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PubMed2006

Network topology and the evolution of dynamics in an artificial genetic regulatory network model created by whole genome duplication and divergence.

Topological measures of large-scale complex networks are applied to a specific artificial regulatory network model created through a whole genome duplication and divergence mechanism. This class of networks share topological features with natural transcriptional regulatory networks. Specifically, these networks display scale-free and small-world topology and possess subgraph distributions similar to those of natural networks. Thus, the topologies inherent in natural networks may be in part due to their method of creation rather than being exclusively shaped by subsequent evolution under selection. The evolvability of the dynamics of these networks is also examined by evolving networks in simulation to obtain three simple types of output dynamics. The networks obtained from this process show a wide variety of topologies and numbers of genes indicating that it is relatively easy to evolve these classes of dynamics in this model.

Computational Biology↗

PubMed2000

Strategic use of statistical thinking in drug development.

The role of the statistician and statistical thinking in the pharmaceutical industry has evolved greatly in the last four or five decades. Regulatory developments and the changing face of the science of drug development have driven this evolution. The increasing regulatory requirement for statistical input in critical areas has facilitated a wider range of applications. The pace of change of science in general has brought statisticians into contact with a wider range of potential customers. More importantly, it has allowed the statistician to become increasingly involved in strategic issues with the possibility of influencing the direction of the business. However, it is not clear that the statistical profession in industry is adequately prepared for these opportunities either in attitude or training. Changing the statisticians' approach to their role and acquiring the correct training and experience are critical for the profession to optimize their contribution to the drug discovery and development processes.

Drug Approval↗

PubMed1990

Regulatory DNA sequence conserved in the course of BK virus evolution.

Within the genome of human polyomavirus BK (BKV), there exists a noncoding regulatory region toward the late region side of the origin of DNA replication. In most BKV strains isolated by viral culture, this regulatory region contains tandem repeats varying in size. Recently, however, several laboratories isolated new BKV strains (designated as archetypal strains) lacking such repeat sequences. To examine the genetic relationship between archetypal strains, a phylogenetic tree was constructed for seven BKV strains, including three archetypal strains, from DNA sequence data on the late genes, those for leader protein (agnoprotein), and those for structural proteins (VP1, VP2, and VP3). For three strains data previously reported were used, whereas for the others sequences were determined in this study. From total numbers of nucleotide substitutions in each pair of strains, a phylogenetic tree was constructed by the unweighted pair-group method. The phylogenetic tree obtained reveals that BKV strains containing the archetypal regulatory region do not constitute a cluster of closely related strains and that these strains, together with those carrying the major part of the archetypal regulatory region, are widespread in the BKV population. This finding suggests that the basic structure of the archetypal regulatory region has been conserved in the course of BKV evolution.

BK Virus↗

PubMed2003

Turnover of binding sites for transcription factors involved in early Drosophila development.

Despite the importance of cis-regulatory regions in evolution, little is know about their evolutionary dynamics. In this report, we analyze the process of evolution of binding sites for transcription factors using as a model a well characterized system, the Drosophila early developmental enhancers. We compare the sequences of eight enhancer regions for early developmental genes between Drosophila melanogaster and other two species, Drosophila virilis and Drosophila pseudoobscura, searching for the presence/absence of 104 biochemically verified binding sites from D. melanogaster. We also modeled the binding specificity of each binding site by the use of well-defined positional weight matrices (PWMs). The comparisons showed that turnover of binding sites seems to fit a molecular clock, at an approximate rate of 0.94% of gain/loss of binding sites per million years. This intense turnover affects both high and low affinity binding sites at the same extent. Furthermore, the subset of overlapping binding sites is also subjected to this high turnover. Conserved binding sites seem to be constrained to maintain not only location but also the exact sequence at each particular position. Finally, we detected a significant decrease in mean PWM scores for the D. virilis binding sites in the case of Hunchback. Possible explanations for this fact are discussed.

Animals↗

PubMed2003

Developmental gene regulatory network architecture across 500 million years of echinoderm evolution.

Evolutionary change in morphological features must depend on architectural reorganization of developmental gene regulatory networks (GRNs), just as true conservation of morphological features must imply retention of ancestral developmental GRN features. Key elements of the provisional GRN for embryonic endomesoderm development in the sea urchin are here compared with those operating in embryos of a distantly related echinoderm, a starfish. These animals diverged from their common ancestor 520-480 million years ago. Their endomesodermal fate maps are similar, except that sea urchins generate a skeletogenic cell lineage that produces a prominent skeleton lacking entirely in starfish larvae. A relevant set of regulatory genes was isolated from the starfish Asterina miniata, their expression patterns determined, and effects on the other genes of perturbing the expression of each were demonstrated. A three-gene feedback loop that is a fundamental feature of the sea urchin GRN for endoderm specification is found in almost identical form in the starfish: a detailed element of GRN architecture has been retained since the Cambrian Period in both echinoderm lineages. The significance of this retention is highlighted by the observation of numerous specific differences in the GRN connections as well. A regulatory gene used to drive skeletogenesis in the sea urchin is used entirely differently in the starfish, where it responds to endomesodermal inputs that do not affect it in the sea urchin embryo. Evolutionary changes in the GRNs since divergence are limited sharply to certain cis-regulatory elements, whereas others have persisted unaltered.

