CiteULike: Group: BergmanLab - library [126 articles]

DNAlive: A tool for the physical analysis of DNA at the genomic scale.

J Ramon Goñi — 2008-06-22T00:34:55-00:00

Bioinformatics (Oxford, England) (9 June 2008)

SUMMARY: DNAlive is a tool for the analysis and graphical display of structural and physical characteristics of genomic DNA. The web server implements a wide repertoire of metrics to derive physical information from DNA sequences with a powerful interface to derive three-dimensional information on large sequences of both naked and protein-bound DNAs. Furthermore, it implements a mesoscopic Metropolis code which allows the inexpensive study of the dynamic properties of chromatin fibers. In addition, our server also surveys other protein and genomic databases allowing the user to combine and explore the physical properties of selected DNA in the context of functional features annotated on those regions. AVAILABILITY: http://mmb.pcb.ub.es/DNAlive/ ; http://www.inab.org/ CONTACT: modesto@mmb.pcb.ub.es SUPPLEMENTARY INFORMATION:

Early vertebrate whole genome duplications were predated by a period of intense genome rearrangement

Andrew Hufton — 2008-07-15T03:47:33-00:00

Genome Res. (14 July 2008), gr.080119.108.

Researchers, supported by data from polyploid plants, have suggested that whole genome duplication (WGD) may induce genomic instability and rearrangement, an idea which could have important implications for vertebrate evolution. Benefiting from the newly released amphioxus genome sequence (Branchiostoma floridae), an invertebrate which researchers have hoped is representative of the ancestral chordate genome, we have used gene proximity conservation to estimate rates of genome rearrangement throughout vertebrates and some of their invertebrate ancestors. We find that, while amphioxus remains the best single source of invertebrate information about the early chordate genome, its genome structure is not particularly well conserved and it cannot be considered a fossilization of the vertebrate pre-duplication genome. In agreement with previous reports, we identify two WGD events in early vertebrates and another in teleost fish. However, we find that the early vertebrate WGD events were not followed by increased rates of genome rearrangement. Indeed, we measure massive genome rearrangement prior to these WGD events. We propose that the vertebrate WGD events may have been symptoms of a pre-existing predisposition toward genomic structural change. Researchers, supported by data from polyploid plants, have suggested that whole genome duplication (WGD) may induce genomic instability and rearrangement, an idea which could have important implications for vertebrate evolution. Benefiting from the newly released amphioxus genome sequence (Branchiostoma floridae), an invertebrate which researchers have hoped is representative of the ancestral chordate genome, we have used gene proximity conservation to estimate rates of genome rearrangement throughout vertebrates and some of their invertebrate ancestors. We find that, while amphioxus remains the best single source of invertebrate information about the early chordate genome, its genome structure is not particularly well conserved and it cannot be considered a fossilization of the vertebrate pre-duplication genome. In agreement with previous reports, we identify two WGD events in early vertebrates and another in teleost fish. However, we find that the early vertebrate WGD events were not followed by increased rates of genome rearrangement. Indeed, we measure massive genome rearrangement prior to these WGD events. We propose that the vertebrate WGD events may have been symptoms of a pre-existing predisposition toward genomic structural change. 10.1101/gr.080119.108

Accelerated sequence divergence of conserved genomic elements in Drosophila melanogaster

Alisha Holloway — 2008-06-29T22:39:44-00:00

Genome Res. (26 June 2008), gr.077131.108.

Recent genomic sequencing of 10 additional Drosophila genomes provides a rich resource for comparative genomics analyses aimed at understanding the similarities and differences between species and between Drosophila and mammals. Using a phylogenetic approach, we identified 64 genomic elements that have been highly conserved over most of the Drosophila tree, but that have experienced a recent burst of evolution along the Drosophila melanogaster lineage. Compared to similarly defined elements in humans, these regions of rapid lineage-specific evolution in Drosophila differ dramatically in location, mechanism of evolution, and functional properties of associated genes. Notably, the majority reside in protein coding regions and primarily result from rapid adaptive synonymous site evolution. In fact, adaptive evolution appears to be driving substitutions to unpreferred codons. Our analysis also highlights interesting noncoding genomic regions, such as regulatory regions in the gene gooseberry-neuro and a putative novel miRNA. 10.1101/gr.077131.108

Retroviral promoters in the human genome

Andrew Conley — 2008-07-07T09:53:47-00:00

Bioinformatics, Vol. 24, No. 14. (15 July 2008), pp. 1563-1567.

Motivation: Endogenous retrovirus (ERV) elements have been shown to contribute promoter sequences that can initiate transcription of adjacent human genes. However, the extent to which retroviral sequences initiate transcription within the human genome is currently unknown. We analyzed genome sequence and high-throughput expression data to systematically evaluate the presence of retroviral promoters in the human genome. Results: We report the existence of 51 197 ERV-derived promoter sequences that initiate transcription within the human genome, including 1743 cases where transcription is initiated from ERV sequences that are located in gene proximal promoter or 5' untranslated regions (UTRs). A total of 114 of the ERV-derived transcription start sites can be demonstrated to drive transcription of 97 human genes, producing chimeric transcripts that are initiated within ERV long terminal repeat (LTR) sequences and read-through into known gene sequences. ERV promoters drive tissue-specific and lineage-specific patterns of gene expression and contribute to expression divergence between paralogs. These data illustrate the potential of retroviral sequences to regulate human transcription on a large scale consistent with a substantial effect of ERVs on the function and evolution of the human genome. Contact: king.jordan@biology.gatech.edu Supplementary information: Supplementary data are available at Bioinformatics online. 10.1093/bioinformatics/btn243

A-to-I RNA editing alters less-conserved residues of highly conserved coding regions: Implications for dual functions in evolution.

