Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures.
Ontology highlight
ABSTRACT:
SUBMITTER: Stark A
PROVIDER: S-EPMC2474711 | biostudies-literature | 2007 Nov
REPOSITORIES: biostudies-literature
Publications
Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures.
Stark Alexander A Lin Michael F MF Kheradpour Pouya P Pedersen Jakob S JS Parts Leopold L Carlson Joseph W JW Crosby Madeline A MA Rasmussen Matthew D MD Roy Sushmita S Deoras Ameya N AN Ruby J Graham JG Brennecke Julius J Hodges Emily E Hinrichs Angie S AS Caspi Anat A Paten Benedict B Park Seung-Won SW Han Mira V MV Maeder Morgan L ML Polansky Benjamin J BJ Robson Bryanne E BE Aerts Stein S van Helden Jacques J Hassan Bassem B Gilbert Donald G DG Eastman Deborah A DA Rice Michael M Weir Michael M Hahn Matthew W MW Park Yongkyu Y Dewey Colin N CN Pachter Lior L Kent W James WJ Haussler David D Lai Eric C EC Bartel David P DP Hannon Gregory J GJ Kaufman Thomas C TC Eisen Michael B MB Clark Andrew G AG Smith Douglas D Celniker Susan E SE Gelbart William M WM Kellis Manolis M
Nature 20071101 7167
Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spur ...[more]
Similar Datasets
Project description:BackgroundHarnessing vast amounts of genomic data in phylogenetic context stemming from massive sequencing of multiple closely related genomes requires new tools and approaches. We present a tool for the genome-wide analysis of frequencies and patterns of amino acid substitutions in multiple alignments of genes' coding regions, and a database of amino acid substitutions in the phylogeny of 12 Drosophila genomes. We illustrate the use of these resources to address three types of evolutionary genomics questions: about fluxes in amino acid composition in proteins, about asymmetries in amino acid substitutions and about patterns of molecular evolution in duplicated genes.ResultsWe demonstrate that amino acid composition of Drosophila proteins underwent a significant shift over the last 70 million years encompassed by the studied phylogeny, with less common amino acids (Cys, Met, His) increasing in frequency and more common ones (Ala, Leu, Glu) becoming less frequent. These fluxes are strongly correlated with polarity of source and destination amino acids, resulting in overall systematic decrease of mean polarity of amino acids found in Drosophila proteins. Frequency and radicality of amino acid substitutions are higher in paralogs than in orthologous single-copy genes and are higher in gene families with paralogs than in gene families without surviving duplications. Rate and radicality of substitutions, as expected, are negatively correlated with overall level and uniformity of gene expression. However, these correlations are not observed for substitutions occurring in duplicated genes, indicating a different selective constraint on the evolution of paralogous sequences. Clades resulting from duplications show a marked asymmetry in rate and radicality of amino acid substitutions, possibly a signal of widespread neofunctionalization. These patterns differ among protein families of different functionality, with genes coding for RNA-binding proteins differing from most other functional groups in terms of amino acid substitution patterns in duplicated and single-copy genes.ConclusionsWe demonstrate that deep phylogenetic analysis of amino acid substitutions can reveal interesting genome-wide patterns. Amino acid composition of drosophilid proteins is shaped by fluxes similar to those previously observed in prokaryotic, yeast and mammalian genomes, indicating globally present patterns. Increased frequency and radicality of amino acid substitutions in duplicated genes and the presence of asymmetry of these parameters between paralogous clades indicate widespread neofunctionalization among paralogs as the mechanism of duplication retention.
| S-EPMC3005911 | biostudies-literature
Project description:The newly sequenced genome sequences of 11 Drosophila species provide the first opportunity to investigate variations in evolutionary rates across a clade of closely related species. Protein-coding genes were predicted using established Drosophila melanogaster genes as templates, with recovery rates ranging from 81%-97% depending on species divergence and on genome assembly quality. Orthology and paralogy assignments were shown to be self-consistent among the different Drosophila species and to be consistent with regions of conserved gene order (synteny blocks). Next, we investigated the rates of diversification among these species' gene repertoires with respect to amino acid substitutions and to gene duplications. Constraints on amino acid sequences appear to have been most pronounced on D. ananassae and least pronounced on D. simulans and D. erecta terminal lineages. Codons predicted to have been subject to positive selection were found to be significantly over-represented among genes with roles in immune response and RNA metabolism, with the latter category including each subunit of the Dicer-2/r2d2 heterodimer. The vast majority of gene duplications (96.5%) and synteny rearrangements were found to occur, as expected, within single Müller elements. We show that the rate of ancient gene duplications was relatively uniform. However, gene duplications in terminal lineages are strongly skewed toward very recent events, consistent with either a rapid-birth and rapid-death model or the presence of large proportions of copy number variable genes in these Drosophila populations. Duplications were significantly more frequent among trypsin-like proteases and DM8 putative lipid-binding domain proteins.
