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Search Results: 1 - 10 of 198692 matches for " Venky N Iyer "
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Widespread Discordance of Gene Trees with Species Tree in Drosophila: Evidence for Incomplete Lineage Sorting
Daniel A Pollard,Venky N Iyer equal contributor,Alan M Moses equal contributor,Michael B Eisen
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020173
Abstract: The phylogenetic relationship of the now fully sequenced species Drosophila erecta and D. yakuba with respect to the D. melanogaster species complex has been a subject of controversy. All three possible groupings of the species have been reported in the past, though recent multi-gene studies suggest that D. erecta and D. yakuba are sister species. Using the whole genomes of each of these species as well as the four other fully sequenced species in the subgenus Sophophora, we set out to investigate the placement of D. erecta and D. yakuba in the D. melanogaster species group and to understand the cause of the past incongruence. Though we find that the phylogeny grouping D. erecta and D. yakuba together is the best supported, we also find widespread incongruence in nucleotide and amino acid substitutions, insertions and deletions, and gene trees. The time inferred to span the two key speciation events is short enough that under the coalescent model, the incongruence could be the result of incomplete lineage sorting. Consistent with the lineage-sorting hypothesis, substitutions supporting the same tree were spatially clustered. Support for the different trees was found to be linked to recombination such that adjacent genes support the same tree most often in regions of low recombination and substitutions supporting the same tree are most enriched roughly on the same scale as linkage disequilibrium, also consistent with lineage sorting. The incongruence was found to be statistically significant and robust to model and species choice. No systematic biases were found. We conclude that phylogenetic incongruence in the D. melanogaster species complex is the result, at least in part, of incomplete lineage sorting. Incomplete lineage sorting will likely cause phylogenetic incongruence in many comparative genomics datasets. Methods to infer the correct species tree, the history of every base in the genome, and comparative methods that control for and/or utilize this information will be valuable advancements for the field of comparative genomics.
MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model
Alan M Moses, Derek Y Chiang, Daniel A Pollard, Venky N Iyer, Michael B Eisen
Genome Biology , 2004, DOI: 10.1186/gb-2004-5-12-r98
Abstract: Different types of genomic features have characteristic patterns of evolution that, when sequences from closely related organisms are available, can be exploited to annotate genomes [1]. Methods for comparative sequence analysis that exploit variation in rates and patterns of nucleotide evolution can identify coding exons [1,2], noncoding sequences involved in the regulation of transcription [3,4] and various types of RNAs [5-7]. While most of these methods have been developed for and applied to pairwise comparisons, sequence data are increasingly available for multiple closely related species [8]. It is therefore of considerable importance to develop sequence-analysis methods that optimally exploit evolutionary information, and to explore the dependence of these methods on the evolutionary relationships of the species in comparison.Sequence-specific DNA-binding proteins involved in transcriptional regulation (transcription factors) play a central role in many biological processes. Despite extensive biochemical and molecular analysis, it remains exceedingly difficult to predict where on the genome a given factor will bind. Transcription factors bind to degenerate families of short (6-20 base-pairs (bp)) sequences that occur frequently in the genome, yet only a small fraction of these sequences are actually bona fide targets of the transcription factor [9]. A major challenge in understanding the regulation of transcription is to be able to distinguish real transcription factor binding sites (TFBSs) from sequences that simply match a factor's binding specificity. Because the evolutionary properties of TFBSs are expected to be different from their nonfunctional counterparts, comparative analyses hold great promise in helping to address this challenge.In the past few years, several methods have been introduced to identify conserved (and presumably functional) TFBSs for a factor of known specificity (in contrast to the larger set of methods that use comparative data in m
Detecting the limits of regulatory element conservation and divergence estimation using pairwise and multiple alignments
Daniel A Pollard, Alan M Moses, Venky N Iyer, Michael B Eisen
BMC Bioinformatics , 2006, DOI: 10.1186/1471-2105-7-376
Abstract: Here we develop a molecular evolution simulation platform, CisEvolver, with models of background noncoding and transcription factor binding site evolution, and use simulated alignments to systematically examine multiple alignment accuracy and its impact on two key molecular evolutionary inferences: transcription factor binding site conservation and divergence estimation. We find that the accuracy of multiple alignments is determined almost exclusively by the pairwise divergence distance of the two most diverged species and that additional species have a negligible influence on alignment accuracy. Conserved transcription factor binding sites align better than surrounding noncoding DNA yet are often found to be misaligned at relatively short divergence distances, such that studies of binding site gain and loss could easily be confounded by alignment error. Divergence estimates from multiple alignments tend to be overestimated at short divergence distances but reach a tool specific divergence at which they cease to increase, leading to underestimation at long divergences. Our most striking finding was that overall alignment accuracy, binding site alignment accuracy and divergence estimation accuracy vary greatly across branches in a tree and are most accurate for terminal branches connecting sister taxa and least accurate for internal branches connecting sub-alignments.Our results suggest that variation in alignment accuracy can lead to errors in molecular evolutionary inferences that could be construed as biological variation. These findings have implications for which species to choose for analyses, what kind of errors would be expected for a given set of species and how multiple alignment tools and phylogenetic inference methods might be improved to minimize or control for alignment errors.Annotation of cis-regulatory sequences, non-coding RNAs and other functional noncoding sequences is a major challenge in molecular genetics today. Whole genome sequences of closel
Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation
Emily E. Hare equal contributor,Brant K. Peterson equal contributor,Venky N. Iyer,Rudolf Meier,Michael B. Eisen
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000106
Abstract: 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.