Yun Yang — 2008-07-03T14:29:42-00:00

RNA (New York, N.Y.) (20 June 2008)

The molecular mechanism and physiological function of recoding by A-to-I RNA editing is well known, but its evolutionary significance remains a mystery. We analyzed the RNA editing of the Kv2 K(+) channel from different insects spanning more than 300 million years of evolution: Drosophila melanogaster, Culex pipiens (Diptera), Pulex irritans (Siphonaptera), Bombyx mori (Lepidoptera), Tribolium castaneum (Coleoptera), Apis mellifera (Hymenoptera), Pediculus humanus (Phthiraptera), and Myzus persicae (Homoptera). RNA editing was detected across all Kv2 orthologs, representing the most highly conserved RNA editing event yet reported in invertebrates. Surprisingly, five of these editing sites were conserved in squid (Mollusca) and were possibly of independent origin, suggesting phylogenetic conservation of editing between mollusks and insects. Based on this result, we predicted and experimentally verified two novel A-to-I editing sites in squid synaptotagmin I transcript. In addition, comparative analysis indicated that RNA editing usually occurred within highly conserved coding regions, but mostly altered less-conserved coding positions of these regions. Moreover, more than half of these edited amino acids are genomically encoded in the orthologs of other species; an example of a conversion model of the nonconservative edited site is addressed. Therefore, these data imply that RNA editing might play dual roles in evolution by extending protein diversity and maintaining phylogenetic conservation.

Transgenesis upgrades for Drosophila melanogaster

Koen Venken — 2007-09-28T16:38:26-00:00

Development, Vol. 134, No. 20. (15 October 2007), pp. 3571-3584.

Drosophila melanogaster is a highly attractive model system for the study of numerous biological questions pertaining to development, genetics, cell biology, neuroscience and disease. Until recently, our ability to manipulate flies genetically relied heavily on the transposon-mediated integration of DNA into fly embryos. However, in recent years significant improvements have been made to the transgenic techniques available in this organism, particularly with respect to integrating DNA at specific sites in the genome. These new approaches will greatly facilitate the structure-function analyses of Drosophila genes, will enhance the ease and speed with which flies can be manipulated, and should advance our understanding of biological processes during normal development and disease. 10.1242/dev.005686

Evolvability and hierarchy in rewired bacterial gene networks

Mark Isalan — 2008-04-16T19:45:06-00:00

Nature, Vol. 452, No. 7189. (17 April 2008), pp. 840-845.

Precise detection of rearrangement breakpoints in mammalian chromosomes

Claire Lemaitre — 2008-06-18T14:00:59-00:00

BMC Bioinformatics, Vol. 9, No. 1. (2008)

BACKGROUND:Genomes undergo large structural changes that alter their organisation. The chromosomal regions affected by these rearrangements are called breakpoints, while those which have not been rearranged are called synteny blocks. We developed a method to precisely delimit rearrangement breakpoints on a genome by comparison with the genome of a related species. Contrary to current methods which search for synteny blocks and simply return what remains in the genome as breakpoints, we propose to go further and to investigate the breakpoints themselves in order to refine them.RESULTS:Given some reliable and non overlapping synteny blocks, the core of the method consists in refining the regions that are not contained in them. By aligning each breakpoint sequence against its specific orthologous sequences in the other species, we can look for weak similarities inside the breakpoint, thus extending the synteny blocks and narrowing the breakpoints. The identification of the narrowed breakpoints relies on a segmentation algorithm and is statistically assessed. Since this method requires as input synteny blocks with some properties which, though they appear natural, are not verified by current methods for detecting such blocks, we further give a formal definition and provide an algorithm to compute them. The whole method is applied to delimit breakpoints on the human genome when compared to the mouse and dog genomes. Among the 355 human-mouse and 240 human-dog breakpoints, 168 and 146 respectively span less than 50 Kb. We compared the resulting breakpoints with some publicly available ones and show that we achieve a better resolution. Furthermore, we suggest that breakpoints are rarely reduced to a point, and instead consist in often large regions that can be distinguished from the sequences around in terms of segmental duplications, similarity with related species, and transposable elements.CONCLUSIONS:Our method leads to smaller breakpoints than already published ones and allows for a better description of their internal structure. In the majority of cases, our refined regions of breakpoint exhibit specific biological properties (no similarity, presence of segmental duplications and of transposable elements). We hope that this new result may provide some insight into the mechanism and evolutionary properties of chromosomal rearrangements.

The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli

Adam Feist — 2008-06-07T15:04:45-00:00

Nature Biotechnology, Vol. 26, No. 6. (06 June 2008), pp. 659-667.

Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA

Nalini Polavarapu — 2008-05-17T14:08:28-00:00

BMC Genomics, Vol. 9 (17 May 2008), 226.

