CiteULike: emptyhb's library [167 articles]

Comparative genomics at the vertebrate extremes.

D Boffelli — 2007-04-04T20:07:25-00:00

Nat Rev Genet, Vol. 5, No. 6. (June 2004), pp. 456-465.

Evolution and Selection in Yeast Promoters: Analyzing the Combined Effect of Diverse Transcription Factor Binding Sites

Daniela Raijman — 2008-01-14T10:40:08-00:00

PLoS Computational Biology, Vol. 4, No. 1. (1 January 2008), e7.

In comparative genomics one analyzes jointly evolutionarily related species in order to identify conserved and diverged sequences and to infer their function. While such studies enabled the detection of conserved sequences in large genomes, the evolutionary dynamics of regulatory regions as a whole remain poorly understood. Here we present a probabilistic model for the evolution of promoter regions in yeast, combining the effects of regulatory interactions of many different transcription factors. The model expresses explicitly the selection forces acting on transcription factor binding sites in the context of a dynamic evolutionary process. We develop algorithms to compute likelihood and to learn de novo collections of transcription factor binding motifs and their selection parameters from alignments. Using the new techniques, we examine the evolutionary dynamics in Saccharomyces species promoters. Analyses of an evolutionary model constructed using all known transcription factor binding motifs and of a model learned from the data automatically reveal relatively weak selection on most binding sites. Moreover, according to our estimates, strong binding sites are constraining only a fraction of the yeast promoter sequence that is under selection. Our study demonstrates how complex evolutionary dynamics in noncoding regions emerges from formalization of the evolutionary consequences of known regulatory mechanisms.

Evolution of Transcription Factor Binding Sites in Mammalian Gene Regulatory Regions: Conservation and Turnover

Emmanouil Dermitzakis — 2007-01-17T02:29:55-00:00

Mol Biol Evol, Vol. 19, No. 7. (1 July 2002), pp. 1114-1121.

Comparisons between human and rodent DNA sequences are widely used for the identification of regulatory regions (phylogenetic footprinting), and the importance of such intergenomic comparisons for promoter annotation is expanding. The efficacy of such comparisons for the identification of functional regulatory elements hinges on the evolutionary dynamics of promoter sequences. Although it is widely appreciated that conservation of sequence motifs may provide a suggestion of function, it is not known as to what proportion of the functional binding sites in humans is conserved in distant species. In this report, we present an analysis of the evolutionary dynamics of transcription factor binding sites whose function had been experimentally verified in promoters of 51 human genes and compare their sequence to homologous sequences in other primate species and rodents. Our results show that there is extensive divergence within the nucleotide sequence of transcription factor binding sites. Using direct experimental data from functional studies in both human and rodents for 20 of the regulatory regions, we estimate that 32%-40% of the human functional sites are not functional in rodents. This is evidence that there is widespread turnover of transcription factor binding sites. These results have important implications for the efficacy of phylogenetic footprinting and the interpretation of the pattern of evolution in regulatory sequences.

Rewiring of the Yeast Transcriptional Network Through the Evolution of Motif Usage

Jan Ihmels — 2005-08-05T18:55:10-00:00

Science, Vol. 309, No. 5736. (05 August 2005), pp. 938-940.

Recent experiments revealed large-scale differences in the transcription programs of related species, yet little is known about the genetic basis underlying the evolution of gene expression and its contribution to phenotypic diversity. Here we describe a large-scale modulation of the yeast transcription program that is connected to the emergence of the capacity for rapid anaerobic growth. Genes coding for mitochondrial and cytoplasmic ribosomal proteins display a strongly correlated expression pattern in Candida albicans, but this correlation is lost in the fermentative yeast Saccharomyces cerevisiae. We provide evidence that this change in gene expression is connected to the loss of a specific cis-regulatory element from dozens of genes following the apparent whole-genome duplication event. Our results shed new light on the genetic mechanisms underlying the large-scale evolution of transcriptional networks.

Gene Regulation by Transcription Factors and MicroRNAs

Oliver Hobert — 2008-03-28T15:00:47-00:00

Science, Vol. 319, No. 5871. (28 March 2008), pp. 1785-1786.

The properties of a cell are determined by the genetic information encoded in its genome. Understanding how such information is differentially and dynamically retrieved to define distinct cell types and cellular states is a major challenge facing molecular biology. Gene regulatory factors that control the expression of genomic information come in a variety of flavors, with transcription factors and microRNAs representing the most numerous gene regulatory factors in multicellular genomes. Here, I review common principles of transcription factor and microRNA-mediated gene regulatory events and discuss conceptual differences in how these factors control gene expression. 10.1126/science.1151651

Transcriptional Control in the Segmentation Gene Network of Drosophila

Mark Schroeder — 2007-01-01T19:51:52-00:00

PLoS Biology, Vol. 2, No. 9. (1 September 2004), e271.

