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PubMed2025

Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to human brain evolution.

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, how astrocytes evolve in primates is unsettled. Here, we obtain human, chimpanzee, and macaque induced pluripotent stem-cell-derived astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We identify new loci contributing to the increased human astrocyte. We show that genes and pathways implicated in long-range intercellular signaling are activated in the human iAstrocytes and partake in controlling iAstrocyte complexity. Genes downregulated in human iAstrocytes frequently relate to neurological disorders and were decreased in adult brain samples. Through regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of "stripe" transcription factor binding sites. Altogether, we reveal the transcriptomic signature of primate astrocyte evolution and a mechanism driving the acquisition of the regulatory potential of enhancers.

Astrocytes↗

PubMedDate not supplied

Recognition of regulatory sites by genomic comparison.

Availability of complete bacterial genomes opens the way to the comparative approach to the recognition of transcription regulatory sites. Assumption of regulon conservation in conjunction with profile analysis provides two lines of independent evidence making it possible to make highly specific predictions. Recently this approach was used to analyze several regulons in eubacteria and archaebacteria. The present review covers recent advances in the comparative analysis of transcriptional regulation in prokaryotes and phylogenetic fingerprinting techniques in eukaryotes, and describes the emerging patterns of the evolution of regulatory systems.

Bacteria↗

PubMed1998

The molecular evolution of development.

Morphological differences between species, from simple single-character differences to large-scale variation in body plans, can be traced to changes in the timing and location of developmental events. This has led to a growing interest in understanding the genetic basis behind the evolution of developmental systems. Molecular evolutionary genetics provides one of several approaches to dissecting the evolution of developmental systems, by allowing us to reconstruct the history of developmental genetic pathways, infer the origin and diversification of developmental gene functions, and assess the relative contributions of various evolutionary forces in shaping regulatory gene evolution.

Animal Population Groups↗

PubMed2005

A conserved transcription factor mediates nuclear control of organelle biogenesis in anciently diverged land plants.

Land plant chloroplasts evolved from those found in the green algae. During land plant evolution, nuclear regulatory mechanisms have been modified to produce morphologically and functionally diverse chloroplasts in distinct developmental contexts. At least some of these mechanisms evolved independently in different plant lineages. In angiosperms, GOLDEN2-LIKE (GLK) transcription factors regulate the development of at least three chloroplast types. To determine whether GLK-mediated regulation of chloroplast development evolved within angiosperms or is a plesiomorphy within land plants, gene function was examined in the moss Physcomitrella patens. Gene expression patterns and loss-of-function mutant phenotypes suggested that GLK gene function is conserved between P. patens and Arabidopsis thaliana, species that diverged >400 million years ago. In support of this suggestion, moss genes partially complement Arabidopsis loss-of-function mutants. Therefore, GLK-mediated regulation of chloroplast development defines one of the most ancient conserved regulatory mechanisms identified in the plant kingdom.

Arabidopsis↗

PubMed1978

Genetic and biochemical basis of enzyme activity variation in natural populations. I. Alcohol dehydrogenase in Drosophila melanogaster.

Recent studies by various authors suggest that variation in gene regulation may be common in nature, and might be of great evolutionary consequence; but the ascertainment of variation in gene regulation has proven to be a difficult problem. In this study, we explore this problem by measuring alcohol dehydrogenase (ADH) activity in Drosophila melanogaster strains homozygous for various combinations of given second and third chromosomes sampled from a natural population. The structural locus (Adh) coding for ADH is on the second chromosome. The results show that: (1) there are genes, other than Adh, that affect the levels of ADH activity; (2) at least some of these "regulatory" genes are located on the third chromosome, and thus are not adjacent to the Adh locus; (3) variation exists in natural populations for such regulatory genes; (4) the effect of these regulatory genes varies as they interact with different second chromosomes; (5) third chromosomes with high-activity genes are either partially or completely dominant over chromosomes with low-activity genes; (6) the effects of the regulatory genes are pervasive throughout development; and (7) the third chromosome genes regulate the levels of ADH activity by affecting the number of ADH molecules in the flies. The results are consistent with the view that the evolution of regulatory genes may play an important role in adaptation.

Alcohol Oxidoreductases↗

PubMed1985

Evolutionary relationship between nonmammalian and mammalian peptides.