Promoter elements associated with RNA Pol II stalling in the Drosophila embryo

David Hendrix — 2008-05-28T08:50:08-00:00

Proceedings of the National Academy of Sciences (27 May 2008), 0802406105.

RNA Polymerase II (Pol II) is bound to the promoter regions of many or most developmental control genes before their activation during Drosophila embryogenesis. It has been suggested that Pol II stalling is used to produce dynamic and rapid responses of developmental patterning genes to transient cues such as extracellular signaling molecules. Here, we present a combined computational and experimental analysis of stalled promoters to determine how they come to bind Pol II in the early Drosophila embryo. At least one-fourth of the stalled promoters contain a shared sequence motif, the "pause button" (PB): KCGRWCG. The PB motif is sometimes located in the position of the DPE, and over one-fifth of the stalled promoters contain the following arrangement of core elements: GAGA, Inr, PB, and/or DPE. This arrangement was used to identify additional stalled promoters in the Drosophila genome, and permanganate footprint assays were used to confirm that the segmentation gene engrailed contains paused Pol II as seen for heat-shock genes. We discuss different models for Pol II binding and gene activation in the early embryo. 10.1073/pnas.0802406105

DataGraph

2008-05-23T15:36:55-00:00

Evidence against the energetic cost hypothesis for the short introns in highly expressed genes

Yi-Fei Huang — 2008-05-20T15:48:01-00:00

BMC Evolutionary Biology, Vol. 8 (20 May 2008), 154.

Expected Gene Order Distances and Model Selection in Bacteria.

Daniel Dalevi — 2008-04-06T21:17:03-00:00

Bioinformatics (Oxford, England) (1 April 2008)

MOTIVATION: The evolutionary distance inferred from gene order comparisons of related bacteria is dependent on the model. Therefore, it is highly important to establish reliable assumptions before inferring its magnitude. RESULTS: We investigate the patterns of dotplots between species of bacteria with the purpose of model selection in gene order problems. We find several categories of data which can be explained by carefully weighing the contributions of reversals, transpositions, symmetrical reversals, single gene transpositions, and single gene reversals. We also derive method of moments distance estimates for some previously uncomputed cases, such as symmetrical reversals, single gene reversals and their combinations, as well as the single gene transpositions edit distance. CONTACT: ner@math.chalmers.se SUPPLEMENTARY INFORMATION: Available at Bioinformatics online.

Report of a chimeric origin of transposable elements in a bovine-coding gene.

LM Almeida — 2008-05-16T14:24:39-00:00

Genetics and molecular research : GMR, Vol. 7, No. 1. (2008), pp. 107-116.

Despite the wide distribution of transposable elements (TEs) in mammalian genomes, part of their evolutionary significance remains to be discovered. Today there is a substantial amount of evidence showing that TEs are involved in the generation of new exons in different species. In the present study, we searched 22,805 genes and reported the occurrence of TE-cassettes in coding sequences of 542 cow genes using the RepeatMasker program. Despite the significant number (542) of genes with TE insertions in exons only 14 (2.6%) of them were translated into protein, which we characterized as chimeric genes. From these chimeric genes, only the FAST kinase domains 3 (FASTKD3) gene, present on chromosome BTA 20, is a functional gene and showed evidence of the exaptation event. The genome sequence analysis showed that the last exon coding sequence of bovine FASTKD3 is approximately 85% similar to the ART2A retrotransposon sequence. In addition, comparison among FASTKD3 proteins shows that the last exon is very divergent from those of Homo sapiens, Pan troglodytes and Canis familiares. We suggest that the gene structure of bovine FASTKD3 gene could have originated by several ectopic recombinations between TE copies. Additionally, the absence of TE sequences in all other species analyzed suggests that the TE insertion is clade-specific, mainly in the ruminant lineage.

Transcription of two human genes from a bidirectional endogenous retrovirus promoter.

Catherine A Dunn — 2006-02-15T12:48:28-00:00

Gene (7 November 2005)

Eight percent of the human genome is derived from endogenous retrovirus (ERV) insertions. ERV long terminal repeats (LTRs) contain strong promoters that are known to contribute to the transcriptional regulation of certain human genes. While some LTRs are known to possess bidirectional promoter activity in vitro, only sense orientation LTR promoters have previously been shown to regulate human gene expression. Here we demonstrate that an ERV1 LTR acts as a bidirectional promoter for the human Down syndrome critical region 4 (DSCR4) and DSCR8 genes. We show that while DSCR4 and DSCR8 are essentially co-expressed, their shared LTR promoter is more active in the sense than the antisense orientation. Through deletion analysis of the LTR we have identified positive and negative regulatory elements, and defined a core region of the promoter that is required for transcriptional activity in both orientations. Finally, we show that the ERV LTR also exists in the genomes of several non-human primates, and present evidence that potential transcription factor binding sites in the core region have been maintained throughout primate evolution.

Retrotransposon Tf1 is targeted to Pol II promoters by transcription activators.

YE Leem — 2008-05-10T08:05:45-00:00

Molecular cell, Vol. 30, No. 1. (11 April 2008), pp. 98-107.