The segmentation gene network of Drosophila consists of maternal and zygotic factors that generate, by transcriptional (cross-) regulation, expression patterns of increasing complexity along the anterior-posterior axis of the embryo. Using known binding site information for maternal and zygotic gap transcription factors, the computer algorithm Ahab recovers known segmentation control elements (modules) with excellent success and predicts many novel modules within the network and genome-wide. We show that novel module predictions are highly enriched in the network and typically clustered proximal to the promoter, not only upstream, but also in intronic space and downstream. When placed upstream of a reporter gene, they consistently drive patterned blastoderm expression, in most cases faithfully producing one or more pattern elements of the endogenous gene. Moreover, we demonstrate for the entire set of known and newly validated modules that Ahab's prediction of binding sites correlates well with the expression patterns produced by the modules, revealing basic rules governing their composition. Specifically, we show that maternal factors consistently act as activators and that gap factors act as repressors, except for the bimodal factor Hunchback. Our data suggest a simple context-dependent rule for its switch from repressive to activating function. Overall, the composition of modules appears well fitted to the spatiotemporal distribution of their positive and negative input factors. Finally, by comparing Ahab predictions with different categories of transcription factor input, we confirm the global regulatory structure of the segmentation gene network, but find odd skipped behaving like a primary pair-rule gene. The study expands our knowledge of the segmentation gene network by increasing the number of experimentally tested modules by 50%. For the first time, the entire set of validated modules is analyzed for binding site composition under a uniform set of criteria, permitting the definition of basic composition rules. The study demonstrates that computational methods are a powerful complement to experimental approaches in the analysis of transcription networks.

Evaluating the role of natural selection in the evolution of gene regulation

JC Fay — 2007-05-24T01:28:47-00:00

Heredity, Vol. aop, No. current.

Rapid analysis of the DNA-binding specificities of transcription factors with DNA microarrays

Sonali Mukherjee — 2004-12-06T02:31:50-00:00

Nature Genetics, Vol. 36, No. 12. (14 November 2004), 1331.

Close sequence comparisons are sufficient to identify human cis-regulatory elements.

Shyam Prabhakar — 2006-06-16T19:46:25-00:00

Genome Res (12 June 2006)

Cross-species DNA sequence comparison is the primary method used to identify functional noncoding elements in human and other large genomes. However, little is known about the relative merits of evolutionarily close and distant sequence comparisons. To address this problem, we identified evolutionarily conserved noncoding regions in primate, mammalian, and more distant comparisons using a uniform approach (Gumby) that facilitates unbiased assessment of the impact of evolutionary distance on predictive power. We benchmarked computational predictions against previously identified cis-regulatory elements at diverse genomic loci and also tested numerous extremely conserved human-rodent sequences for transcriptional enhancer activity using an in vivo enhancer assay in transgenic mice. Human regulatory elements were identified with acceptable sensitivity (53%-80%) and true-positive rate (27%-67%) by comparison with one to five other eutherian mammals or six other simian primates. More distant comparisons (marsupial, avian, amphibian, and fish) failed to identify many of the empirically defined functional noncoding elements. Our results highlight the practical utility of close sequence comparisons, and the loss of sensitivity entailed by more distant comparisons. We derived an intuitive relationship between ancient and recent noncoding sequence conservation from whole-genome comparative analysis that explains most of the observations from empirical benchmarking. Lastly, we determined that, in addition to strength of conservation, genomic location and/or density of surrounding conserved elements must also be considered in selecting candidate enhancers for in vivo testing at embryonic time points.

Conservation of regulatory elements between two species of Drosophila.

E Emberly — 2006-09-28T20:46:21-00:00

BMC Bioinformatics, Vol. 4 (20 November 2003)

BACKGROUND: One of the important goals in the post-genomic era is to determine the regulatory elements within the non-coding DNA of a given organism's genome. The identification of functional cis-regulatory modules has proven difficult since the component factor binding sites are small and the rules governing their arrangement are poorly understood. However, the genomes of suitably diverged species help to predict regulatory elements based on the generally accepted assumption that conserved blocks of genomic sequence are likely to be functional. To judge the efficacy of strategies that prefilter by sequence conservation it is important to know to what extent the converse assumption holds, namely that functional elements common to both species will fall within these conserved blocks. The recently completed sequence of a second Drosophila species provides an opportunity to test this assumption for one of the experimentally best studied regulatory networks in multicellular organisms, the body patterning of the fly embryo. RESULTS: We find that 50%-70% of known binding sites reside in conserved sequence blocks, but these percentages are not greatly enriched over what is expected by chance. Finally, a computational genome-wide search in both species for regulatory modules based on clusters of binding sites suggests that genes central to the regulatory network are consistently recovered. CONCLUSIONS: Our results indicate that binding sites remain clustered for these "core modules" while not necessarily residing in conserved blocks. This is an important clue as to how regulatory information is encoded in the genome and how modules evolve.

Comprehensive identification of Drosophila dorsal-ventral patterning genes using a whole-genome tiling array

Frederic Biemar — 2007-09-18T00:01:30-00:00

Proceedings of the National Academy of Sciences, Vol. 103, No. 34. (22 August 2006), pp. 12763-12768.

Dorsal-ventral (DV) patterning of the Drosophila embryo is initiated by Dorsal, a sequence-specific transcription factor distributed in a broad nuclear gradient in the precellular embryo. Previous studies have identified as many as 70 protein-coding genes and one microRNA (miRNA) gene that are directly or indirectly regulated by this gradient. A gene regulation network, or circuit diagram, including the functional interconnections among 40 Dorsal target genes and 20 associated tissue-specific enhancers, has been determined for the initial stages of gastrulation. Here, we attempt to extend this analysis by identifying additional DV patterning genes using a recently developed whole-genome tiling array. This analysis led to the identification of another 30 protein-coding genes, including the Drosophila homolog of Idax, an inhibitor of Wnt signaling. In addition, remote 5' exons were identified for at least 10 of the approx100 protein-coding genes that were missed in earlier annotations. As many as nine intergenic uncharacterized transcription units were identified, including two that contain known microRNAs, miR-1 and -9a. We discuss the potential functions of these recently identified genes and suggest that intronic enhancers are a common feature of the DV gene network. 10.1073/pnas.0604484103

Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model.