Animals↗

PubMedDate not supplied

Redox regulation and modification of proteins controlling chloroplast gene expression.

Chloroplasts are typical organelles of plant cells and represent the site of photosynthesis. As one very remarkable feature, they possess their own genome and a complete machinery to express the genetic information in it. The plastid gene expression machinery is a unique assembly of prokaryotic-, eukaryotic-, and phage-like components because chloroplasts acquired a great number of regulatory proteins during evolution. Such proteins can be found at all levels of gene expression. They significantly expand the functional and especially the regulatory properties of the "old" gene expression system that chloroplasts inherited from their prokaryotic ancestors. Recent results show that photosynthesis has a strong regulatory effect on plastid gene expression. The redox states of electron transport components, redox-active molecules coupled to photosynthesis, and pools of reactive oxygen species act as redox signals. They provide a functional feedback control, which couples the expression of chloroplast genes to the actual function of photosynthesis and, by this means, helps to acclimate the photosynthetic process to environmental cues. The redox signals are mediated by various specific signaling pathways that involve many of the "new" regulatory proteins. Chloroplasts therefore are an ideal model to study redox-regulated mechanisms in gene expression control. Because of the multiple origins of the expression machinery, these observations are of great relevance for many other biological systems.

Chloroplasts↗

PubMed2006

Repression and loss of gene expression outpaces activation and gain in recently duplicated fly genes.

Evolutionists widely acknowledge that regulatory genetic changes are of paramount importance for morphological and genomic evolution. Nevertheless, mechanistic complexity and a paucity of data from nonmodel organisms have prevented testing and quantifying universal hypotheses about the macroevolution of gene regulatory mechanisms. Here, we use a phylogenetic approach to provide a quantitative demonstration of a previously hypothesized trend, whereby the evolutionary rate of repression or loss of gene expression regions is significantly higher than the rate of activation or gain. Such a trend is expected based on case studies in regulatory evolution and under models of molecular evolution where duplicated genes lose duplicated expression patterns in a complementary fashion. The trend is important because repression of gene expression is a hypothesized mechanism for the origin of evolutionarily novel morphologies through specialization.

Animals↗

PubMed2002

Molecular characterization and evolution of the protein phosphatase 2A B' regulatory subunit family in plants.

Type 2A serine/threonine protein phosphatases (PP2A) are important components in the reversible protein phosphorylation events in plants and other organisms. PP2A proteins are oligomeric complexes constituted by a catalytic subunit and several regulatory subunits that modulate the activity of these phosphatases. The analysis of the complete genome of Arabidopsis allowed us to characterize four novel genes, AtB'epsilon, AtB'zeta, AtB'eta, and AtB'theta;, belonging to the PP2A B' regulatory subunit family. Because four genes of this type had been described previously, this family is composed of eight members. Reverse transcriptase-polymerase chain reaction experiments showed that AtB'epsilon mRNAs are present in all Arabidopsis tissues analyzed, and their levels do not respond significantly to heat stress. Expressed sequence tags corresponding to AtB'zeta, AtB'eta, and AtB'theta; have been identified, indicating that the new genes are actively transcribed. The genomic organization of this family of PP2A regulatory subunits is reported, as well as its chromosomal location. An extensive survey of the family has been carried out in plants, characterizing B' subunits in a number of different species, and performing a phylogenetic study that included several B' regulatory proteins from animals. Our results indicate that the animal and plant proteins have evolved independently, that there is a relationship between the number of B' isoforms and the complexity of the organism, and that there are at least three main subfamilies of regulatory subunits in plants, which we have named alpha, eta, and kappa.

Amino Acid Sequence↗

PubMed2001

Mechanism and regulation of transcription in archaea.

The archaeal basal transcription machinery resembles the core components of the eucaryal RNA polymerase II apparatus. Thus, studies of the archaeal basal machinery over the last few years have shed light on fundamentally conserved aspects of the mechanisms of transcription pre-initiation complex assembly in both eucarya and archaea. Intriguingly, it has become increasingly apparent that regulators of archaeal transcription resemble regulators initially identified in bacteria. The presence of these shared bacterial-archaeal regulators has given insight into the evolution of gene regulatory processes in all three domains of life.

