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PubMed1989

Novel phytochrome sequences in Arabidopsis thaliana: structure, evolution, and differential expression of a plant regulatory photoreceptor family.

Phytochrome is a plant regulatory photoreceptor that mediates red light effects on a wide variety of physiological and molecular responses. DNA blot analysis indicates that the Arabidopsis thaliana genome contains four to five phytochrome-related gene sequences. We have isolated and sequenced cDNA clones corresponding to three of these genes and have deduced the amino acid sequence of the full-length polypeptide encoded in each case. One of these proteins (phyA) shows 65-80% amino acid sequence identity with the major, etiolated-tissue phytochrome apoproteins described previously in other plant species. The other two polypeptides (phyB and phyC) are unique in that they have low sequence identity (approximately 50%) with each other, with phyA, and with all previously described phytochromes. The phyA, phyB, and phyC proteins are of similar molecular mass, have related hydropathic profiles, and contain a conserved chromophore attachment region. However, the sequence comparison data indicate that the three phy genes diverged early in plant evolution, well before the divergence of the two major groups of angiosperms, the monocots and dicots. The steady-state level of the phyA transcript is high in dark-grown A. thaliana seedlings and is down-regulated by light. In contrast, the phyB and phyC transcripts are present at lower levels and are not strongly light-regulated. These findings indicate that the red/far light-responsive phytochrome photoreceptor system in A. thaliana, and perhaps in all higher plants, consists of a family of chromoproteins that are heterogeneous in structure and regulation.

Amino Acid Sequence↗

PubMed2005

Evolution of novel functions: cryptocyanin helps build new exoskeleton in Cancer magister.

Hemocyanin, the blue blood protein of many arthropods and molluscs, reversibly binds oxygen at its highly conserved copper-oxygen-binding sites and supplies tissues with oxygen. Cryptocyanin, closely related structurally and phylogenetically to arthropod hemocyanin, lacks several of the six critical copper-binding histidines, however, and has lost the ability to bind oxygen. Despite this loss of function, cryptocyanin continues to be synthesized, an indication that it has been exploited to carry out new functions. Here, we show that cryptocyanin is present in extremely high concentrations in the hemolymph of the crab during the premolt portion of the molt cycle. Both proteins are specifically expressed in the same type of cell in the hepatopancreas and secreted into the hemolymph, but cryptocyanin plays a major role in forming the new exoskeleton, while hemocyanin functions in oxygen transport. A cessation in cryptocyanin, but not hemocyanin, synthesis after eyestalk ablation supports our hypothesis that cryptocyanin is closely regulated by molting hormones. The contrasts between the two gene products illustrate how a gene duplication of a copper-oxygen protein and its subsequent mutation may work in concert with the evolution of new regulatory mechanisms, leading to the assumption of new functions.

Animals↗

PubMed1987

Structure and evolution of human apolipoprotein genes: identification of regulatory elements of the human apolipoprotein E gene.

The structures of the major human apolipoprotein genes have been determined. The genes for apoE, apoC-I, apoC-II, apoC-III, apoA-I, apoA-II and apoA-IV have similar structures, consisting of four exons and three introns, which suggests that they evolved from a common ancestral gene. The third and fourth exons of the ancestral gene appear to have evolved from the duplication of a 66-nucleotide repeat unit that encodes a 22-residue alpha-helical peptide element of amphipathic character. The apoA-I, apoC-III and apoA-IV genes are linked closely within a 20-kilobase (kb) span of chromosome 11. The apoE and apoC-I genes, together with an apoC-I' pseudogene, are linked closely within a 25-kb span of chromosome 19. To characterize potential functional relationships among the apolipoprotein genes, initial studies have been done to identify the molecular elements involved in the regulation of the human apoE gene. Fragments of the 5'-flanking portion of this gene were inserted into appropriate plasmid vectors, which contained the bacterial chloramphenicol acetyl transferase gene, and were examined for promoter activity and potential enhancer activity after transfection into cultured mammalian cells. Deletion mapping of the promoter region has identified multiple functional elements, including an enhancer, two G-C boxes (Sp 1 transcription factor binding sites) and an upstream control element. In addition, there is an enhancer located in the first intron. Interactions among these various control elements are likely to determine the ways in which the expression of the apoE gene is regulated.

Apolipoproteins E↗

PubMed1996

Evolution of proneural atonal expression during distinct regulatory phases in the developing Drosophila eye.