AJ Carter — 2007-12-11T20:54:55-00:00

Proc Biol Sci, Vol. 269, No. 1494. (7 May 2002), pp. 953-960.

The evolution of cis-regulatory elements (or enhancers) appears to proceed at dramatically different rates in different taxa. Vertebrate enhancers are often very highly conserved in their sequences, and relative positions, across distantly related taxa. In contrast, functionally equivalent enhancers in closely related Drosophila species can differ greatly in their sequences and spatial organization. We present a population-genetic model to explain this difference. The model examines the dynamics of fixation of pairs of individually deleterious, but compensating, mutations. As expected, small populations are predicted to have a high rate of evolution, and the rate decreases with increasing population size. In contrast to previous models, however, this model predicts that the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals, to the point of greatly exceeding the neutral rate. Application of this model predicts that species with moderate population sizes will have relatively conserved enhancers, whereas species with larger populations will be expected to evolve their enhancers at much higher rates. We propose that the different degree of conservation seen in vertebrate and Drosophila enhancers may be explained solely by differences in their population sizes and generation times.

Intragenic Recombination and Diversifying Selection Contribute to the Evolution of Downy Mildew Resistance at the RPP8 Locus of Arabidopsis

John Mcdowell — 2007-11-28T14:15:10-00:00

Plant Cell, Vol. 10, No. 11. (1 November 1998), pp. 1861-1874.

Pathogen resistance (R) genes of the NBS-LRR class (for nucleotide binding site and leucine-rich repeat) are found in many plant species and confer resistance to a diverse spectrum of pathogens. Little is known about the mechanisms that drive NBS-LRR gene evolution in the host-pathogen arms race. We cloned the RPP8 gene (for resistance to Peronospora parasitica) and compared the structure of alleles at this locus in resistant Landsberg erecta (Ler-0) and susceptible Columbia (Col-0) accessions. RPP8-Ler encodes an NBS-LRR protein with a putative N-terminal leucine zipper and is more closely related to previously cloned R genes that confer resistance to bacterial pathogens than it is to other known RPP genes. The RPP8 haplotype in Ler-0 contains the functional RPP8-Ler gene and a nonfunctional homolog, RPH8A. In contrast, the rpp8 locus in Col-0 contains a single chimeric gene, which was likely derived from unequal crossing over between RPP8-Ler and RPH8A ancestors within a Ler-like haplotype. Sequence divergence among RPP8 family members has been accelerated by positive selection on the putative ligand binding region in the LRRs. These observations indicate that NBS-LRR molecular evolution is driven by the same mechanisms that promote rapid sequence diversification among other genes involved in non-self-recognition. 10.1105/tpc.10.11.1861

Genome-wide Prediction of Mammalian Enhancers Based on Analysis of Transcription-Factor Binding Affinity

Outi Hallikas — 2006-01-13T01:55:02-00:00

Cell, Vol. 124, No. 1. (13 January 2006), pp. 47-59.

SummaryUnderstanding the regulation of human gene expression requires knowledge of the "second genetic code," which consists of the binding specificities of transcription factors (TFs) and the combinatorial code by which TF binding sites are assembled to form tissue-specific enhancer elements. Using a novel high-throughput method, we determined the DNA binding specificities of GLIs 1-3, Tcf4, and c-Ets1, which mediate transcriptional responses to the Hedgehog (Hh), Wnt, and Ras/MAPK signaling pathways. To identify mammalian enhancer elements regulated by these pathways on a genomic scale, we developed a computational tool, enhancer element locator (EEL). We show that EEL can be used to identify Hh and Wnt target genes and to predict activated TFs based on changes in gene expression. Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes.

Genomic Inferences of the cis-Regulatory Nucleotide Polymorphisms Underlying Gene Expression Differences between Drosophila melanogaster Mating Races.

Naoki Osada — 2006-06-09T21:42:11-00:00

Mol Biol Evol (5 June 2006)

Nucleotide sequence polymorphisms affecting gene expression occur in the regulatory region of genes (in cis) and elsewhere in the genome (in trans). Further study is required to weight the relative importance of cis- and trans-acting mutations in mediating gene expression differences within and between species. Here, microarray hybridization experiments were used to isolate 363 gene expression differences between the female fly head transcriptomes of two D. melanogaster strains. One strain (French) represented the Cosmopolitan M mating race and the other strain (ZS30) represented the Z mating race derived from Zimbabwe, Africa. From chromosomal substitution strains engineered from the two strains we inferred that the expression differences between M and Z alleles largely could be attributed to the genotype of the chromosomes where the differentially expressed genes were located, i.e. cis-regulatory polymorphisms prominently influence gene expression differences between M and Z. The effects of trans-regulatory polymorphisms were apparent yet difficult to quantify. Results have implications for models of gene regulatory evolution as well as experimental studies trying to identify the nucleotide sequence polymorphisms underlying gene expression differences between Drosophila strains.

Frequent Gain and Loss of Functional Transcription Factor Binding Sites

Scott Doniger — 2007-05-26T03:59:06-00:00

PLoS Computational Biology, Vol. 3, No. 5. (1 May 2007), e99.