| S-EPMC2099592 | biostudies-literature
Project description:BackgroundMiniature inverted-repeat transposable elements (MITEs) are non-autonomous DNA-mediated transposable elements (TEs) derived from autonomous TEs. Unlike in many plants or animals, MITEs and other types of DNA-mediated TEs were previously thought to be either rare or absent in Drosophila. Most other TE families in Drosophila exist at low or intermediate copy number (around < 100 per genome).ResultsWe present evidence here that the dispersed repeat Drosophila interspersed element 1 (DINE-1; also named INE-1 and DNAREP1) is a highly abundant DNA-mediated TE containing inverted repeats found in all 12 sequenced Drosophila genomes. All DINE-1s share a similar sequence structure, but are more homogeneous within species than they are among species. The inferred phylogenetic relationship of the DINE-1 consensus sequence from each species is generally consistent with the known species phylogeny, suggesting vertical transmission as the major mechanism for DINE-1 propagation. Exceptions observed in D. willistoni and D. ananassae could be due to either horizontal transfer or reactivation of ancestral copies. Our analysis of pairwise percentage identity of DINE-1 copies within species suggests that the transpositional activity of DINE-1 is extremely dynamic, with some lineages showing evidence for recent transpositional bursts and other lineages appearing to have silenced their DINE-1s for long periods of time. We also find that all species have many DINE-1 insertions in introns and adjacent to protein-coding genes. Finally, we discuss our results in light of a recent proposal that DINE-1s belong to the Helitron family of TEs.ConclusionWe find that all 12 Drosophila species with whole-genome sequence contain the high copy element DINE-1. Although all DINE-1s share a similar structure, species-specific variation in the distribution of average pairwise divergence suggests that DINE-1 has gone through multiple independent cycles of activation and suppression. DINE-1 also has had a significant impact on gene structure evolution.
| S-EPMC2374699 | biostudies-literature
Project description:RNA molecules fold into characteristic secondary and tertiary structures that account for their diverse functional activities. Many of these RNA structures, or certain structural motifs within them, are thought to recur in multiple genes within a single organism or across the same gene in several organisms and provide a common regulatory mechanism. Search algorithms, such as RNAMotif, can be used to mine nucleotide sequence databases for these repeating motifs. RNAMotif allows users to capture essential features of known structures in detailed descriptors and can be used to identify, with high specificity, other similar motifs within the nucleotide database. However, when the descriptor constraints are relaxed to provide more flexibility, or when there is very little a priori information about hypothesized RNA structures, the number of motif 'hits' may become very large. Exhaustive methods to search for similar RNA structures over these large search spaces are likely to be computationally intractable. Here we describe a powerful new algorithm based on evolutionary computation to solve this problem. A series of experiments using ferritin IRE and SRP RNA stem-loop motifs were used to verify the method. We demonstrate that even when searching extremely large search spaces, of the order of 10(23) potential solutions, we could find the correct solution in a fraction of the time it would have taken for exhaustive comparisons.
| S-EPMC137967 | biostudies-literature
Project description:BackgroundRecent genomic scale survey of epigenetic states in the mammalian genomes has shown that promoters and enhancers are correlated with distinct chromatin signatures, providing a pragmatic way for systematic mapping of these regulatory elements in the genome. With rapid accumulation of chromatin modification profiles in the genome of various organisms and cell types, this chromatin based approach promises to uncover many new regulatory elements, but computational methods to effectively extract information from these datasets are still limited.ResultsWe present here a supervised learning method to predict promoters and enhancers based on their unique chromatin modification signatures. We trained Hidden Markov models (HMMs) on the histone modification data for known promoters and enhancers, and then used the trained HMMs to identify promoter or enhancer like sequences in the human genome. Using a simulated annealing (SA) procedure, we searched for the most informative combination and the optimal window size of histone marks.ConclusionCompared with the previous methods, the HMM method can capture the complex patterns of histone modifications particularly from the weak signals. Cross validation and scanning the ENCODE regions showed that our method outperforms the previous profile-based method in mapping promoters and enhancers. We also showed that including more histone marks can further boost the performance of our method. This observation suggests that the HMM is robust and is capable of integrating information from multiple histone marks. To further demonstrate the usefulness of our method, we applied it to analyzing genome wide ChIP-Seq data in three mouse cell lines and correctly predicted active and inactive promoters with positive predictive values of more than 80%. The software is available at http://http:/nash.ucsd.edu/chromatin.tar.gz.
| S-EPMC2657164 | biostudies-literature
Project description:The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term 'induced dependence'. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies.