BACKGROUND: Receptors of the Notch family affect the determination of many cell types. In the Drosophila eye, Notch antagonises the basic helix-loop-helix (bHLH) protein atonal, which is required for R8 photoreceptor determination. Similar antagonism between Notch and proneural bHLH proteins regulates most neural cell determination, however, it is uncertain whether the mechanisms are similar in all cases. Here, we have analyzed the sensitivity of atonal expression to Notch signalling using a temperature-sensitive Notch allele, by the expression of activated Notch or of the ligand Serrate, and by monitoring expression of the atonal-dependant gene scabrous and of the Notch-dependent Enhancer of split genes. RESULTS: The atonal expression pattern evolves from general "prepattern' expression, through transient "intermediate groups' to R8 precursor-specific expression. Successive phases of atonal expression differ in sensitivity to Notch. Prepattern expression of atonal is not inhibited. Inhibition begins at the intermediate group stage, corresponding to the period when atonal gene function is required for its own expression. At the transition to R8 cell-specific expression, Notch is activated in all intermediate group cells except the R8 cell precursor. R8 cells remain sensitive to inhibition in columns 0 and 1, but become less sensitive thereafter; non-R8 cells do not require Notch activity to keep atonal expression inactive. Thus, Notch signaling is coupled to atonal repression for only part of the atonal expression pattern. Accordingly, the Enhancer-of-split m delta protein is expressed reciprocally to atonal at the intermediate group and early R8 stages, but is expressed in other patterns before and after. CONCLUSIONS: In eye development, inhibition by Notch activity is restricted to specific phases of proneural gene expression, beginning when prepattern decays and is replaced by autoregulation. We suggest that Notch signalling inhibits atonal autoregulation, but not expression by other mechanisms, and that a transition from prepattern to autoregulation is necessary for patterning neural cell determination. Distinct neural tissues might differ in their proneural prepatterns, but use Notch in a similar mechanism.

Animals↗

PubMed2002

Contrasting evolutionary forces in the Arabidopsis thaliana floral developmental pathway.

The floral developmental pathway in Arabidopsis thaliana is composed of several interacting regulatory genes, including the inflorescence architecture gene TERMINAL FLOWER1 (TFL1), the floral meristem identity genes LEAFY (LFY), APETALA1 (AP1), and CAULIFLOWER (CAL), and the floral organ identity genes APETALA3 (AP3) and PISTILLATA (PI). Molecular population genetic analyses of these different genes indicate that the coding regions of AP3 and PI, as well as AP1 and CAL, share similar levels and patterns of nucleotide diversity. In contrast, the coding regions of TFL1 and LFY display a significant reduction in nucleotide variation, suggesting that these sequences have been subjected to a recent adaptive sweep. Moreover, the promoter of TFL1, unlike its coding region, displays high levels of diversity organized into two distinct haplogroups that appear to be maintained by selection. These results suggest that patterns of molecular evolution differ among regulatory genes in this developmental pathway, with the earlier acting genes exhibiting evidence of adaptive evolution.

Arabidopsis↗

PubMed2003

In silico analysis reveals substantial variability in the gene contents of the gamma proteobacteria LexA-regulon.

MOTIVATION: Motif-prediction algorithm capabilities for the analysis of bacterial regulatory networks and the prediction of new regulatory sites can be greatly enhanced by the use of comparative genomics approaches. In this study, we make use of a consensus-building algorithm and comparative genomics to conduct an in-depth analysis of the LexA-regulon of gamma proteobacteria, and we use the inferred results to study the evolution of this regulatory network and to examine the usefulness of the control sequences and gene contents of regulons in phylogenetic analysis. RESULTS: We show, for the first time, the substantial heterogeneity that the LexA-regulon of gamma proteobacteria displays in terms of gene content and we analyze possible branching points in its evolution. We also demonstrate the feasibility of using regulon-related information to derive sound phylogenetic inferences. AVAILABILITY: Complementary analysis data and both the source code and the Windows-executable files of the consensus-building software are available at http://www.cnm.es/~ivan/RCGScanner/

Algorithms↗

PubMed1983

Evolution of Ca2+- and cAMP-dependent regulatory mechanisms during ram spermatogenesis.

Calmodulin level and cAMP-dependent protein kinase activity of ram germ cells at different stages of spermatogenesis have been determined. Calmodulin levels decrease during maturation. Simultaneously, calmodulin localization changes during cell differentiation. In round, elongating, and elongated spermatids, calmodulin is closely associated with the developing acrosome; in spermatozoa, it becomes present in the postacrosome, the neck region and the tail. Protein kinase activity is relatively low in testicular cells but increases dramatically during epididymal maturation of spermatozoa. A concerted regulation by cAMP and Ca2+ of biochemical events in spermatogenic cells and spermatozoa is suggested.