Cis-regulatory sequences are not always conserved across species. Divergence within cis-regulatory sequences may result from the evolution of species-specific patterns of gene expression or the flexible nature of the cis-regulatory code. The identification of functional divergence in cis-regulatory sequences is therefore important for both understanding the role of gene regulation in evolution and annotating regulatory elements. We have developed an evolutionary model to detect the loss of constraint on individual transcription factor binding sites (TFBSs). We find that a significant fraction of functionally constrained binding sites have been lost in a lineage-specific manner among three closely related yeast species. Binding site loss has previously been explained by turnover, where the concurrent gain and loss of a binding site maintains gene regulation. We estimate that nearly half of all loss events cannot be explained by binding site turnover. Recreating the mutations that led to binding site loss confirms that these sequence changes affect gene expression in some cases. We also estimate that there is a high rate of binding site gain, as more than half of experimentally identified S. cerevisiae binding sites are not conserved across species. The frequent gain and loss of TFBSs implies that cis-regulatory sequences are labile and, in the absence of turnover, may contribute to species-specific patterns of gene expression.

Ten Simple Rules for a Good Poster Presentation

Thomas Erren — 2007-05-25T15:27:15-00:00

PLoS Computational Biology, Vol. 3, No. 5. (1 May 2007), e102.

Microfluidics device for single cell gene expression analysis in Saccharomyces cerevisiae.

J Ryley — 2008-07-18T04:01:48-00:00

Yeast (Chichester, England), Vol. 23, No. 14-15. (v 2006), pp. 1065-1073.

We have measured single-cell gene expression over time using a microfluidics-based flow cell which physically traps individual yeast using microm-sized structures (yeast jails). Our goal was to determine variability of gene expression within a cell over time, as well as variability between individual cells. In our flow cell system, yeast jails are fabricated out of PDMS and gene expression is visualized using fluorescently-tagged proteins of interest. Previously, single-cell yeast work has been done using micromanipulation on agar, or FACS. In the present device agar is eliminated, resulting in a superior optical system. The flow of media through the flow cell washes daughter cells away, eliminating the need for micromanipulation. Unlike FACS, the described device can track individual yeast over a time course of many hours. The flow cells are compatible with the needs of quantitative fluorescence microscopy, and allow simultaneous measurements to be done on a large number of individual yeast. We used these flow cells to determine the expression of HSP104-GFPand RAS2-YFP, genes known to affect yeast life span. The results demonstrate inter-cell variation in expression of both genes that could not have been detected without this single-cell analysis.

[duplicate] Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene.

Hilde Janssens — 2008-07-17T19:54:20-00:00

Nat Genet (17 September 2006)

Here we present a quantitative and predictive model of the transcriptional readout of the proximal 1.7 kb of the control region of the Drosophila melanogaster gene even skipped (eve). The model is based on the positions and sequence of individual binding sites on the DNA and quantitative, time-resolved expression data at cellular resolution. These data demonstrated new expression features, first reported here. The model correctly predicts the expression patterns of mutations in trans, as well as point mutations, insertions and deletions in cis. It also shows that the nonclassical expression of stripe 7 driven by this fragment is activated by the protein Caudal (Cad), and repressed by the proteins Tailless (Tll) and Giant (Gt).

Nearest-neighbor non-additivity versus long-range non-additivity in TATA-box structure and its implications for TBP-binding mechanism

Hana Faiger — 2008-04-29T04:53:33-00:00

Nucl. Acids Res., Vol. 35, No. 13. (26 July 2007), pp. 4409-4419.

TBP recognizes its target sites, TATA boxes, by recognizing their sequence-dependent structure and flexibility. Studying this mode of TATA-box recognition, termed indirect readout', is important for elucidating the binding mechanism in this system, as well as for developing methods to locate new binding sites in genomic DNA. We determined the binding stability and TBP-induced TATA-box bending for consensus-like TATA boxes. In addition, we calculated the individual information score of all studied sequences. We show that various non-additive effects exist in TATA boxes, dependent on their structural properties. By several criterions, we divide TATA boxes to two main groups. The first group contains sequences with 3-4 consecutive adenines. Sequences in this group have a rigid context-independent cooperative structure, best described by a nearest-neighbor non-additive model. Sequences in the second group have a flexible, context-dependent conformation, which cannot be described by an additive model or by a nearest-neighbor non-additive model. Classifying TATA boxes by these and other structural rules clarifies the different recognition pathways and binding mechanisms used by TBP upon binding to different TATA boxes. We discuss the structural and evolutionary sources of the difficulties in predicting new binding sites by probabilistic weight-matrix methods for proteins in which indirect readout is dominant. 10.1093/nar/gkm451

Functional Analysis of Repressor Binding Sites in the iab-2 Regulatory Region of the abdominal-A Homeotic Gene

Mary Shimell — 2008-07-10T15:43:08-00:00

Developmental Biology, Vol. 218, No. 1. (1 February 2000), pp. 38-52.

Spatial boundaries of homeotic gene expression are initiated and maintained by two sets of transcriptional repressors: the gap gene products and the Polycomb group proteins. Previously, the Hunchback (HB) protein has been implicated in setting the anterior expression limit of the UBX homeotic protein in parasegment 6. Here we investigate DNA elements and trans-acting repressors that control spatial expression of the Abdominal-A (ABD-A) homeotic protein. Analysis of a 1.7-kb enhancer element [iab-2(1.7)] from the iab-2 regulatory region shows that in contrast to Ubx enhancer elements, both HB and Krüppel (KR) are required to set the ABD-A anterior boundary in parasegment 7. DNase I footprinting and site-directed mutagenesis show that HB and KR are direct regulators of this iab-2 enhancer. The single KR site can be moved to a new location 100 bp away and still maintain repressive activity, whereas relocation by 300 bp abolishes activity. These results suggest that KR repression occurs through a local quenching mechanism. We also show that the gap repressor Giant (GT) initially establishes a posterior expression limit at PS9, which shifts posteriorly after the blastoderm stage. Finally, we show that this iab-2 enhancer contains multiple binding sites for the Polycomb group protein Pleiohomeotic (PHO). These iab-2 PHO sites are required in vivo for chromosome pairing-dependent repression of a mini-white reporter. However, the PHO sites are not sufficient to maintain repression of a homeotic reporter gene anterior to PS7. Full maintenance at late embryonic stages requires additional sequences adjacent to the iab-2(1.7) enhancer.