The LTR-retrotransposon Tf1 preserves the coding capacity of its host Schizosaccharomyces pombe by integrating upstream of open reading frames (ORFs). To determine which features of the target sites were recognized by the transposon, we introduced plasmids containing candidate insertion sites into S. pombe and mapped the positions of integration. We found that Tf1 was targeted specifically to the promoters of Pol II-transcribed genes. A detailed analysis of integration in plasmids that contained either ade6 or fbp1 revealed insertions occurred in the promoters at positions where transcription factors bound. Further experiments revealed that the activator Atf1p and its binding site were required for directing integration to the promoter of fbp1. An interaction between Tf1 integrase and Atf1p was observed, indicating that integration at fbp1 was mediated by the activator bound to its promoter. Surprisingly, we found Tf1 contained sequences that activated transcription, and these substituted for elements of the ade6 promoter disrupted by integration.

Molecular dissection of Penelope transposable element regulatory machinery

Nataliya Schostak — 2008-03-13T15:17:44-00:00

Nucl. Acids Res. (4 March 2008), gkm1166.

Penelope-like elements (PLEs) represent a new class of retroelements identified in more than 80 species belonging to at least 10 animal phyla. Penelope isolated from Drosophila virilis is the only known transpositionally active representative of this class. Although the size and structure of the Penelope major transcript has been previously described in both D. virilis and D. melanogaster transgenic strains, the architecture of the Penelope regulatory region remains unknown. In order to determine the localization of presumptive Penelope promoter and enhancer-like elements, segments of the putative Penelope regulatory region were linked to a CAT reporter gene and introduced into D. melanogaster by P-element-mediated transformation. The results obtained using ELISA to measure CAT expression levels and RNA studies, including RTPCR, suggest that the active Penelope transposon contains an internal promoter similar to the TATA-less promoters of LINEs. The results also suggest that some of the Penelope regulatory sequences control the preferential expression in the ovaries of the adult flies by enhancing expression in the ovary and reducing expression in the carcass. The possible significance of the intron within Penelope for the function and evolution of PLEs, and the effect of Penelope insertions on adjacent genes, are discussed. 10.1093/nar/gkm1166

Possible involvement of SINEs in mammalian-specific brain formation.

T Sasaki — 2008-04-20T11:53:45-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 11. (18 March 2008), pp. 4220-4225.

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.

Transcription factor and microRNA motif discovery: The Amadeus platform and a compendium of metazoan target sets.

Chaim Linhart — 2008-04-18T07:36:36-00:00

Genome research (14 April 2008)

We present a three-fold contribution to the computational task of motif discovery, a key component in the effort of delineating the regulatory map of a genome: 1) We constructed a comprehensive large-scale, publicly-available compendium of transcription factor and microRNA target gene sets derived from diverse high-throughput experiments in several metazoans. We used the compendium as a benchmark for motif discovery tools. 2) We developed Amadeus, a highly efficient, user-friendly software platform for genome-scale detection of novel motifs, applicable to a wide range of motif discovery tasks. Amadeus improves upon extant tools in terms of accuracy, running time, output information and ease-of-use, and is the only program that attained a high success rate on the metazoan compendium. 3) We demonstrate that by searching for motifs based on their genome-wide localization or chromosomal distributions (without using a pre-defined target set), Amadeus uncovers diverse known phenomena, as well as novel regulatory motifs.

Correlation between the abundance of yeast transfer RNAs and the occurrence of the respective codons in protein genes. Differences in synonymous codon choice patterns of yeast and Escherichia coli with reference to the abundance of isoaccepting transfer RNAs.

T Ikemura — 2005-11-25T12:16:03-00:00

J Mol Biol, Vol. 158, No. 4. (15 July 1982), pp. 573-597.

The Cost of Expression of Escherichia coli lac Operon Proteins Is in the Process, Not in the Products.

DM Stoebel — 2008-04-23T07:22:37-00:00

Genetics, Vol. 178, No. 3. (March 2008), pp. 1653-1660.

Transcriptional regulatory networks allow bacteria to express proteins only when they are needed. Adaptive hypotheses explaining the evolution of regulatory networks assume that unneeded expression is costly and therefore decreases fitness, but the proximate cause of this cost is not clear. We show that the cost in fitness to Escherichia coli strains constitutively expressing the lactose operon when lactose is absent is associated with the process of making the lac gene products, i.e., associated with the acts of transcription and/or translation. These results reject the hypotheses that regulation exists to prevent the waste of amino acids in useless protein or the detrimental activity of unnecessary proteins. While the cost of the process of protein expression occurs in all of the environments that we tested, the expression of the lactose permease could be costly or beneficial, depending on the environment. Our results identify the basis of a single selective pressure likely acting across the entire E. coli transcriptome.

Systems biology of SNPs

Neema Jamshidi — 2006-08-02T10:44:09-00:00

Mol Syst Biol, Vol. 2 (4 July 2006), pp. E1-E4.

Transposable elements and the evolution of regulatory networks.

Cédric Feschotte — 2008-03-31T08:19:51-00:00

Nat Rev Genet (27 March 2008)

The control and coordination of eukaryotic gene expression rely on transcriptional and post-transcriptional regulatory networks. Although progress has been made in mapping the components and deciphering the function of these networks, the mechanisms by which such intricate circuits originate and evolve remain poorly understood. Here I revisit and expand earlier models and propose that genomic repeats, and in particular transposable elements, have been a rich source of material for the assembly and tinkering of eukaryotic gene regulatory systems.