Animals↗

PubMed2001

The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.

Evolution of the human heart has incorporated a variety of successful strategies for motion used throughout the animal kingdom. One such strategy is to add the efficiency of torsion to compression so that blood is wrung, as well as pumped, out of the heart. Models of cardiac torsion have assumed uniform contractile properties of muscle fibers throughout the heart. Here, we show how a spatial gradient of myosin light chain phosphorylation across the heart facilitates torsion by inversely altering tension production and the stretch activation response. To demonstrate the importance of cardiac light chain phosphorylation, we cloned a myosin light chain kinase from a human heart and have identified a gain-in-function mutation in two individuals with cardiac hypertrophy.

Animals↗

PubMed2004

Molecular origins of rapid and continuous morphological evolution.

Mutations in cis-regulatory sequences have been implicated as being the predominant source of variation in morphological evolution. We offer a hypothesis that gene-associated tandem repeat expansions and contractions are a major source of phenotypic variation in evolution. Here, we describe a comparative genomic study of repetitive elements in developmental genes of 92 breeds of dogs. We find evidence for selection for divergence at coding repeat loci in the form of both elevated purity and extensive length polymorphism among different breeds. Variations in the number of repeats in the coding regions of the Alx-4 (aristaless-like 4) and Runx-2 (runt-related transcription factor 2) genes were quantitatively associated with significant differences in limb and skull morphology. We identified similar repeat length variation in the coding repeats of Runx-2, Twist, and Dlx-2 in several other species. The high frequency and incremental effects of repeat length mutations provide molecular explanations for swift, yet topologically conservative morphological evolution.

Alleles↗

PubMed2004

Mathematical methods for inferring regulatory networks interactions: application to genetic regulation.

This paper deals with the problem of reconstruction of the intergenic interaction graph from the raw data of genetic co-expression coming with new technologies of bio-arrays (DMA-arrays, protein-arrays, etc.). These new imaging devices in general only give information about the asymptotical part (fixed configurations of co-expression or limit cycles of such configurations) of the dynamical evolution of the regulatory networks (genetic and/or proteic) underlying the functioning of living systems. Extracting the casual structure and interaction coefficients of a gene interaction network from the observed configurations is a complex problem. But if all the fixed configurations are supposedly observed and if they are factorizable into two or more subsets of values, then the interaction graph possesses as many connected components as the number of factors and the solution is obtained in polynomial time. This new result allows us for example to partly solve the topology of the genetic regulatory network ruling the flowering in Arabidopsis thaliana .

Algorithms↗

PubMed2004

Variation in sequence and organization of splicing regulatory elements in vertebrate genes.

Although core mechanisms and machinery of premRNA splicing are conserved from yeast to human, the details of intron recognition often differ, even between closely related organisms. For example, genes from the pufferfish Fugu rubripes generally contain one or more introns that are not properly spliced in mouse cells. Exploiting available genome sequence data, a battery of sequence analysis techniques was used to reach several conclusions about the organization and evolution of splicing regulatory elements in vertebrate genes. The classical splice site and putative branch site signals are completely conserved across the vertebrates studied (human, mouse, pufferfish, and zebrafish), and exonic splicing enhancers also appear broadly conserved in vertebrates. However, another class of splicing regulatory elements, the intronic splicing enhancers, appears to differ substantially between mammals and fish, with G triples (GGG) very abundant in mammalian introns but comparatively rare in fish. Conversely, short repeats of AC and GT are predicted to function as intronic splicing enhancers in fish but are not enriched in mammalian introns. Consistent with this pattern, exonic splicing enhancer-binding SR proteins are highly conserved across all vertebrates, whereas heterogeneous nuclear ribonucleoproteins, which bind many intronic sequences, vary in domain structure and even presence/absence between mammals and fish. Exploiting differences in intronic sequence composition, a statistical model was developed to predict the splicing phenotype of Fugu introns in mammalian systems and was used to engineer the spliceability of a Fugu intron in human cells by insertion of specific sequences, thereby rescuing splicing in human cells.

Animals↗

PubMed1992

Conserved regulatory mechanisms of tyrosinase genes in mice and humans.