Genetic drift in an infinite population. The pseudohitchhiking model.

JH Gillespie — 2008-07-09T18:37:43-00:00

Genetics, Vol. 155, No. 2. (June 2000), pp. 909-919.

Selected substitutions at one locus can induce stochastic dynamics that resemble genetic drift at a closely linked neutral locus. The pseudohitchhiking model is a one-locus model that approximates these effects and can be used to describe the major consequences of linked selection. As the changes in neutral allele frequencies when hitchhiking are rapid, diffusion theory is not appropriate for studying neutral dynamics. A stationary distribution and some results on substitution processes are presented that use the theory of continuous-time Markov processes with discontinuous sample paths. The coalescent of the pseudohitchhiking model is shown to have a random number of branches at each node, which leads to a frequency spectrum that is different from that of the equilibrium neutral model. If genetic draft, the name given to these induced stochastic effects, is a more important stochastic force than genetic drift, then a number of paradoxes that have plagued population genetics disappear.

Natural Selection Shapes Genome-Wide Patterns of Copy-Number Polymorphism in Drosophila melanogaster

JJ Emerson — 2008-06-20T11:15:27-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1629-1631.

The role that natural selection plays in governing the locations and early evolution of copy-number mutations remains largely unexplored. We used high-density full-genome tiling arrays to create a fine-scale genomic map of copy-number polymorphisms (CNPs) in Drosophila melanogaster. We inferred a total of 2658 independent CNPs, 56% of which overlap genes. These include CNPs that are likely to be under positive selection, most notably high-frequency duplications encompassing toxin-response genes. The locations and frequencies of CNPs are strongly shaped by purifying selection, with deletions under stronger purifying selection than duplications. Among duplications, those overlapping exons or introns, as well as those falling on the X chromosome, seem to be subject to stronger purifying selection. 10.1126/science.1158078

A simplified miRNA-based gene silencing method for Drosophila melanogaster

Benjamin Haley — 2008-07-08T02:21:58-00:00

Developmental Biology, Vol. In Press, Accepted Manuscript

Functional Architecture and Evolution of Transcriptional Elements That Drive Gene Coexpression

Christopher Brown — 2007-09-14T17:12:44-00:00

Science, Vol. 317, No. 5844. (14 September 2007), pp. 1557-1560.

Transcriptional coexpression of interacting gene products is required for complex molecular processes; however, the function and evolution of cis-regulatory elements that orchestrate coexpression remain largely unexplored. We mutagenized 19 regulatory elements that drive coexpression of Ciona muscle genes and obtained quantitative estimates of the cis-regulatory activity of the 77 motifs that comprise these elements. We found that individual motif activity ranges broadly within and among elements, and among different instantiations of the same motif type. The activity of orthologous motifs is strongly constrained, although motif arrangement, type, and activity vary greatly among the elements of different co-regulated genes. Thus, the syntactical rules governing this regulatory function are flexible but become highly constrained evolutionarily once they are established in a particular element. 10.1126/science.1145893

Coordination of a Transcriptional Switch by HMGI(Y) Acetylation

Nikhil Munshi — 2008-07-03T22:28:56-00:00

Science, Vol. 293, No. 5532. (10 August 2001), pp. 1133-1136.

10.1126/science.293.5532.1133

An Atomic Model of the Interferon-[beta] Enhanceosome

Daniel Panne — 2008-07-03T22:25:09-00:00

Cell, Vol. 129, No. 6. (15 June 2007), pp. 1111-1123.

Summary Transcriptional activation of the interferon-[beta] (IFN-[beta]) gene requires assembly of an enhanceosome containing ATF-2/c-Jun, IRF-3/IRF-7, and NF[kappa]B. These factors bind cooperatively to the IFN-[beta] enhancer and recruit coactivators and chromatin-remodeling proteins to the IFN-[beta] promoter. We describe here a crystal structure of the DNA-binding domains of IRF-3, IRF-7, and NF[kappa]B, bound to one half of the enhancer, and use a previously described structure of the remaining half to assemble a complete picture of enhanceosome architecture in the vicinity of the DNA. Association of eight proteins with the enhancer creates a continuous surface for recognizing a composite DNA-binding element. Paucity of local protein-protein contacts suggests that cooperative occupancy of the enhancer comes from both binding-induced changes in DNA conformation and interactions with additional components such as CBP. Contacts with virtually every nucleotide pair account for the evolutionary invariance of the enhancer sequence.

Information display by transcriptional enhancers

Meghana Kulkarni — 2008-07-02T21:43:37-00:00

Development, Vol. 130, No. 26. (29 December 2003), pp. 6569-6575.