Large-Scale Turnover of Functional Transcription Factor Binding Sites in Drosophila
Alan M Moses,Daniel A Pollard,David A Nix,Venky N Iyer,Xiao-Yong Li,Mark D Biggin,Michael B Eisen
PLOS Computational Biology , 2006, DOI: 10.1371/journal.pcbi.0020130
Abstract: The gain and loss of functional transcription factor binding sites has been proposed as a major source of evolutionary change in cis-regulatory DNA and gene expression. We have developed an evolutionary model to study binding-site turnover that uses multiple sequence alignments to assess the evolutionary constraint on individual binding sites, and to map gain and loss events along a phylogenetic tree. We apply this model to study the evolutionary dynamics of binding sites of the Drosophila melanogaster transcription factor Zeste, using genome-wide in vivo (ChIP–chip) binding data to identify functional Zeste binding sites, and the genome sequences of D. melanogaster, D. simulans, D. erecta, and D. yakuba to study their evolution. We estimate that more than 5% of functional Zeste binding sites in D. melanogaster were gained along the D. melanogaster lineage or lost along one of the other lineages. We find that Zeste-bound regions have a reduced rate of binding-site loss and an increased rate of binding-site gain relative to flanking sequences. Finally, we show that binding-site gains and losses are asymmetrically distributed with respect to D. melanogaster, consistent with lineage-specific acquisition and loss of Zeste-responsive regulatory elements.
Big Genomes Facilitate the Comparative Identification of Regulatory Elements
Brant K. Peterson, Emily E. Hare, Venky N. Iyer, Steven Storage, Laura Conner, Daniel R. Papaj, Rick Kurashima, Eric Jang, Michael B. Eisen
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004688
Abstract: The identification of regulatory sequences in animal genomes remains a significant challenge. Comparative genomic methods that use patterns of evolutionary conservation to identify non-coding sequences with regulatory function have yielded many new vertebrate enhancers. However, these methods have not contributed significantly to the identification of regulatory sequences in sequenced invertebrate taxa. We demonstrate here that this differential success, which is often attributed to fundamental differences in the nature of vertebrate and invertebrate regulatory sequences, is instead primarily a product of the relatively small size of sequenced invertebrate genomes. We sequenced and compared loci involved in early embryonic patterning from four species of true fruit flies (family Tephritidae) that have genomes four to six times larger than those of Drosophila melanogaster. Unlike in Drosophila, where virtually all non-coding DNA is highly conserved, blocks of conserved non-coding sequence in tephritids are flanked by large stretches of poorly conserved sequence, similar to what is observed in vertebrate genomes. We tested the activities of nine conserved non-coding sequences flanking the even-skipped gene of the teprhitid Ceratis capitata in transgenic D. melanogaster embryos, six of which drove patterns that recapitulate those of known D. melanogaster enhancers. In contrast, none of the three non-conserved tephritid non-coding sequences that we tested drove expression in D. melanogaster embryos. Based on the landscape of non-coding conservation in tephritids, and our initial success in using conservation in tephritids to identify D. melanogaster regulatory sequences, we suggest that comparison of tephritid genomes may provide a systematic means to annotate the non-coding portion of the D. melanogaster genome. We also propose that large genomes be given more consideration in the selection of species for comparative genomics projects, to provide increased power to detect functional non-coding DNAs and to provide a less biased view of the evolution and function of animal genomes.
Correction: Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm
Xiao-yong Li,Stewart MacArthur,Richard Bourgon,David Nix,Daniel A. Pollard,Venky N. Iyer,Aaron Hechmer,Lisa Simirenko,Mark Stapleton,Cris L. Luengo Hendriks,Hou Cheng Chu,Nobuo Ogawa,William Inwood,Victor Sementchenko,Amy Beaton,Richard Weiszmann,Susan E. Celniker,David W. Knowles,Tom Gingeras,Terence P. Speed,Michael B. Eisen,Mark D. Biggin
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060190
Abstract:
Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm
Xiao-yong Li,Stewart MacArthur,Richard Bourgon,David Nix,Daniel A. Pollard,Venky N. Iyer,Aaron Hechmer,Lisa Simirenko,Mark Stapleton,Cris L. Luengo Hendriks,Hou Cheng Chu,Nobuo Ogawa,William Inwood,Victor Sementchenko,Amy Beaton,Richard Weiszmann,Susan E. Celniker,David W. Knowles,Tom Gingeras,Terence P. Speed,Michael B. Eisen,Mark D. Biggin
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060027
Abstract: Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior–posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal–ventral patterning genes, whose expression we show to be quantitatively modulated by anterior–posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.
Correction: Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm
Xiao-yong Li,Stewart MacArthur,Richard Bourgon,David Nix,Daniel A Pollard,Venky N Iyer,Aaron Hechmer,Lisa Simirenko,Mark Stapleton,Cris L Luengo Hendriks,Hou Cheng Chu,Nobuo Ogawa,William Inwood,Victor Sementchenko,Amy Beaton,Richard Weiszmann,Susan E Celniker,David W Knowles,Tom Gingeras,Terence P Speed,Michael B Eisen,Mark D Biggin
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060190
Abstract:
Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm
Xiao-yong Li equal contributor,Stewart MacArthur equal contributor,Richard Bourgon,David Nix,Daniel A Pollard,Venky N Iyer,Aaron Hechmer,Lisa Simirenko,Mark Stapleton,Cris L. Luengo Hendriks,Hou Cheng Chu,Nobuo Ogawa,William Inwood,Victor Sementchenko,Amy Beaton,Richard Weiszmann,Susan E Celniker,David W Knowles,Tom Gingeras,Terence P Speed,Michael B Eisen ? ,Mark D Biggin ?
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060027
Abstract: Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior–posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal–ventral patterning genes, whose expression we show to be quantitatively modulated by anterior–posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.
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