In vertebrates, melanin production is restricted to pigment cells. This cell type-specific melanogenesis is considered to involve cell type-specific expression of the tyrosinase gene. Recently, there have been several reports that sequences in the 5' flanking region of the mouse tyrosinase gene are responsible for cell type-specific expression of the transgene in mice. As the first step in the study of the evolution of the regulatory mechanisms for tyrosinase gene function in vertebrates, we constructed a fused gene, hg-Tyrs-J, which includes a 1.0-kb 5' flanking sequence of the human tyrosinase gene fused with mouse tyrosinase cDNA. By introducing the fused gene into fertilized eggs of albino mice, we obtained two mice that exhibited pigmentation in the skin and eyes and established a transgenic line from one of them. Further analyses revealed that the transgene was expressed cell type-specifically in these transgenic mice. We conclude, therefore, that the 1.0 kb 5' upstream region of the human tyrosinase gene contains conserved cis-elements essential for cell type-specific expression of the tyrosinase genes in mice and humans. Results of our study may provide a clue to elucidate the evolutionary process of regulatory mechanisms of the tyrosinase gene.

Animals↗

PubMed1987

Ubiquitous upstream repression sequences control activation of the inducible arginase gene in yeast.

Expression of the yeast arginase gene (CAR1) responds to both induction and nitrogen catabolite repression. Regulation is mediated through sequences that both positively and negatively modulate CAR1 transcription. A short sequence, 5'-TAGCCGCCGAGGG-3', possessing characteristics of a repressor binding site, plays a central role in the induction process. A fragment containing this upstream repression sequence (URS1) repressed gene expression when placed either 5' or 3' to the upstream activation sequences of the heterologous gene CYC1. Action of the URS and its cognate repressor was overcome by CAR1 induction when the URS was situated cis to the CAR1 flanking sequences. This was not observed, however, when it was situated downstream of a heterologous CYC1 upstream activation sequence indicating that URS function is specifically neutralized by cis-acting elements associated with CAR1 induction. Searches of sequences in various gene banks revealed that URS1-like sequences occur ubiquitously in genetic regulatory regions including those of bacteriophage lambda, yeast, mammalian, and viral genes. In a significant number of cases the sequence is contained in a region associated with negative control of yeast gene regulation. These data suggest the URS identified in this work is a generic repressor target site that apparently has been conserved during the evolution of transcriptional regulatory systems.

Arginase↗

PubMed2005

Evolution of the signaling system in relaxin-family peptides.

Recent studies have characterized two G-protein-coupled receptors (GPCRs), LGR7 and LGR8, as relaxin receptors. Later studies have shown that LGR7 and LGR8 also are cognate receptors for the relaxin-family peptides, INSL7/relaxin3 and INSL3, respectively. In addition, INSL7/relaxin3 signals through two orphan GPCRs, GPCR135 and GPCR142, whereas INSL5 is a select ligand for GPCR142. These findings have greatly enhanced our understanding of the physiology and signaling of this unique group of peptide hormones. Phylogenetic analysis of relaxin-family peptides and their co-evolved receptors suggests that the ancestor relaxin gene duplicated multiple times in a vertebrate branch-specific manner. Among the seven human relaxin-family peptides (relaxin1, relaxin2, INSL3/RLF, INSL4/EPIL, INSL5/RIF2, INSL6/RIF1, and INSL7/relaxin3), INSL7 and INSL5 could represent the most ancient form. By contrast, the most widely studied family peptides, human relaxins H1 and H2, appear to be derived from recent gene duplication in mammals. Therefore, relaxin-family peptides could be important for the evolution and adaptation to lineage-specific physiologic processes during evolution. Duplicated relaxin-family genes assumed regulatory roles in newly evolved reproductive processes, and relaxin/LGR signaling was harnessed for signaling in the uterus and mammary gland in addition to other tissues. Although the precise evolutionary history of relaxin ligand/receptor pairs remains to be elucidated, these findings indicate that the expansion of relaxin-family genes and their specific regulatory functions have evolved during vertebrate evolution to allow the development of a tissue-specific regulatory mechanism in a lineage-specific manner and provide a revealing portrait of molecular evolution in action.

Animals↗

PubMed2003

Evolution of Brachyury proteins: identification of a novel regulatory domain conserved within Bilateria.

Orthologues of Brachyury, a subfamily of T-box transcription factors, specify distinct cell types in different metazoan phyla, suggesting that the function of these genes has changed through the course of evolution. To investigate this evolutionary process, we have compared the activities of Brachyury orthologues from all major phyla in a single cellular context, the pluripotent Xenopus laevis animal cap. In this assay, an ancestral function is revealed: most orthologues, including the Hydra protein, mimic the action of endogenous Xenopus Brachyury, in that they induce mesoderm but not endoderm. Orthologues from Drosophila and ascidians, however, display an additional derived property, represented in our assay by the induction of endoderm. Misexpression of chimeric versions of Brachyury reveals that the C-terminal half of the protein is important for the strength of the induced response but not for its specificity. In contrast, amino acids located within the T-domain and in a short N-terminal peptide are involved in restricting the activity of Brachyury proteins to induction of mesoderm and not endoderm. Possession of this N-terminal motif is correlated with early circumblastoporal expression of Brachyury orthologues. We propose that restriction of Brachyury activity by this motif plays a conserved role in the control of Bilaterian gastrulation.