Transcriptional enhancers integrate positional and temporal information to regulate the complex expression of developmentally controlled genes. Current models suggest that enhancers act as computational devices, receiving multiple inputs from activators and repressors and resolving them into a single positive or a negative signal that is transmitted to the basal transcriptional machinery. We show that a simple, compact enhancer is capable of representing both repressed and activated states at the same time and in the same nucleus. This finding suggests that closely apposed factor binding sites, situated within compact cis-elements, can be independently interpreted by the transcriptional machinery, possibly through successive enhancer-promoter interactions. These results provide clear evidence that the computational functions usually ascribed to the enhancer itself are actually shared with the basal machinery. In contrast to the autonomous computer model of enhancer function, an information-display or `billboard' model of enhancer activity may better describe many developmentally regulated transcriptional enhancers. 10.1242/dev.00890

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

Emily Hare — 2008-06-27T18:46:42-00:00

PLoS Genet, Vol. 4, No. 6. (27 June 2008), e1000106.

The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function.

A matter of timing: microRNA-controlled temporal identities in worms and flies

Manfred Frasch — 2008-06-29T19:01:14-00:00

Genes Dev., Vol. 22, No. 12. (15 June 2008), pp. 1572-1576.

The first microRNAs were identified in Caenorhabditis elegans based on their functions in the temporal regulation of stage-specific cell fate decisions. Until now, it was not known whether the so-called heterochronic genes that encode miRNAs are also involved in controlling developmental transitions in other organisms. New findings by Sokol et al. (this issue of Genes & Development, pp. 1591-1596) demonstrate that the Drosophila counterpart of a heterochronic miRNA gene from C. elegans, let-7, does indeed play a role in promoting stage-specific developmental events in neuromuscular tissues during the transition from larval to adult stages, thus pointing to a more widespread utilization of miRNAs in temporal regulation of animal development. 10.1101/gad.1690608

Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites

Rickard Sandberg — 2008-06-20T15:33:43-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1643-1647.

Messenger RNA (mRNA) stability, localization, and translation are largely determined by sequences in the 3' untranslated region (3'UTR). We found a conserved increase in expression of mRNAs terminating at upstream polyadenylation sites after activation of primary murine CD4+ T lymphocytes. This program, resulting in shorter 3'UTRs, is a characteristic of gene expression during immune cell activation and correlates with proliferation across diverse cell types and tissues. Forced expression of full-length 3'UTRs conferred reduced protein expression. In some cases the reduction in protein expression could be reversed by deletion of predicted microRNA target sites in the variably included region. Our data indicate that gene expression is coordinately regulated, such that states of increased proliferation are associated with widespread reductions in the 3'UTR-based regulatory capacity of mRNAs. 10.1126/science.1155390

Explicit equilibrium modeling of transcription-factor binding and gene regulation.

JA Granek — 2008-06-29T02:17:23-00:00

Genome biology, Vol. 6, No. 10. (2005)

We have developed a computational model that predicts the probability of transcription factor binding to any site in the genome. GOMER (generalizable occupancy model of expression regulation) calculates binding probabilities on the basis of position weight matrices, and incorporates the effects of cooperativity and competition by explicit calculation of coupled binding equilibria. GOMER can be used to test hypotheses regarding gene regulation that build upon this physically principled prediction of protein-DNA binding.

A mutation accumulation assay reveals a broad capacity for rapid evolution of gene expression

Scott Rifkin — 2005-11-10T04:45:11-00:00

Nature, Vol. 438, No. 7065., pp. 220-223.

The genomic and epidemiological dynamics of human influenza A virus

Andrew Rambaut — 2008-04-17T05:20:03-00:00

Nature (16 April 2008)

A Test of the Null Model for 5' UTR Evolution Based on GC Content

Max Reuter — 2008-04-14T19:36:59-00:00

Mol Biol Evol, Vol. 25, No. 5. (1 May 2008), pp. 801-804.

Eukaryotic mRNAs are headed by a stretch of noncoding sequence, the 5' untranslated region (UTR). It has been proposed that the length of 5' UTRs is selectively neutral and evolves under a process of stochastic destruction and recruitment of core promoter elements, combined with selection against the premature initiation of translation. We test this null model by investigating whether 5' UTR length varies with genomic GC content, an implicit prediction of the model. Using simulations, we show that the null model predicts a positive relationship between GC content and UTR length for genes regulated by a TATA box. Although this prediction is borne out qualitatively in genomic data from yeast, fruit flies, and humans, we find marked quantitative discrepancies. We conclude that UTR length may be shaped to some degree by the forces considered in the null model but that the model fails to provide a complete explanation for UTR length evolution. 10.1093/molbev/msn044

The evolution of transcription-initiation sites.

M Lynch — 2006-07-11T16:00:10-00:00

Mol Biol Evol, Vol. 22, No. 4. (April 2005), pp. 1137-1146.

Unlike the situation in prokaryotes, most eukaryotic messenger RNAs contain a moderately long 5' untranslated region (UTR). Such leader sequences impose a burden on eukaryotic genes by providing substrate for the mutational origin of premature translation-initiation codons, which generally result in defective proteins. To gain an insight into the expansion of 5' UTRs in eukaryotic genomes, we present a simple null model in which the evolution of transcription-initiation sites is entirely driven by the stochastic mutational flux of core-promoter sequences and premature translation-initiation codons. This model yields results consistent with a variety of heretofore disconnected observations, including the form of length distributions of 5' UTRs, the relatively low variance in UTR features among distantly related eukaryotes, the universal reliance on relatively simple core-promoter sequences, and the elevated density of introns in the 5' UTR. We suggest that the reduced effective population sizes of most eukaryotes impose a population-genetic environment conducive to the movement of core promoters to random positions, subject to the constraint imposed by the upstream accumulation of premature translation-initiation codons. If this hypothesis is correct, then selection for gene-specific regulatory features need not be invoked to explain either the origin of lengthy eukaryotic 5' UTRs or the 1,000-fold range of 5'-UTR lengths among genes within species. Nevertheless, once permanently established, expanded 5' UTRs may have provided a novel substrate for the evolution of mechanisms for posttranscriptional regulation of eukaryotic gene expression. These results provide a further example of how an increase in the power of random genetic drift can passively promote the evolution of forms of gene architecture that ultimately facilitate the evolution of organismal complexity.