Overlapping genes in the human and mouse genomes

Chaitanya Sanna — 2008-04-15T18:39:20-00:00

BMC Genomics, Vol. 9 (14 April 2008), 169.

Non-random retention of protein-coding overlapping genes in Metazoa

Giulia Solda' — 2008-04-17T06:42:58-00:00

BMC Genomics, Vol. 9 (16 April 2008), 174.

Birth and death of gene overlaps in vertebrates

Izabela Makalowska — 2007-10-20T20:23:52-00:00

BMC Evolutionary Biology, Vol. 7 (16 October 2007), 193.

Local conservation scores without a priori assumptions on neutral substitution rates

Janis Dingel — 2008-04-11T13:25:22-00:00

BMC Bioinformatics, Vol. 9, No. 1. (2008)

BACKGROUND:Comparative genomics aims to detect signals of evolutionary conservation as an indicator of functional constraint. Surprisingly, results of the ENCODE project revealed that about half of the experimentally verified functional elements found in non-coding DNA were classified as unconstrained by computational predictions. Following this observation, it has been hypothesized that this may be partly explained by biased estimates on neutral evolutionary rates used by existing sequence conservation metrics. All methods we are aware of rely on a comparison with the neutral rate and conservation is estimated by measuring the deviation of a particular genomic region from this rate. Consequently, it is a reasonable assumption that inaccurate neutral rate estimates may lead to biased conservation and constraint estimates.RESULTS:We propose a conservation signal that is produced by local Maximum Likelihood estimation of evolutionary parameters using an optimized sliding window and present a Kullback-Leibler projection that allows multiple different estimated parameters to be transformed into a conservation measure. This conservation measure does not rely on assumptions about neutral evolutionary substitution rates and little a priori assumptions on the properties of the conserved regions are imposed. We show the accuracy of our approach (KuLCons) on synthetic data and compare it to the scores generated by state-of-the-art methods (phastCons, GERP, SCONE) in an ENCODE region. We find that KuLCons is most often in agreement with the conservation/constraint signatures detected by GERP and SCONE while qualitatively very different patterns from phastCons are observed. Opposed to standard methods KuLCons can be extended to more complex evolutionary models, e.g. taking insertion and deletion events into account and corresponding results show that scores obtained under this model can diverge significantly from scores using the simpler model.CONCLUSIONS:Our results suggest that discriminating among the different degrees of conservation is possible without making assumptions about neutral rates. We find, however, that it cannot be expected to discover considerably different constraint regions than GERP and SCONE. Consequently, we conclude that the reported discrepancies between experimentally verified functional and computationally identified constraint elements are likely not to be explained by biased neutral rate estimates.

Multiple effects govern endogenous retrovirus survival patterns in human gene introns

Louie van de Lagemaat — 2006-09-28T08:52:45-00:00

Genome Biology, Vol. 7 (27 September 2006), R86.

Turning junk into gold: domestication of transposable elements and the creation of new genes in eukaryotes

Jean-Nicolas Volff — 2006-08-26T11:34:49-00:00

BioEssays, Vol. 28, No. 9. (2006), pp. 913-922.

Autonomous transposable elements, generally considered as junk and selfish, encode transposition proteins that can bind, copy, break, join or degrade nucleic acids as well as process or interact with other proteins. Such a repertoire of activities might be of interest for the host cell. There is indeed substantial evidence that mobile DNA can serve as a dynamic reservoir for new cellular functions. Transposable element genes encoding transposase, integrase, reverse transcriptase as well as structural and envelope proteins have been repeatedly recruited by their host during evolution in most eukaryotic lineages. Such domesticated sequences protect us against infections, are necessary for our reproduction, allow the replication of our chromosomes and control cell proliferation and death; others are essential for plant development. Many new candidates for domesticated sequences have been revealed by sequencing projects. Their functional analysis will uncover new aspects of evolutionary alchemy, the turning of junk into gold within genomes. BioEssays 28: 913-922, 2006. © 2006 Wiley periodicals, Inc.

Influence of the transposable element neighborhood on human gene expression in normal and tumor tissues

Emmanuelle Lerat — 2008-04-02T13:14:04-00:00

Gene, Vol. 396, No. 2. (15 July 2007), pp. 303-311.

Transposable elements (TEs) are genomic sequences able to replicate themselves, and to move from one chromosomal position to another within the genome. Many TEs contain their own regulatory regions, which means that they may influence the expression of neighboring genes. TEs may also be activated and transcribed in various cancers. We therefore tested whether gene expression in normal and tumor tissues is influenced by the neighboring TEs. To do this, we associated all human genes to the nearest TEs. We analyzed the expression of these genes in normal and tumor tissues using SAGE and EST data, and related this to the presence and type of TEs in their vicinity. We confirmed that TEs tend to be located in antisense orientation relative to their hosting genes. We found that the average number of tissues where a gene is expressed varies depending on the type of TEs located near the gene, and that the difference in expression level between normal and tumor tissues is greatest for genes that host SINE elements. This deregulation increases with the number of SINE copies in the gene vicinity. This suggests that SINE elements might contribute to the cascade of gene deregulation in cancer cells.