An hypothesis has been developed to rationalize the evolution of regulatory peptides. In order to account for critical relationships involving peptide regulators, their receptors, and peptide processing enzymes, the following generalizations will be supported: (1) peptides arose from protein precursors as proteolytic digestion by-products and acquired hormonal status during the course of natural selection; (2) initially, peptides served primarily nutritional roles, thereby permitting increased growth rates and reproductive advantages for recipient cells; (3) specific peptide sequences were conserved during evolution and were associated with biological activities which were essential for survival of species as divergent as unicellular organisms, amphibians, and mammals; and (4) regulatory peptides probably arose simultaneously with their membrane-oriented, macromolecular receptor sites. In support of the conservation of sequence information or function, or both, during evolutionary development, evidence has been obtained to indicate that peptide sequences which occur in two classes of amphibian peptides appear to be extensively conserved in mammals. Studies with an antiserum directed against the N-terminal sequence of amphibian physalaemin have permitted the recognition of a mammalian octapeptide which exhibits 80% homology with residues 1-5 in that region. Another study with an antiserum directed against the midregion (sequence 5-8) of amphibian bombesin has indicated the existence of milk peptides which mimic bombesin in several pharmacological bioassays. These studies indicate that radioimmunoassays can be powerful tools in facilitating recognition of peptide sequences conserved throughout evolution.

Amino Acid Sequence↗

PubMed2002

Multiple regulatory changes contribute to the evolution of the Caenorhabditis lin-48 ovo gene.

Recent work points to the importance of changes in gene expression patterns in species-specific differences. Here, we investigate the evolution of the nematode lin-48 ovo gene. lin-48 is expressed in several cells in both Caenorhabditis elegans and Caenorhabditis briggsae, but acts in the excretory duct cell only in C. elegans. We find the differences result both from alterations in the cis-regulatory sequences and in proteins that mediate lin-48 expression. One factor that contributes to the species differences is the bZip protein CES-2. Our results indicate the accumulation of several regulatory changes affecting one gene can contribute to evolutionary change.

Animals↗

PubMed2004

Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements.

BACKGROUND: The primate-specific Alu elements, which originated 65 million years ago, exist in over a million copies in the human genome. These elements have been involved in genome shuffling and various diseases not only through retrotransposition but also through large scale Alu-Alu mediated recombination. Only a few subfamilies of Alus are currently retropositionally active and show insertion/deletion polymorphisms with associated phenotypes. Retroposition occurs by means of RNA intermediates synthesised by a RNA polymerase III promoter residing in the A-Box and B-Box in these elements. Alus have also been shown to harbour a number of transcription factor binding sites, as well as hormone responsive elements. The distribution of Alus has been shown to be non-random in the human genome and these elements are increasingly being implicated in diverse functions such as transcription, translation, response to stress, nucleosome positioning and imprinting. RESULTS: We conducted a retrospective analysis of putative functional sites, such as the RNA pol III promoter elements, pol II regulatory elements like hormone responsive elements and ligand-activated receptor binding sites, in Alus of various evolutionary ages. We observe a progressive loss of the RNA pol III transcriptional potential with concomitant accumulation of RNA pol II regulatory sites. We also observe a significant over-representation of Alus harboring these sites in promoter regions of signaling and metabolism genes of chromosome 22, when compared to genes of information pathway components, structural and transport proteins. This difference is not so significant between functional categories in the intronic regions of the same genes. CONCLUSIONS: Our study clearly suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome. Exaptation of regulatory elements in the preexisting genes through Alus could thus have contributed to evolution of novel regulatory networks in the primate genomes. With such a wide spectrum of regulatory sites present in Alus, it also becomes imperative to screen for variations in these sites in candidate genes, which are otherwise repeat-masked in studies pertaining to identification of predisposition markers.

Alu Elements↗

PubMed2004

FixJ-regulated genes evolved through promoter duplication in Sinorhizobium meliloti.

The FixLJ two-component system of Sinorhizobium meliloti is a global regulator, turning on nitrogen-fixation genes in microaerobiosis. Up to now, nifA and fixK were the only genes known to be directly regulated by FixJ. We used a genomic SELEX approach in order to isolate new FixJ targets in the genome. This led to the identification of 22 FixJ binding sites, including the known sites in the fixK1 and fixK2 promoters. FixJ binding sites are unevenly distributed among the three replicons constituting the S. meliloti genome: a majority are carried either by pSymA or by a short chromosomal region of non-chromosomal origin. Thus FixJ binding sites appear to be preferentially associated with the pSymA replicon, which carries the fixJ gene. Functional analysis of FixJ targets led to the discovery of two new FixJ-regulated genes, smc03253 and proB2. This FixJ-dependent regulation appears to be mediated by a duplication of the whole fixK promoter region, including the beginning of the fixK gene. Similar duplications were previously reported for the nifH promoter. By systematic comparison of all promoter regions we found 17 such duplications throughout the genome, indicating that promoter duplication is a common mechanism for the evolution of regulatory pathways in S. meliloti.