Archaea↗

PubMed2006

The origin and evolution of stereotyped patterns of macrochaetes on the nota of cyclorraphous Diptera.

A long-standing problem in evolutionary biology is how genetic variation arises within populations and evolves to make species anatomically different. Many of the morphological differences in body plans between animal groups are thought to result from changes in gene expression during development. The rules governing the structure and evolution of cis-regulatory gene sequences are unknown, however, and the evolution of traits between closely related species remains relatively unexplored at a molecular level. To study the evolution of gene regulation, it is necessary to find a tractable trait that varies between species and for which the genetic regulation is well known in at least one of the species. The stereotyped, two-dimensional pattern of bristles on the thorax of Drosophila has been intensively investigated and is due to a precise spatial expression of proneural genes. Other species of flies have different bristle patterns and so comparisons between them provide a good paradigm for the study of changes in gene regulation. Here, we review the current state of understanding of these changes.

Animals↗

PubMed2002

Discovering regulatory and signalling circuits in molecular interaction networks.

MOTIVATION: In model organisms such as yeast, large databases of protein-protein and protein-DNA interactions have become an extremely important resource for the study of protein function, evolution, and gene regulatory dynamics. In this paper we demonstrate that by integrating these interactions with widely-available mRNA expression data, it is possible to generate concrete hypotheses for the underlying mechanisms governing the observed changes in gene expression. To perform this integration systematically and at large scale, we introduce an approach for screening a molecular interaction network to identify active subnetworks, i.e., connected regions of the network that show significant changes in expression over particular subsets of conditions. The method we present here combines a rigorous statistical measure for scoring subnetworks with a search algorithm for identifying subnetworks with high score. RESULTS: We evaluated our procedure on a small network of 332 genes and 362 interactions and a large network of 4160 genes containing all 7462 protein-protein and protein-DNA interactions in the yeast public databases. In the case of the small network, we identified five significant subnetworks that covered 41 out of 77 (53%) of all significant changes in expression. Both network analyses returned several top-scoring subnetworks with good correspondence to known regulatory mechanisms in the literature. These results demonstrate how large-scale genomic approaches may be used to uncover signalling and regulatory pathways in a systematic, integrative fashion.

Algorithms↗

PubMed2006

Variation within and among species in gene expression: raw material for evolution.

Heritable variation in regulatory or coding regions is the raw material for evolutionary processes. The advent of microarrays has recently promoted examination of the extent of variation in gene expression within and among taxa and examination of the evolutionary processes affecting variation. This review examines these issues. We find: (i) microarray-based measures of gene expression are precise given appropriate experimental design; (ii) there is large inter-individual variation, which is composed of a minor nongenetic component and a large heritable component; (iii) variation among populations and species appears to be affected primarily by neutral drift and stabilizing selection, and to a lesser degree by directional selection; and (iv) neutral evolutionary divergence in gene expression becomes nonlinear with greater divergence times due to functional constraint. Evolutionary analyses of gene expression reviewed here provide unique insights into partitioning of regulatory variation in nature. However, common limitations of these studies include the tendency to assume a linear relationship between expression divergence and species divergence, and failure to test explicit hypotheses that involve the ecological context of evolutionary divergence.

Animals↗

PubMed2006

Differentiated evolutionary rates in alternative exons and the implications for splicing regulation.

BACKGROUND: Alternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences. RESULTS: We find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values. CONCLUSION: We conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.

Alternative Splicing↗

PubMed2003

Functional evolution in the ancestral lineage of vertebrates or when genomic complexity was wagging its morphological tail.

Early vertebrate evolution is characterized by a significant increase of organismal complexity over a relatively short time span. We present quantitative evidence for a high rate of increase in morphological complexity during early vertebrate evolution. Possible molecular evolutionary mechanisms that underlie this increase in complexity fall into a small number of categories, one of which is gene duplication and subsequent structural or regulatory neofunctionalization. We discuss analyses of two gene families whose regulatory and structural evolution shed light on the connection between gene duplication and increases in organismal complexity.

Animals↗

PubMed2000

Bacterial virulence gene regulation: an evolutionary perspective.

Coevolution between bacteria and their plant or animal hosts determines characteristics of the interaction, the bacterial virulence genes involved, and the regulatory systems controlling expression of virulence genes. The long-standing association between Salmonellae and their animal hosts has resulted in the acquisition by Salmonella subspecies of a variety of virulence genes and the evolution of complex regulatory networks. The particular repertoire of virulence genes acquired by different Salmonella enterica subspecies and the regulatory systems that control them dictate subspecies-specific infection characteristics. Although the association between Vibrio cholerae and humans appears to be more recent, to reflect a simpler pathogenic strategy, and to involve fewer virulence genes than that of Salmonellae, complex virulence-regulatory networks have nonetheless evolved. In contrast, there is no evidence for acquisition of virulence genes by horizontal gene transfer in bordetellae, and their virulence regulon is less complex in overall structure than those of salmonellae and Vibrio cholerae. In Bordetellae, subspecies-specific differences in pathogenic strategy appear to result from differential gene expression within and across Bordetella subspecies.