| S-EPMC5141297 | biostudies-literature
Project description:Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Drosophila species to study the gain and loss of genes at unprecedented resolution. We find large numbers of both gains and losses, with over 40% of all gene families differing in size among the Drosophila. Approximately 17 genes are estimated to be duplicated and fixed in a genome every million years, a rate on par with that previously found in both yeast and mammals. We find many instances of extreme expansions or contractions in the size of gene families, including the expansion of several sex- and spermatogenesis-related families in D. melanogaster that also evolve under positive selection at the nucleotide level. Newly evolved gene families in our dataset are associated with a class of testes-expressed genes known to have evolved de novo in a number of cases. Gene family comparisons also allow us to identify a number of annotated D. melanogaster genes that are unlikely to encode functional proteins, as well as to identify dozens of previously unannotated D. melanogaster genes with conserved homologs in the other Drosophila. Taken together, our results demonstrate that the apparent stasis in total gene number among species has masked rapid turnover in individual gene gain and loss. It is likely that this genomic revolving door has played a large role in shaping the morphological, physiological, and metabolic differences among species.
| S-EPMC2065885 | biostudies-literature
Project description:The availability of sequenced genomes from 12 Drosophila species has enabled the use of comparative genomics for the systematic discovery of functional elements conserved within this genus. We have developed quantitative metrics for the evolutionary signatures specific to protein-coding regions and applied them genome-wide, resulting in 1193 candidate new protein-coding exons in the D. melanogaster genome. We have reviewed these predictions by manual curation and validated a subset by directed cDNA screening and sequencing, revealing both new genes and new alternative splice forms of known genes. We also used these evolutionary signatures to evaluate existing gene annotations, resulting in the validation of 87% of genes lacking descriptive names and identifying 414 poorly conserved genes that are likely to be spurious predictions, noncoding, or species-specific genes. Furthermore, our methods suggest a variety of refinements to hundreds of existing gene models, such as modifications to translation start codons and exon splice boundaries. Finally, we performed directed genome-wide searches for unusual protein-coding structures, discovering 149 possible examples of stop codon readthrough, 125 new candidate ORFs of polycistronic mRNAs, and several candidate translational frameshifts. These results affect >10% of annotated fly genes and demonstrate the power of comparative genomics to enhance our understanding of genome organization, even in a model organism as intensively studied as Drosophila melanogaster.
| S-EPMC2099591 | biostudies-literature
Project description:BackgroundThe spatiotemporal regulation of gene expression largely depends on the presence and absence of cis-regulatory sites in the promoter. In the economically highly important grass family, our knowledge of transcription factor binding sites and transcriptional networks is still very limited. With the completion of the sorghum genome and the available rice genome sequence, comparative promoter analyses now allow genome-scale detection of conserved cis-elements.ResultsIn this study, we identified thousands of phylogenetic footprints conserved between orthologous rice and sorghum upstream regions that are supported by co-expression information derived from three different rice expression data sets. In a complementary approach, cis-motifs were discovered by their highly conserved co-occurrence in syntenic promoter pairs. Sequence conservation and matches to known plant motifs support our findings. Expression similarities of gene pairs positively correlate with the number of motifs that are shared by gene pairs and corroborate the importance of similar promoter architectures for concerted regulation. This strongly suggests that these motifs function in the regulation of transcript levels in rice and, presumably also in sorghum.ConclusionOur work provides the first large-scale collection of cis-elements for rice and sorghum and can serve as a paradigm for cis-element analysis through comparative genomics in grasses in general.
| S-EPMC2714861 | biostudies-literature
Project description:The availability of 12 complete genomes of various species of genus Drosophila provides a unique opportunity to analyze genome-scale chromosomal rearrangements among a group of closely related species. This article reports on the comparison of gene order between these 12 species and on the fixed rearrangement events that disrupt gene order. Three major themes are addressed: the conservation of syntenic blocks across species, the disruption of syntenic blocks (via chromosomal inversion events) and its relationship to the phylogenetic distribution of these species, and the rate of rearrangement events over evolutionary time. Comparison of syntenic blocks across this large genomic data set confirms that genetic elements are largely (95%) localized to the same Muller element across genus Drosophila species and paracentric inversions serve as the dominant mechanism for shuffling the order of genes along a chromosome. Gene-order scrambling between species is in accordance with the estimated evolutionary distances between them and we find it to approximate a linear process over time (linear to exponential with alternate divergence time estimates). We find the distribution of synteny segment sizes to be biased by a large number of small segments with comparatively fewer large segments. Our results provide estimated chromosomal evolution rates across this set of species on the basis of whole-genome synteny analysis, which are found to be higher than those previously reported. Identification of conserved syntenic blocks across these genomes suggests a large number of conserved blocks with varying levels of embryonic expression correlation in Drosophila melanogaster. On the other hand, an analysis of the disruption of syntenic blocks between species allowed the identification of fixed inversion breakpoints and estimates of breakpoint reuse and lineage-specific breakpoint event segregation.
| S-EPMC2475759 | biostudies-literature