Amino Acid Sequence↗

PubMed2026

Evidence for dual pathways of Tc1/mariner domestication in Drosophila.

BACKGROUND: The domestication of transposable elements is a key source of evolutionary innovation, yet the pathways by which their functional modules are repurposed by the host remain poorly understood. The Tc1/mariner superfamily is a widespread group of DNA transposons, but the prevalence and patterns of their domestication are underexplored. RESULTS: We performed a systematic genomic screen across 43 drosophilid species using stringent criteria for molecular domestication. This analysis identified five high-confidence, evolutionarily conserved genes derived from Tc1/mariner transposases. Phylogenetic and structural analyses suggest domestication via two distinct molecular pathways: co-option of the DNA-binding module and co-option of the catalytic domain. The DNA-binding module pathway includes CG4570, the previously known genes cag and toy (the latter fused with a homeodomain), and a lineage-restricted gene in the Drosophila obscura group that exhibits signatures of recent domestication. In contrast, the catalytic domain pathway is represented solely by CG14478. Structural modeling reveals that CG14478 protein preserves a canonical DDE endonuclease fold. Co-expression network analysis suggests potential cellular roles of these genes: CG14478 is linked to RNA/chromatin-related processes, CG4570 to cell cycle/chromosome functions, cag to ciliary and nuclear functions, and toy to neuronal development. CONCLUSIONS: This study establishes a stringent framework for identifying domesticated TEs, demonstrating that Tc1/mariner elements are co-opted via two distinct pathways: retention of either catalytic or DNA-binding modules. Our findings suggest that domestication is a dynamic continuum, ranging from recent, lineage-specific events to ancient, conserved genes, and underscore how genomic conflict with TEs can drive eukaryotic evolution and regulatory complexity.

Animals↗

PubMed2000

Rapid speciation via parallel, directional selection on regulatory genetic pathways.

Regulatory genetic pathways are ubiquitous in organisms and play a central role in the realization of the phenotype during development. We explored the proposition that these pathways can provide a plausible source of the epistatic variation that has been implicated in the evolution of postzygotic reproductive isolation. We modeled gene regulation as a matching function between the product of one locus and the promoter site of the next locus in the pathway, with binding strength determining the amount of product. When the phenotype is subject to parallel selection in a pair of independent populations, we find that the fitnesses of F(1)and F(2)hybrids often drop to very low values as the populations respond in genetically different and incompatible ways. The simulations support the predictions of the analytical models. Hybrid fitness reduction occurs more often as the number of loci in the pathway increases, and as the binding site interactions become more complex. Less hybrid fitness reduction is seen when the populations start with imperfect binding in the pathway. In contrast, when we constructed the phenotype without gene regulation using multiplicative rules, isomorphic to the additive phenotype commonly assumed in evolutionary models, we found no appreciable F(1)fitness reduction and only slight F(2)fitness reduction. The interaction of genetic drift and mutation, even at very high rates, did not reduce hybrid fitness at all on the time-scales we considered. Clearly, the evolution of regulatory genetic pathways can play an important role in speciation, but much more empirical information is needed on the effect of allelic variability in regulatory site interactions before this role is fully understood.

Animals↗

PubMed2001

OTD/OTX2 functional equivalence depends on 5' and 3' UTR-mediated control of Otx2 mRNA for nucleo-cytoplasmic export and epiblast-restricted translation.