Phylogenetic and genomewide analyses suggest a functional relationship between kayak, the Drosophila fos homolog, and fig, a predicted protein phosphatase 2c nested within a kayak intron.

SG Hudson — 2008-03-28T07:23:23-00:00

Genetics, Vol. 177, No. 3. (November 2007), pp. 1349-1361.

A gene located within the intron of a larger gene is an uncommon arrangement in any species. Few of these nested gene arrangements have been explored from an evolutionary perspective. Here we report a phylogenetic analysis of kayak (kay) and fos intron gene (fig), a divergently transcribed gene located in a kay intron, utilizing 12 Drosophila species. The evolutionary relationship between these genes is of interest because kay is the homolog of the proto-oncogene c-fos whose function is modulated by serine/threonine phosphorylation and fig is a predicted PP2C phosphatase specific for serine/threonine residues. We found that, despite an extraordinary level of diversification in the intron-exon structure of kay (11 inversions and six independent exon losses), the nested arrangement of kay and fig is conserved in all species. A genomewide analysis of protein-coding nested gene pairs revealed that approximately 20% of nested pairs in D. melanogaster are also nested in D. pseudoobscura and D. virilis. A phylogenetic examination of fig revealed that there are three subfamilies of PP2C phosphatases in all 12 species of Drosophila. Overall, our phylogenetic and genomewide analyses suggest that the nested arrangement of kay and fig may be due to a functional relationship between them.

Modern origin of numerous alternatively spliced human introns from tandem arrays

Degen Zhuo — 2007-01-17T12:54:25-00:00

PNAS, Vol. 104, No. 3. (16 January 2007), pp. 882-886.

Despite the widespread occurrence of spliceosomal introns in the genomes of higher eukaryotes, their origin remains controversial. One model proposes that the duplication of small genomic portions could have provided the boundaries for new introns. If this mechanism has occurred recently, the 5' and 3' boundaries of each resulting intron should display distinctive sequence similarity. Here, we report that the human genome contains an excess of introns with perfect matching sequences at boundaries. One-third of these introns interrupt the protein-coding sequences of known genes. Introns with the best-matching boundaries are invariably found in tandem arrays of direct repeats. Sequence analysis of the arrays indicates that many intron-breeding repeats have disseminated in several genes at different times during human evolution. A comparison with orthologous regions in mouse and chimpanzee suggests a young age for the human introns with the most-similar boundaries. Finally, we show that these human introns are alternatively spliced with exceptionally high frequency. Our study indicates that genomic duplication has been an important mode of intron gain in mammals. The alternative splicing of transcripts containing these intron-breeding repeats may provide the plasticity required for the rapid evolution of new human proteins. 10.1073/pnas.0604777104

Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons

Xiang Zhang — 2006-09-06T10:02:52-00:00

PNAS, Vol. 103, No. 36. (5 September 2006), pp. 13427-13432.

Orthologous gene structures in eight vertebrate species were compared on a genomic scale to detect the birth and maturation of new internal exons during the course of evolution. We found that 40% of new human exons are alternatively spliced, and most of these are cassette exons (exons that are either included or skipped in their entirety) with low inclusion rates. This proportion decreases steadily as older and older exons are examined, even as splicing efficiency increases. Remarkably, the great majority of new cassette exons are composed of highly repeated sequences, especially Alu. Many new cassette exons are 5' untranslated exons; the proportion that code for protein increases steadily with age. New protein-coding exons evolve at a high rate, as evidenced by the initially high substitution rates (Ks and Ka), as well as the SNP density compared with older exons. This dynamic picture suggests that de novo recruitment rather than shuffling is the major route by which exons are added to genes, and that species-specific repeats could play a significant role in recent evolution. 10.1073/pnas.0603042103

Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes

Yi Xing — 2006-06-18T11:48:06-00:00

Nature Reviews Genetics, Vol. 7, No. 7. (13 June 2006), pp. 499-509.

Genome-wide analyses of alternative splicing have established its nearly ubiquitous role in gene regulation in many organisms. Genome sequencing and comparative genomics have made it possible to look in detail at the evolutionary history of specific alternative exons or splice sites, resulting in a flurry of publications in recent years. Here, we consider how alternative splicing has contributed to the evolution of modern genomes, and discuss constraints on evolution associated with alternative splicing that might have important medical implications.

Gene function and expression level influence the insertion/fixation dynamics of distinct transposon families in mammalian introns

Manuela Sironi — 2006-12-20T22:02:30-00:00

Genome Biology, Vol. 7 (20 December 2006), R120.

Fixation of conserved sequences shapes human intron size and influences transposon-insertion dynamics.

M Sironi — 2008-03-06T12:13:24-00:00

Trends Genet, Vol. 21, No. 9. (September 2005), pp. 484-488.

The basis for intron expansion in humans is largely unexplored. In this article, we demonstrate that intron expansion has primarily been determined by fixation of multispecies conserved sequences (MCSs) over time. The presence of MCSs has shaped intron features: the insertion of transposable elements (TEs) has been constrained as more MCSs were fixed. Analysis of TE and MCS distribution suggested an unprecedented estimate of information requirements for proper splicing of long introns with indication of sequence constraints extending up to >3 kb downstream 5' splice sites.