The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans

Dee Denver — 2005-04-27T18:51:48-00:00

Nature Genetics, Vol. 37, No. 5. (24 April 2005), pp. 544-548.

The effect of recombination on the neutral evolution of genetic robustness

Gergely Szöllosi — 2008-05-27T00:42:37-00:00

Mathematical Biosciences, Vol. In Press, Corrected Proof

Conventional population genetics considers the evolution of a limited number of genotypes corresponding to phenotypes with different fitness. As model phenotypes, in particular RNA secondary structure, have become computationally tractable, however, it has become apparent that the context dependent effect of mutations and the many-to-one nature inherent in these genotype-phenotype maps can have fundamental evolutionary consequences. It has previously been demonstrated that populations of genotypes evolving on the neutral networks corresponding to all genotypes with the same secondary structure only through neutral mutations can evolve mutational robustness [E. van Nimwegen, J.P. Crutchfield, M. Huynen, Neutral evolution of mutational robustness, Proc. Natl. Acad. Sci. USA 96(17), 9716-9720 (1999)], by concentrating the population on regions of high neutrality. Introducing recombination we demonstrate, through numerically calculating the stationary distribution of an infinite population on ensembles of random neutral networks that mutational robustness is significantly enhanced and further that the magnitude of this enhancement is sensitive to details of the neutral network topology. Through the simulation of finite populations of genotypes evolving on random neutral networks and a scaled down microRNA neutral network, we show that even in finite populations recombination will still act to focus the population on regions of locally high neutrality.

Interference among deleterious mutations favours sex and recombination in finite populations

Peter Keightley — 2006-09-07T05:09:32-00:00

Nature, Vol. 443, No. 7107., pp. 89-92.

Two strategies for gene regulation by promoter nucleosomes

Itay Tirosh — 2008-04-30T23:22:56-00:00

Genome Res. (30 April 2008), gr.076059.108.

Chromatin structure is central for the regulation of gene expression, but its genome-wide organization is only beginning to be understood. Here, we examine the connection between patterns of nucleosome occupancy and the capacity to modulate gene expression upon changing conditions, i.e. transcriptional plasticity. By analyzing a genome-wide data of nucleosome positioning in yeast, we find that the presence of nucleosomes close to the transcription start site is associated with high transcriptional plasticity, while nucleosomes at more distant upstream positions are negatively correlated with transcriptional plasticity. Based on this, we identify two typical promoter structures associated with low or high plasticity, respectively. The first class is characterized by a relatively large nucleosome free region close to the start site coupled with well-positioned nucleosomes further upstream, whereas the second class displays a more evenly distributed and dynamic nucleosome positioning, with high occupancy close to the start site. The two classes are further distinguished by multiple promoter features, including histone turnover, binding sites location, H2A.Z occupancy, expression noise and expression diversity. Analysis of nucleosome positioning in human promoters reproduce the main observations. Our results suggest two distinct strategies for gene regulation by chromatin, which are selectively employed by different genes. 10.1101/gr.076059.108

Genes that control dorsoventral polarity affect gene expression along the anteroposterior axis of the Drosophila embryo.

SB Carroll — 2008-05-20T14:48:09-00:00

Development (Cambridge, England), Vol. 99, No. 3. (March 1987), pp. 327-332.

At least 13 genes control the establishment of dorsoventral polarity in the Drosophila embryo and more than 30 genes control the anteroposterior pattern of body segments. Each group of genes is thought to control pattern formation along one body axis, independently of the other group. We have used the expression of the fushi tarazu (ftz) segmentation gene as a positional marker to investigate the relationship between the dorsoventral and anteroposterior axes. The ftz gene is normally expressed in seven transverse stripes. Changes in the striped pattern in embryos mutant for other genes (or progeny of females homozygous for maternal-effect mutations) can reveal alterations of cell fate resulting from such mutations. We show that in the absence of any of ten maternal-effect dorsoventral polarity gene functions, the characteristic stripes of ftz protein are altered. Normally there is a difference between ftz stripe spacing on the dorsal and ventral sides of the embryo; in dorsalized mutant embryos the ftz stripes appear to be altered so that dorsal-type spacing occurs on all sides of the embryo. These results indicate that cells respond to dorsoventral positional information in establishing early patterns of gene expression along the anteroposterior axis and that there may be more significant interactions between the different axes of positional information than previously determined.

Evolutionary developmental biology and the problem of variation.

DL Stern — 2007-02-05T18:26:44-00:00

Evolution Int J Org Evolution, Vol. 54, No. 4. (August 2000), pp. 1079-1091.