How gene activity is translated into phenotype and how it can modify morphogenetic pathways is of central importance when studying the evolution of regulatory control mechanisms. Previous studies in mouse have suggested that, despite the homeodomain-restricted homology, Drosophila orthodenticle (otd) and murine Otx1 genes share functional equivalence and that translation of Otx2 mRNA in epiblast and neuroectoderm might require a cell type-specific post-transcriptional control depending on its 5' and 3' untranslated sequences (UTRs). In order to study whether OTD is functionally equivalent to OTX2 and whether synthesis of OTD in epiblast is molecularly dependent on the post-transcriptional control of Otx2 mRNA, we generated a first mouse model (otd(2)) in which an Otx2 region including 213 bp of the 5' UTR, exons, introns and the 3' UTR was replaced by an otd cDNA and a second mutant (otd(2FL)) replacing only exons and introns of Otx2 with the otd coding sequence fused to intact 5' and 3' UTRs of Otx2. otd(2) and otd(2FL) mRNAs were properly transcribed under the Otx2 transcriptional control, but mRNA translation in epiblast and neuroectoderm occurred only in otd(2FL) mutants. Phenotypic analysis revealed that visceral endoderm (VE)-restricted translation of otd(2) mRNA was sufficient to rescue Otx2 requirement for early anterior patterning and proper gastrulation but it failed to maintain forebrain and midbrain identity. Importantly, epiblast and neuroectoderm translation of otd(2FL) mRNA rescued maintenance of anterior patterning as it did in a third mouse model replacing, as in otd(2FL), exons and introns of Otx2 with an Otx2 cDNA (Otx2(2c)). The molecular analysis has revealed that Otx2 5' and 3' UTR sequences, deleted in the otd(2) mRNA, are required for nucleo-cytoplasmic export and epiblast-restricted translation. Indeed, these molecular impairments were completely rescued in otd(2FL) and Otx2(2c) mutants. These data provide novel in vivo evidence supporting the concept that during evolution pre-existing gene functions have been recruited into new developmental pathways by modifying their regulatory control.

3' Untranslated Regions↗

PubMed2006

Co-evolution of transcription factors and their targets depends on mode of regulation.

BACKGROUND: Differences in the transcription regulation network are at the root of much of the phenotypic variation observed among organisms. These differences may be achieved either by changing the repertoire of regulators and/or their targets, or by rewiring the network. Following these changes and studying their logic is crucial for understanding the evolution of regulatory networks. RESULTS: We use the well characterized transcription regulatory network of Escherichia coli K12 and follow the evolutionary changes in the repertoire of regulators and their targets across a large number of fully sequenced gamma-proteobacteria. By focusing on close relatives of E. coli K12, we study the dynamics of the evolution of transcription regulation across a relatively short evolutionary timescale. We show significant differences in the evolution of repressors and activators. Repressors are only lost from a genome once their targets have themselves been lost, or once the network has significantly rewired. In contrast, activators are often lost even when their targets remain in the genome. As a result, E. coli K12 repressors that regulate many targets are rarely absent from organisms that are closely related to E. coli K12, while activators with a similar number of targets are often absent in these organisms. CONCLUSION: We demonstrate that the mode of regulation exerted by transcription factors has a strong effect on their evolution. Repressors co-evolve tightly with their target genes. In contrast, activators can be lost independently of their targets. In fact, loss of an activator can lead to efficient shutdown of an unnecessary pathway.

Escherichia coli↗

PubMed2004

Distribution of short paired duplications in mammalian genomes.

Mammalian genomes are densely populated with long duplicated sequences. In this paper, we demonstrate the existence of doublets, short duplications between 25 and 100 bp, distinct from previously described repeats. Each doublet is a pair of exact matches, separated by some distance. The distribution of these intermatch distances is strikingly nonrandom. An unexpectedly high number of doublets have matches either within 100 bp (adjacent) or at distances tightly concentrated approximately 1,000 bp apart (nearby). We focus our study on these proximate doublets. First, they tend to have both matches on the same strand. By comparing nearby doublets shared in human and chimpanzee, we can also see that these doublets seem to arise by an insertion event that produces a copy without markedly affecting the surrounding sequence. Most doublets in humans are shared with chimpanzee, but many new pairs arose after the divergence of the species. Doublets found in human but not chimpanzee are most often composed of almost tandem matches, whereas older doublets (found in both species) are more likely to have matches spaced by approximately 1 kb, indicating that the nearly tandem doublets may be more dynamic. The spacing of doublets is highly conserved. So far, we have found clearly recognizable doublets in the following genomes: Homo sapiens, Mus musculus, Arabidopsis thaliana, and Caenorhabditis elegans, indicating that the mechanism generating these doublets is widespread. A mechanism that generates short local duplications while conserving polarity could have a profound impact on the evolution of regulatory and protein-coding sequences.

Animals↗

PubMed2025

The evolutionary trajectories and gene regulatory roles of nuclear-integrated plastid DNA: clues for enhancing environmental adaptation in Caryophyllales.