The origin of recent introns: transposons?

SW Roy — 2008-03-26T12:24:19-00:00

Genome Biol, Vol. 5, No. 12. (2004)

The long-standing question of how genes acquire introns has provoked much debate. A recent study makes considerable progress by identifying numerous recently gained introns in nematodes - although it remains difficult to distinguish definitively between models of intron gain.

RNA-editing-mediated exon evolution

Galit Lev-Maor — 2007-02-28T21:28:40-00:00

Genome Biology, Vol. 8 (27 February 2007), R29.

Identification of splicing silencers and enhancers in sense Alus: a role for pseudoacceptors in splice site repression.

H Lei — 2008-03-26T12:12:22-00:00

Mol Cell Biol, Vol. 25, No. 16. (August 2005), pp. 6912-6920.

Auxiliary splicing signals in introns play an important role in splice site selection, but these elements are poorly understood. We show that a subset of serine/arginine (SR)-rich proteins activate a cryptic 3' splice site in a sense Alu repeat located in intron 4 of the human LST1 gene. Utilization of this cryptic splice site is controlled by juxtaposed Alu-derived splicing silencers and enhancers between closely linked short tandem repeats TNFd and TNFe. Systematic mutagenesis of these elements showed that AG dinucleotides that were not preceded by purine residues were critical for repressing exon inclusion of a chimeric splicing reporter. Since the splice acceptor-like sequences are present in excess in exonic splicing silencers, these signals may contribute to inhibition of a large number of pseudosites in primate genomes.

Regulation of gene expression by alternative untranslated regions

Thomas Hughes — 2006-03-02T09:57:11-00:00

Trends in Genetics, Vol. 22, No. 3. (March 2006), pp. 119-122.

The untranslated regions of mRNAs can determine gene expression by influencing mRNA stability and translational efficiency. Recent reports show that gene expression can be regulated by the differential use of alternative untranslated regions. Tissue-specific expression of transcripts that have different untranslated regions (UTRs) can control protein expression enabling developmental, physiological and pathological regulation. Several examples of alternative UTRs have been characterized, including those found in AXIN2, FGF1 and BRCA1. Results from bioinformatics studies indicate that this mechanism is more common than previously appreciated.

LINE-1 retrotransposons: Modulators of quantity and quality of mammalian gene expression?

JS Han — 2005-08-03T15:16:17-00:00

Bioessays, Vol. 27, No. 8. (August 2005), pp. 775-784.

LINE-1 (L1) retrotransposons are replicating repetitive elements that, by mass, are the most-abundant sequences in the human genome. Over one-third of mammalian genomes are the result, directly or indirectly, of L1 retrotransposition. L1 encodes two proteins: ORF1, an RNA-binding protein, and ORF2, an endonuclease/reverse transcriptase. Both proteins are required for L1 mobilization. Apart from the obvious function of self-replication, it is not clear what other roles, if any, L1 plays within its host. The sheer magnitude of L1 sequences in our genome has fueled speculation that over evolutionary time L1 insertions may structurally modify endogenous genes and regulate gene expression. Here we provide a review of L1 replication and its potential functional consequences. BioEssays 27:775-784, 2005. (c) 2005 Wiley Periodicals, Inc.

Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes

Jeffrey Han — 2006-05-28T08:03:24-00:00

Nature, Vol. 429, No. 6989. (20 May 2004), pp. 268-274.

Chimeric retrogenes suggest a role for the nucleolus in LINE amplification.

A Buzdin — 2008-03-26T11:42:46-00:00

FEBS Lett, Vol. 581, No. 16. (26 June 2007), pp. 2877-2882.

Chimeric retrogenes, found in mammalian and fungal genomes, are bipartite elements composed of DNA copies of cellular transcripts either directly fused to each other or fused to the 3' part of a LINE retrotransposon. These cellular transcripts correspond to messenger RNAs, ribosomal RNAs, small nuclear RNAs and 7SL RNA. The chimeras are likely formed by RNA template switches during reverse transcription of LINE elements by their retrotranspositional machinery. The 5' part of chimeras are copies of nucleolar RNAs, suggesting that the nucleolus plays a significant role in LINE retrotransposition. RNAs from the nucleolus might have protective function against retroelement invasion or, alternatively, the nucleolus may be required for retrotranspositional complex assembly and maturation. These hypotheses will be discussed in this review.

At least 50% of human-specific HERV-K (HML-2) long terminal repeats serve in vivo as active promoters for host nonrepetitive DNA transcription.

A Buzdin — 2008-02-18T09:12:29-00:00

J Virol, Vol. 80, No. 21. (November 2006), pp. 10752-10762.

