expressed in two longitudinal stripes on the medial scutum that prefigure the development of the rows of acrostichal and dorsocentral bristles. This result suggests that a stripe-like expression pattern of sc may be an ancestral feature and may have preceded the evolution of proneural clusters. The implications for the evolution of the cis-regulatory elements responsible for sc expression in the proneural clusters of Drosophila, and function of Pnr are discussed.

Amino Acid Sequence↗

PubMed2005

The agr radiation: an early event in the evolution of staphylococci.

Agr is a global regulatory system in the staphylococci, operating by a classical two-component signaling module and controlling the expression of most of the genes encoding extracellular virulence factors. As it is autoinduced by a peptide, encoded within the locus, that is the ligand for the signal receptor, it is a sensor of population density or a quorum sensor and is the only known quorum-sensing system in the genus. agr is conserved throughout the staphylococci but has diverged along lines that appear to parallel speciation and subspeciation within the genus. This divergence has given rise to a novel type of interstrain and interspecies cross-inhibition that represents a fundamental aspect of the organism's biology and may be a predominant feature of the evolutionary forces that have driven it. We present evidence, using a newly developed, luciferase-based agr typing scheme, that the evolutionary divergence of the agr system was an early event in the evolution of the staphylococci and long preceded the development of the nucleotide polymorphisms presently used for genotyping. These polymorphisms developed, for the most part, within different agr groups; mobile genetic elements appear also to have diffused recently and, with a few notable exceptions, have come to reside largely indiscriminately within the several agr groups.

Bacterial Proteins↗

PubMed1999

Molecular population genetics of floral homeotic loci. Departures from the equilibrium-neutral model at the APETALA3 and PISTILLATA genes of Arabidopsis thaliana.

Molecular variation in genes that regulate development provides insights into the evolutionary processes that shape the diversification of morphogenetic pathways. Intraspecific sequence variation at the APETALA3 and PISTILLATA floral homeotic genes of Arabidopsis thaliana was analyzed to infer the extent and nature of diversity at these regulatory loci. Comparison of AP3 and PI diversity with three previously studied genes revealed several features in the patterning of nucleotide polymorphisms common between Arabidopsis nuclear loci, including an excess of low-frequency nucleotide polymorphisms and significantly elevated levels of intraspecific replacement variation. This pattern suggests that A. thaliana has undergone recent, rapid population expansion and now exists in small, inbred subpopulations. The elevated intraspecific replacement levels may thus represent slightly deleterious polymorphisms that differentiate distinct ecotypes. The distribution of replacement and synonymous changes in AP3 and PI core and noncore functional domains also indicates differences in the patterns of molecular evolution between these interacting floral regulatory genes.

Alleles↗

PubMed2003

Archaeal protein kinases and protein phosphatases: insights from genomics and biochemistry.

Protein phosphorylation/dephosphorylation has long been considered a recent addition to Nature's regulatory arsenal. Early studies indicated that this molecular regulatory mechanism existed only in higher eukaryotes, suggesting that protein phosphorylation/dephosphorylation had emerged to meet the particular signal-transduction requirements of multicellular organisms. Although it has since become apparent that simple eukaryotes and even bacteria are sites of protein phosphorylation/dephosphorylation, the perception widely persists that this molecular regulatory mechanism emerged late in evolution, i.e. after the divergence of the contemporary phylogenetic domains. Only highly developed cells, it was reasoned, could afford the high 'overhead' costs inherent in the acquisition of dedicated protein kinases and protein phosphatases. The advent of genome sequencing has provided an opportunity to exploit Nature's phylogenetic diversity as a vehicle for critically examining this hypothesis. In tracing the origins and evolution of protein phosphorylation/dephosphorylation, the members of the Archaea, the so-called 'third domain of life', will play a critical role. Whereas several studies have demonstrated that archaeal proteins are subject to modification by covalent phosphorylation, relatively little is known concerning the identities of the proteins affected, the impact on their functional properties, or the enzymes that catalyse these events. However, examination of several archaeal genomes has revealed the widespread presence of several ostensibly 'eukaryotic' and 'bacterial' protein kinase and protein phosphatase paradigms. Similar findings of 'phylogenetic trespass' in members of the Eucarya (eukaryotes) and the Bacteria suggest that this versatile molecular regulatory mechanism emerged at an unexpectedly early point in development of 'life as we know it'.

Archaea↗

PubMed2006

Retinoids and nonvertebrate chordate development.