Environmental stimuli can induce the transfer of chloroplast DNA to the nuclear genome, resulting in nuclear-integrated plastid DNAs (NUPTs). However, their role in plant adaptability remains unclear. Species within the Caryophyllales order, known for their adaptation to extreme environments, provide an ideal model for studying the evolutionary dynamics and functions of NUPTs. In this study, we analyzed NUPTs in 24 Caryophyllales species to investigate their evolution and regulatory roles in gene expression, particularly in response to environmental stimuli. We found significant interspecies variation in NUPT abundance, ranging from 566 insertions in Amaranthus cruentus to 3585 in Beta vulgaris, with sizes spanning from 100 bp to over 100 kb. Approximately 62% of NUPTs were inserted within the last 20 million years, while some species exhibit insertion peaks dating back 49 million years. NUPT presence/absence polymorphisms in six related species suggest that NUPT insertions and deletions are dynamic processes influenced by phylogeny. NUPTs predominantly integrate into intergenic regions but also insert into genes and promoters, with certain regions acting as hotspots. Notably, NUPTs introduce numerous environmental-responsive cis-acting elements in promoter regions. Genes with NUPT insertions in their promoters are significantly enriched for functions related to environmental response. Further luciferase assays in Spinacia oleracea demonstrated that NUPT insertions can regulate the expression of genes related to environmental responses, indicating their potential role in adaptive evolution. Overall, our study provides insights into NUPT evolution and their influence on gene function and plant adaptability to environmental stimuli.

Plastids↗

PubMed2002

Length polymorphism of thymidylate synthase regulatory region in Chinese populations and evolution of the novel alleles.

The tandemly repeated 28-bp sequence in the 5'-terminal regulatory region of human thymidylate synthase (TSER), which has been reported to be polymorphic in different populations, was surveyed in 668 Chinese from 9 Han groups, 8 ethnic populations, and 36 individuals representing a three-generation pedigree. Amplified fragments were separated by electrophoresis on 4% agarose gel. In addition to the reported double and triple repeats of the 28-bp sequence in TSER, we also detected a novel quintuple repeat in this region. The transient expression activity of TSER with the quintuple repeat is almost the same as that of the reported TSER with the triple repeat. All three alleles of the repeat type (2, 3, and 5) were further confined by sequencing. The frequencies of the TSER allele 2 and 3 were 18.82 and 81% in totally unrelated Chinese samples, respectively, while the frequency of allele 3 was variable in different Chinese populations with a range from 62 to 95%. On the basis of the sequences of the different alleles, the existence of the tandem repeats in each allele might be explained by slipped-strand mispairing during DNA replication.

Alleles↗

PubMedDate not supplied

New trends in regulatory rules and surveillance of antimicrobial resistance in bacteria of animal origin.

Since the introduction in the 1940s of antibiotics as drugs against bacterial infections in human and then veterinary medicine, two major events have caused a shift in the antibiotherapy era: (1) the emergence of resistant bacteria and (2) the awareness of the limits of new drug development. It rapidly became urgent to set up measures in order to evaluate the importance of resistant bacteria and their origin as well as to limit the dissemination of resistant vectors (bacteria and bacterial genes). This led to the establishment of guidelines and regulatory rules necessary for risk assessment and clearly dependent upon monitoring and research organisations. At a veterinary level, the possible dissemination of multiresistant bacteria from animals to humans, through feeding, urged various national European and international institutions to give general recommendations to monitor and contain the emergence and diffusion of resistant strains. This paper gives an overview of the evolution of regulatory rules and monitoring systems dealing with multiresistant bacteria.

Animal Diseases↗

PubMed2000

Conservation of plasma regulatory proteins of the complement system in evolution: humans and fish.

The complement system is an important defense system of innate immunity. The recent identification of structurally and functionally related complement regulatory proteins in the teleost, barred sand bass (Paralabrax nebulifer), and humans, two species which are separated in evolution by 100 million years, indicates a high level of conservation and the early presence of this defense system in evolution. The complement regulatory protein of barred sand bass, SBP1, is related to both the human alternative pathway regulator factor H, and to the classical pathway regulator C4bp, and displays regulatory activities in both human pathways. In addition, molecules with homology to the recently identified human factor-H-related proteins are also present in the sand bass genome. Here, we summarize the structural and functional aspects of these homologies and discuss the consequences for the evolution of the complement system.

Animals↗