One of the oldest problems in evolutionary biology remains largely unsolved. Which mutations generate evolutionarily relevant phenotypic variation? What kinds of molecular changes do they entail? What are the phenotypic magnitudes, frequencies of origin, and pleiotropic effects of such mutations? How is the genome constructed to allow the observed abundance of phenotypic diversity? Historically, the neo-Darwinian synthesizers stressed the predominance of micromutations in evolution, whereas others noted the similarities between some dramatic mutations and evolutionary transitions to argue for macromutationism. Arguments on both sides have been biased by misconceptions of the developmental effects of mutations. For example, the traditional view that mutations of important developmental genes always have large pleiotropic effects can now be seen to be a conclusion drawn from observations of a small class of mutations with dramatic effects. It is possible that some mutations, for example, those in cis-regulatory DNA, have few or no pleiotropic effects and may be the predominant source of morphological evolution. In contrast, mutations causing dramatic phenotypic effects, although superficially similar to hypothesized evolutionary transitions, are unlikely to fairly represent the true path of evolution. Recent developmental studies of gene function provide a new way of conceptualizing and studying variation that contrasts with the traditional genetic view that was incorporated into neo-Darwinian theory and population genetics. This new approach in developmental biology is as important for microevolutionary studies as the actual results from recent evolutionary developmental studies. In particular, this approach will assist in the task of identifying the specific mutations generating phenotypic variation and elucidating how they alter gene function. These data will provide the current missing link between molecular and phenotypic variation in natural populations.

Regulation of even-skipped stripe 2 in the Drosophila embryo.

S Small — 2008-04-24T09:15:41-00:00

The EMBO journal, Vol. 11, No. 11. (November 1992), pp. 4047-4057.

In an effort to determine how crude gradients of transcriptional activators and repressors specify sharp stripes of gene expression in the early embryo, we have conducted a detailed study of even-skipped (eve) stripe 2. A combination of promoter fusions and P-transformation assays were used to show that a 480 bp region of the eve promoter is both necessary and sufficient to direct a stripe of LacZ expression within the limits of the endogenous eve stripe 2. The maternal morphogen bicoid (bcd) and the gap proteins hunchback (hb), Kruppel (Kr) and giant (gt) all bind with high affinity to closely linked sites within this small promoter element. Activation appears to depend on cooperative interactions among bcd and hb proteins, since disrupting single binding sites cause catastrophic reductions in expression. gt is directly involved in the formation of the anterior border, although additional repressors may participate in this process. Forming the posterior border of the stripe involves a delicate balance between limiting amounts of the bcd activator and the Kr repressor. We propose that the clustering of activator and repressor binding sites in the stripe 2 element is required to bring these weakly interacting regulatory factors into close apposition so that they can function both cooperatively and synergistically to control transcription.

Levers and fulcrums: progress in cis-regulatory motif models

Ewan Birney — 2008-03-28T16:35:47-00:00

Nature Methods, Vol. 5, No. 4., pp. 297-298.

Evolution of alternative transcriptional circuits with identical logic

Annie Tsong — 2006-09-28T08:03:10-00:00

Nature, Vol. 443, No. 7110. (2006), pp. 415-420.

Cannot Earthquakes Be Predicted?

Max Wyss; — 2008-05-14T05:18:39-00:00

Science, Vol. 278, No. 5337. (17 October 1997), pp. 487-490.

10.1126/science.278.5337.487

Earthquakes Cannot Be Predicted

Robert Geller — 2008-05-14T05:17:20-00:00

Science, Vol. 275, No. 5306. (14 March 1997), pp. 1616-0.

10.1126/science.275.5306.1616

From the Cover: Emergence of tempered preferential attachment from optimization

Raissa D'Souza — 2008-05-09T08:21:28-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 15. (10 April 2007), pp. 6112-6117.

We show how preferential attachment can emerge in an optimization framework, resolving a long-standing theoretical controversy. We also show that the preferential attachment model so obtained has two novel features, saturation and viability, which have natural interpretations in the underlying network and lead to a power-law degree distribution with exponential cutoff. Moreover, we consider a generalized version of this preferential attachment model with independent saturation and viability, leading to a broader class of power laws again with exponential cutoff. We present a collection of empirical observations from social, biological, physical, and technological networks, for which such degree distributions give excellent fits. We suggest that, in general, optimization models that give rise to preferential attachment with saturation and viability effects form a good starting point for the analysis of many networks. 10.1073/pnas.0606779104

Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance.

TA Sangster — 2005-10-04T20:38:57-00:00

Bioessays, Vol. 26, No. 4. (April 2004), pp. 348-362.

The environmentally responsive molecular chaperone Hsp90 assists the maturation of many key regulatory proteins. An unexpected consequence of this essential biochemical function is that genetic variation can accumulate in genomes and can remain phenotypically silent until Hsp90 function is challenged. Notably, this variation can be revealed by modest environmental change, establishing an environmentally responsive exposure mechanism. The existence of diverse cryptic polymorphisms with a plausible exposure mechanism in evolutionarily distant lineages has implications for the pace and nature of evolutionary change. Chaperone-mediated storage and release of genetic variation is undoubtedly rooted in protein-folding phenomena. As we discuss, proper protein folding crucially affects the trajectory from genotype to phenotype. Indeed, the impact of protein quality-control mechanisms and other fundamental cellular processes on evolution has heretofore been overlooked. A true understanding of evolutionary processes will require an integration of current evolutionary paradigms with the many new insights accruing in protein science.

Hsp90 as a capacitor for morphological evolution

Suzanne Rutherford — 2006-09-11T18:44:04-00:00

Nature, Vol. 396, No. 6709. (26 November 1998), pp. 336-342.