Amino Acid Sequence↗

PubMed2003

Composition-sensitive analysis of the human genome for regulatory signals.

Known transcription regulatory signals which generally act as transcription factor binding sites (TFs) differ significantly in their base composition. Therefore, their occurrence in a genome largely depends on the local base composition. In an attempt to initiate an all human genome analysis for the occurrence of potential TFs, we systematically analyzed the GC-content of distinct functional regions (e. g., upstream and downstream gene regions, exons, long and short introns, repetitive elements) and correlated the frequencies of potential binding sites of a representative set of TFs in these regions. For these analyses, we used the pattern collection of the TRANSFAC database on transcriptional regulation, the information about functionally relevant combinations of them from the database TRANSCompel, and our new resource, TRANSGenomeTM, which provides an overall annotation of the human genome with emphasis on its regulatory characteristics. We show that the occurrence of sequence patterns with regulatory potential may be supported by, but cannot be fully explained by either the GC content of a whole chromosome or its putative promoter regions, nor by the information content of the patterns. Several patterns, HNF-3, NFAT, and GC box, show a clear overrepresentation in all promoter groups as well as in all chromosomes. Other patterns, like E2F and CRE-BP1, are underrepresented in all promoter groups as well as in all chromosomes in comparison with random sequences. Simultaneously, both patterns are over-represented in promoters in comparison with repetitive elements. We define several structural characteristics of the proximal promoters that differentiate them from other functional genomic regions. Two well-known promoter elements, GC- and TATA-boxes, are statistically enriched in promoters in comparison with random sequences, repetitive elements and exons. Altogether, our findings provide insights into the macroheterogeneity amongst the individual chromosomes, into the microheterogeneity among different functional regions of individual chromosomes, contribute to further understanding of structural organization of gene regulatory regions, and give first hints on the development of regulatory features during evolution.

Animals↗

PubMedDate not supplied

Intrinsically driven changes in gene interaction complexity. I. Growth of regulatory complexes and increase in number of genes.

A two-step process, previously considered in the literature, and here named coadaptational drive, is deemed to be largely responsible for both increases in the complexity of transcriptional control and increases in the total gene number, along lines of descent leading to more complex organisms. Coadaptational drive consists in a succession of modifications in the interaction among informational macromolecules, namely, structural decay spread by genetic drift and repair spread by selection. Increased genetic complexity, drawing on the opportunities offered by gene duplication, may be considered to be a secondary effect of such processes of decay and repair. The evolution toward higher regulatory complexity is thus considered to be obligatorily founded in part on random genetic drift. Increases in this complexity would represent primarily a trend intrinsic to the internal molecular environment, with the external environment having only to concur. Direct selection of mutations that increase complexity without the intervention of a phase of genetic drift is acknowledged likely to be a significant process as well, but it is claimed that a sequence of events of direct selection cannot be unlimited and will eventually stall, and that the roots of such a sequence ultimately are to be traced to an episode of coadaptational drive. Controller gene diseases, mostly mild, therefore seem to be essential for the evolution of increased biological complexity. The attempt is made to show or to confirm that (i) a conservative force (repair) provides a mechanism for the generation of novelty, (ii) a prominent part of selection, counterpart to Darwinian selection, originates from the internal environment and derives from the mechanics of genomic processes, and (iii) this selection is at times directional and leads to increases in complexity.

Animals↗

PubMed2005

Prediction of cis-regulatory elements using binding site matrices--the successes, the failures and the reasons for both.

Protein-DNA interactions control many aspects of animal development and cellular responses to the environment. Although profiling of individual transcription factor binding sites is not a reliable guide for predicting the position of cis-regulatory elements in large genomes, modelling the evolution and the organization of regulatory elements has provided enough information to make some successful predictions. For vertebrate genomes, the field is limited by the lack of sufficient experimental data upon which to build reliable models. Nonetheless, a combination of experimental, computational and comparative data is likely to reveal aspects of complex regulatory networks in vertebrates, just as it has already done for simple eukaryotic genomes.

Animals↗