Biological Evolution↗

PubMed2005

Sequence turnover and tandem repeats in cis-regulatory modules in drosophila.

The path by which regulatory sequence can change, yet preserve function, is an important open question for both evolution and bioinformatics. The recent sequencing of two additional species of Drosophila plus the wealth of data on gene regulation in the fruit fly provides new means for addressing this question. For regulatory sequences, indels account for more base pairs (bp) of change than substitutions (between Drosophila melanogaster and Drosophila yakuba), though they are fewer in number. Using Drosophila pseudoobscura as an out-group, we can distinguish insertions from deletions (with maximum parsimony criteria), and find a ratio between 1 and 5 (insertions to deletions) that is species dependent and much larger than the ratio of 1/8 for neutral sequences (Petrov and Hartl 1998). Because neutral sequence is rapidly cleared from the genome, most noncoding regions which preserve their length between D. melanogaster-D. pseudoobscura and have an excess of insertions over deletions should be functional. A fraction of 15%-18% (i.e., more than 20 standard deviations from random expectation) of the regulatory sequence is covered by low copy number tandem repeats whose repeating unit has an average length of 5-10 bp and which occur preferentially (25%-45% coverage) in indels. All indels may be due to tandem repeats if we extrapolate the detection efficiency of the repeat-finding algorithms using the observed point mutation rate between the species we compare. Sequence creation by local duplication accords with the tendency for multiple copies of transcription factor-binding sites to occur in regulatory modules. Thus, indel events and tandem repeats in particular need to be incorporated into models of regulatory evolution because they can alter the rate at which beneficial variants arise and should also influence bioinformatic algorithms that parse regulatory sequences into binding sites.

Animals↗

PubMed1998

The evolutionary analysis of the Tnt1 retrotransposon in Nicotiana species reveals the high variability of its regulatory sequences.

We studied the evolution of the tobacco Tnt1 retrotransposon by analyzing Tnt1 partial sequences containing both coding domains and U3 regulatory sequences obtained from a number of Nicotiana species. We detected three different subfamilies of Tnt1 elements, Tnt1A, Tnt1B, and Tnt1C, that differ completely in their U3 regions but share conserved flanking coding and LTR regions. U3 divergence between the three subfamilies is found in the region that contains the regulatory sequences that control the expression of the well-characterized Tnt1-94 element. This suggests that expression of the three Tnt1 subfamilies might be differently regulated. The three Tnt1 subfamilies were present in the Nicotiana genome at the time of species divergence, but have evolved independently since then in the different genomes. Each Tnt1 subfamily seems to have conserved its ability to transpose in a limited and different number of Nicotiana species. Our results illustrate the high variability of Tnt1 regulatory sequences. We propose that this high sequence variability could allow these elements to evolve regulatory mechanisms in order to optimize their coexistence with their host genome.

Base Sequence↗

PubMed1991

The main regulatory region of mammalian mitochondrial DNA: structure-function model and evolutionary pattern.

The evolution of the main regulatory region (D-loop) of the mammalian mitochondrial genome was analyzed by comparing the sequences of eight mammalian species: human, common chimpanzee, pygmy chimpanzee, dolphin, cow, rat, mouse, and rabbit. The best alignment of the sequences was obtained by optimization of the sequence similarities common to all these species. The two peripheral left and right D-loop domains, which contain the main regulatory elements so far discovered, evolved rapidly in a species-specific manner generating heterogeneity in both length and base composition. They are prone to the insertion and deletion of elements and to the generation of short repeats by replication slippage. However, the preservation of some sequence blocks and similar cloverleaf-like structures in these regions, indicates a basic similarity in the regulatory mechanisms of the mitochondrial genome in all mammalian species. We found, particularly in the right domain, significant similarities to the telomeric sequences of the mitochondrial (mt) and nuclear DNA of Tetrahymena thermophila. These sequences may be interpreted as relics of telomeres present in ancestral linear forms of mtDNA or may simply represent efficient templates of RNA primase-like enzymes. Due to their peculiar evolution, the two peripheral domains cannot be used to estimate in a quantitative way the genetic distances between mammalian species. On the other hand the central domain, highly conserved during evolution, behaves as a good molecular clock. Reliable estimates of the times of divergence between closely and distantly related species were obtained from the central domain using a Markov model and assuming nonhomogeneous evolution of nucleotide sites.

Animals↗