Retinoic acid (RA) is required for the differentiation and morphogenesis of chordate-specific features, such as the antero-posterior regionalization of the dorsal hollow nerve cord and neural crest cells. RA receptors (RARs) have been reported exclusively in chordates, suggesting that the acquisition of the RAR gene was important for chordate evolution. A scenario is presented here for the establishment of an RAR-mediated developmental regulatory system during the course of chordate evolution. In the common chordate ancestor, RAR came to control the spatial expression pattern of Hox genes in the ectoderm and endoderm along the antero-posterior axis. In these germ layers, RA was required for the differentiation of epidermal sensory neurons and the morphogenesis of pharyngeal gill slits, respectively. As the diffuse epidermal nerve net in the chordate ancestor became centralized to form the dorsal nerve cord, the epidermal Hox expression pattern was carried into the central nervous system. Because the Hox code here came to specify neuronal identity along the antero-posterior axis, RA became inextricably linked to the antero-posterior patterning of the chordate central nervous system.

Animals↗

PubMed2005

Chicken genome: current status and future opportunities.

The chicken genome sequence is important for several reasons. First, the chicken shared a common ancestor with mammals approximately 310 million years ago (Mya) at a phylogenetic distance not previously covered by other genome sequences. It therefore fills a gap in our knowledge and understanding of the evolution and conservation of genes, regulatory sequences, genomes, and karyotypes. The chicken is also a major source of protein in the world, with billions of birds used in meat and egg production each year. It is the first livestock species to be sequenced and so leads the way for others. The sequence and the 2.8 million genetic polymorphisms defined in a parallel project are expected to benefit agriculture and cast new light on animal domestication. Also, as the first bird to be sequenced, it is a model for the 9600 avian species thought to exist today. Many of the features of the chicken genome and its biology make it an ideal organism for studies in development and evolution, along with applications in agriculture and medicine.

Animals↗

PubMed2001

Molecular evolution of the teosinte branched gene among maize and related grasses.

Several authors have proposed that changes in a small number of regulatory genes may be sufficient for the evolution of novel morphologies. Recent analyses have indicated that teosinte branched1 (tb1), a putative bHLH transcription factor, played such a role during the morphological evolution of maize from its wild ancestor, teosinte. To address whether or not tb1 played a similar role during the evolution of the Andropogoneae, the tribe to which maize belongs, and to examine the rate and pattern of tb1 evolution within this tribe, we analyzed tb1-like sequences from 23 members of the Andropogoneae and five other grasses. Our analysis revealed that the TB1 protein evolves slowly within three conserved domains but rapidly outside these domains. The nonconserved regions of the gene are characterized by both a high nonsynonymous substitution rate and frequent indels. The ratio of nonsynonymous substitutions per nonsynonymous site (d(N)) to synonymous substitutions per synonymous site (d(S)) was not significantly greater than 1.0, providing no evidence for positive selection. However, the d(N)/d(S) ratio varied significantly among lineages and was high compared with those of other plant nuclear genes. Variation in the d(N)/d(S) ratio among the Andropogoneae could be explained by unequal levels of purifying selection among lineages. Consistent with this interpretation, the rate of nonsynonymous substitution differed along several lineages, while the synonymous substitution rate did not differ significantly. Finally, using tb1, we examined phylogenetic relationships within the Andropogoneae. The phylogeny suggests that the tribe underwent a rapid radiation during its early history and that the monoecious Andropogoneae are polyphyletic.

Amino Acid Sequence↗

PubMed2002

Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system.

The primordial combinatorial immune recognition repertoire arose in the evolution of jawed vertebrates approximately 450 million years ago as a rapid genetic process independent of antigenic selection. We propose that it encompassed the entire repertoire of innate immunity involving molecules that had evolved over billions of years. The 'antigen-driven' compartment involving invasive pathogens operates in 'real time' showing inducibility and increases in affinity. Individuals within a species differ in their repertoires because of distinct antigenic challenges, genetics, or local environmental effects. The 'homeostatic' compartment that recognizes invariant cell and serum components should be conserved in all individuals of a species. The potential to recapitulate the entire recognition spectrum must be regenerated during the formation of new species. Evidence for the capacity of the combinatorial response to encompass the entire preexisting repertoire was obtained in studies of natural human IgG antibodies present in intravenous immunoglobulin. Since essential cellular recognition and regulatory elements are conserved throughout evolution, we propose that the natural antibodies of sharks, the most anciently emerged vertebrates to possess the combinatorial immune response, will resemble those of mammals in showing specificity for the conserved recognition/regulatory molecules. If verified, this hypothesis will establish the fundamental importance of natural antibodies not only in defense, but in regulation and functional homeostasis of the individual.

Animals↗

PubMed1999

Evidence for the recent horizontal transfer of long terminal repeat retrotransposon.

The evolutionary dynamics existing between transposable elements (TEs) and their host genomes have been likened to an "arms race." The selfish drive of TEs to replicate, in turn, elicits the evolution of host-mediated regulatory mechanisms aimed at repressing transpositional activity. It has been postulated that horizontal (cross-species) transfer may be one effective strategy by which TEs and other selfish genes can escape host-mediated silencing mechanisms over evolutionary time; however, to date, the most definitive evidence that TEs horizontally transfer between species has been limited to class II or DNA-type elements. Evidence that the more numerous and widely distributed retroelements may also be horizontally transferred between species has been more ambiguous. In this paper, we report definitive evidence for a recent horizontal transfer of the copia long terminal repeat retrotransposon between Drosophila melanogaster and Drosophila willistoni.

Animals↗

PubMed2006

Comparative phylogenetic analysis reveals multiple non-imprinted isoforms of opossum Dlk1.

Imprinted genes are monoallelically expressed in a parent-of-origin manner and were previously identified in both marsupials and eutherians, but not in monotremes. Phylogenetic comparison of imprinted domains is a powerful tool for investigating the molecular and adaptive evolution of this unique gene regulatory mechanism. Herein, we report that multiple transcripts of Dlk1 (Delta, Drosophila, Homolog-like 1) are expressed in the opossum, but none are imprinted. Thus, we provide the first example of a reciprocally imprinted gene domain in which imprinting evolved in a common ancestor to eutherian rather than therian mammals. Moreover, the reciprocally imprinted Meg3 (Maternally Expressed Gene 3), found downstream of Dlk1 in eutherian mammals, is absent in the opossum. We propose that the Meg3 sequence integrated into the eutherian Dlk1 domain via a LINE-1 element and that Dlk1 became imprinted in eutherian mammals only after this downstream integration. These findings clearly demonstrate that imprinted genes did not all evolve before the divergence of marsupials and eutherians.

Animals↗

PubMed2002

Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. Macrophage migration inhibitory factor (MIF), a cytokine with potent inflammatory functions, was thus considered to be important in atherosclerotic lesion evolution. METHODS AND RESULTS: We studied the presence and distribution of MIF immunoreactivity (MIF-IR) and MIF mRNA in internal mammary arteries with a normal histology and arteries with plaques in different stages of human atherosclerosis. To address a potential role for the coactivator Jab1 as a cellular mediator of MIF effects in vascular tissue, we correlated the expression of MIF to that of Jab1 by using immunohistochemistry and coimmunoprecipitation. We further sought to determine a potential functional role for endothelium-derived MIF in early atherogenesis by studying the effects of oxidized LDL on MIF expression in cultured human umbilical vascular endothelial cells. The results showed that MIF-IR and Jab1-IR are found in all cell types present in atherosclerotic lesions, that MIF-IR is upregulated during progression of atherosclerosis, that MIF is produced locally in the arterial wall, and that all MIF(+) cells are simultaneously Jab1(+). Coimmunoprecipitation experiments demonstrated in vivo complex formation between MIF and Jab1 in plaques. MIF expression in human umbilical vascular endothelial cells and a macrophage line was upregulated after stimulation with oxidized LDL. CONCLUSIONS: MIF is produced abundantly by various cells in all types of human atherosclerotic lesions and thus may play an important role in early plaque development and advanced complicated lesions. MIF-Jab1 complexes could serve critical regulatory functions in atherosclerotic lesion evolution.

Aortic Diseases↗

PubMed2002

On the evolution of programmed cell death: apoptosis of the unicellular eukaryote Leishmania major involves cysteine proteinase activation and mitochondrion permeabilization.

Leishmania major is a protozoan parasite from one of the most ancient phylogenic branches of unicellular eukaryotes, and containing only one giant mitochondrion. Here we report that staurosporine, that induces apoptosis in all mammalian nucleated cells, also induces in L. major a death process with several cytoplasmic and nuclear features of apoptosis, including cell shrinkage, phosphatidyl serine exposure, maintenance of plasma membrane integrity, mitochondrial transmembrane potential (DeltaPsim) loss and cytochrome c release, nuclear chromatin condensation and fragmentation, and DNA degradation. Nuclear apoptosis-like features were prevented by cysteine proteinase inhibitors, and cell free assays using dying L. major cytoplasmic extracts indicated that the cysteine proteinases involved (i) also induced nuclear apoptosis-like features in isolated mammalian nuclei, and (ii) shared at least two nuclear substrates, but no cleavage site preference, with human effector caspases. Finally, isolated L. major mitochondria released cytochrome c and cysteine proteinases with nuclear pro-apoptotic activity when incubated with human recombinant Bax, even (although much less efficiently) when Bax was deleted of its transmembrane domain required for insertion in mitochondrial outermembranes, implying that L. major mitochondrion may express proteins able to interact with Bax. The recruitment of cysteine proteinases and mitochondria to the cell death machinery may be of very ancient evolutionary origin. Alternately, host/parasite interactions may have exerted selective pressures on the cell death phenotype of kinetoplastid parasites, resulting in the more recent emergence of an apoptotic machinery through a process of convergent evolution.

Animals↗

PubMed2001

Differences in Krox20-dependent regulation of Hoxa2 and Hoxb2 during hindbrain development.

During hindbrain development, segmental regulation of the paralogous Hoxa2 and Hoxb2 genes in rhombomeres (r) 3 and 5 involves Krox20-dependent enhancers that have been conserved during the duplication of the vertebrate Hox clusters from a common ancestor. Examining these evolutionarily related control regions could provide important insight into the degree to which the basic Krox20-dependent mechanisms, cis-regulatory components, and their organization have been conserved. Toward this goal we have performed a detailed functional analysis of a mouse Hoxa2 enhancer capable of directing reporter expression in r3 and r5. The combined activities of five separate cis-regions, in addition to the conserved Krox20 binding sites, are involved in mediating enhancer function. A CTTT (BoxA) motif adjacent to the Krox20 binding sites is important for r3/r5 activity. The BoxA motif is similar to one (Box1) found in the Hoxb2 enhancer and indicates that the close proximity of these Box motifs to Krox20 sites is a common feature of Krox20 targets in vivo. Two other rhombomeric elements (RE1 and RE3) are essential for r3/r5 activity and share common TCT motifs, indicating that they interact with a similar cofactor(s). TCT motifs are also found in the Hoxb2 enhancer, suggesting that they may be another common feature of Krox20-dependent control regions. The two remaining Hoxa2 cis-elements, RE2 and RE4, are not conserved in the Hoxb2 enhancer and define differences in some of components that can contribute to the Krox20-dependent activities of these enhancers. Furthermore, analysis of regulatory activities of these enhancers in a Krox20 mutant background has uncovered differences in their degree of dependence upon Krox20 for segmental expression. Together, this work has revealed a surprising degree of complexity in the number of cis-elements and regulatory components that contribute to segmental expression mediated by Krox20 and sheds light on the diversity and evolution of Krox20 target sites and Hox regulatory elements in vertebrates.

Animals↗

PubMed2006

Advances in fish cytokine biology give clues to the evolution of a complex network.

Complex immune systems require complex regulatory mechanisms. Whilst the control of innate and inflammatory responses is likely to be ancient in origin, and potentially ubiquitous in the animal kingdom, clearly the evolution of an adaptive immune system in vertebrates is likely to coincide with new regulatory mechanisms and molecules. Key amongst these is the cytokine network, well characterised in mammals and becoming increasingly well characterised in fish and birds. This article will review our current understanding of which components of this network are crucial for adaptive immunity and evolved early, being present from fish to mammals. It will also consider which components of this network potentially evolved later (after the fish-tetrapod divergence) leading to unique cytokine genes in particular vertebrate groups.

Animals↗

PubMed2001

Comparative insect developmental genetics: phenotypes without mutants.

The last decade has seen a dramatic increase in interest in the extent to which morphological evolution depends on changes in regulatory pathways. Insects provide a fertile ground for study because of their diversity and our high level of understanding of the genetic regulation of development in Drosophila melanogaster. However, comparable genetic approaches are presently possible in only a small number of non-Drosophilid insects. In a recent paper, Hughes and Kaufman have used a new methodology, RNA interference, in the milkweed bug, Oncopeltus fasciatus, to phenocopy the effects of mutations in Hox genes. RNA interference involves the injection of double-stranded RNA of the same sequence as the relevant mRNA resulting in a depletion of that transcript. Hughes and Kaufman focused on the gnathal segments, which elaborate specialized appendages important to feeding. Their results indicate that gnathal adaptations in this bug are correlated with changes in Hox gene functions and interactions.

Animals↗