We report the first genome-wide comparison of in vivo promoter activities of a group of human-specific endogenous retroviruses in healthy and cancerous germ line tissues. To this end, we employed a recently developed technique termed genomic repeat expression monitoring. We found that at least 50% of human-specific long terminal repeats (LTRs) possessed promoter activity, and many of them were up- or downregulated in a seminoma. Individual LTRs were expressed at markedly different levels, ranging from approximately 0.001 to approximately 3% of the housekeeping beta-actin gene transcript level. We demonstrated that the main factors affecting the LTR promoter activity were the LTR type (5'-proviral, 3' proviral, or solitary) and position with regard to genes. The averaged promoter strengths of solitary and 3'-proviral LTRs were almost identical in both tissues, whereas 5'-proviral LTRs displayed two- to fivefold higher promoter activities. The relative content of promoter-active LTRs in gene-rich regions was significantly higher than that in gene-poor loci. This content was maximal in those regions where LTRs "overlapped" readthrough transcripts. Although many promoter-active LTRs were mapped near known genes, no clear-cut correlation was observed between transcriptional activities of genes and neighboring LTRs. Our data also suggest a selective suppression of transcription for LTRs located in gene introns.

Exonization of the LTR transposable elements in human genome

Jittima Piriyapongsa — 2007-08-29T05:42:08-00:00

BMC Genomics, Vol. 8 (28 August 2007), 291.

Characterization of new hAT transposable elements in 12 Drosophila genomes.

Mauro de Freitas Ortiz — 2008-03-15T19:59:29-00:00

Genetica (14 March 2008)

In silico searches for sequences homologous to hAT elements in 12 Drosophila genomes have allowed us to identify 37 new hAT elements (8 in D. ananassae, 11 in D. mojavensis, 2 in D. sechellia, 1 in D. simulans, 2 in D. virilis, 3 in D. yakuba, 3 in D. persimilis, 1 in D. grimshawi, 5 in D. willistoni and 1 in D. pseudobscura). The size of these elements varies from 2,359 to 4,962 bp and the terminal inverted repeats (TIRs) show lengths ranging from 10 to 24 bp. Several elements show intact transposase ORFs, suggesting that they are active. Conserved amino acid motifs were identified that correspond to those important for transposase activity. These elements are highly variable and phylogenetic analysis showed that they can be clustered into four different families. Incongruencies were observed between the phylogenies of the transposable elements and those of their hosts, suggesting that horizontal transfer may have occurred between some of the species.

Computation-Based Discovery of Cis-Regulatory Modules by Hidden Markov Model.

Jing Wu — 2008-03-13T19:44:59-00:00

J Comput Biol (11 March 2008)

A key component in genome sequence analysis is the identification of regions of the genome that contain regulatory information. In higher eukaryotes, this information is organized into modular units called cis-regulatory modules. Each module contains multiple binding sites for a specific combination of several transcription factors. In this article, we propose a hidden Markov model (HMM) to identify transcription factor binding sites (TFBSs) and cis-regulatory modules (CRMs). For a given genomic sequence, we first select potential TFBSs from a large database (e.g., TRANSFAC), then construct an HMM where the TFBSs are only counted when they occur within a specialized CRM state. The novel features of the proposed method include that it does not assume a small set of TFBSs for a given gene; on the other hand, the method utilizes information from a large collection of well-characterized TFBSs and therefore is computationally more efficient and robust than the de novo methods. Our approach is applied to three data sets with experimentally evaluated TFBSs. The method shows better specificity and sensitivity than other similar computational tools in identifying CRMs and TFBSs. The executable codes of our programs and module predictions across the fly Drosophila genome are available at www.stat.purdue.edu/ approximately jingwu/module/.

Selective inhibition of Alu retrotransposition by APOBEC3G

Amy Hulme — 2008-03-10T15:50:54-00:00

Gene, Vol. 390, No. 1-2. (1 April 2007), pp. 199-205.

The non-LTR retrotransposon LINE-1 (L1) comprises ~ 17% of the human genome, and the L1-encoded proteins can function in trans to mediate the retrotransposition of non-autonomous retrotransposons (i.e., Alu and probably SVA elements) and cellular mRNAs to generate processed pseudogenes. Here, we have examined the effect of APOBEC3G and APOBEC3F, cytidine deaminases that inhibit Vif-deficient HIV-1 replication, on Alu retrotransposition and other L1-mediated retrotransposition processes. We demonstrate that APOBEC3G selectively inhibits Alu retrotransposition in an ORF1p-independent manner. An active cytidine deaminase site is not required for the inhibition of Alu retrotransposition and the resultant integration events lack G to A or C to T hypermutation. These data demonstrate a differential restriction of L1 and Alu retrotransposition by APOBEC3G, and suggest that the Alu ribonucleoprotein complex may be targeted by APOBEC3G.

Cellular inhibitors of long interspersed element 1 and Alu retrotransposition

Hal Bogerd — 2006-10-10T13:59:31-00:00

PNAS, Vol. 103, No. 23. (6 June 2006), pp. 8780-8785.

Long interspersed element (LINE) 1 retrotransposons are major genomic parasites that represent approx17% of the human genome. The LINE-1 ORF2 protein is also responsible for the mobility of Alu elements, which constitute a further approx11% of genomic DNA. Representative members of each element class remain mobile, and deleterious retrotransposition events can induce spontaneous genetic diseases. Here, we demonstrate that APOBEC3A and APOBEC3B, two members of the APOBEC3 family of human innate antiretroviral resistance factors, can enter the nucleus, where LINE-1 and Alu reverse transcription occurs, and specifically inhibit both LINE-1 and Alu retrotransposition. These data suggest that the APOBEC3 protein family may have evolved, at least in part, to defend the integrity of the human genome against endogenous retrotransposons. 10.1073/pnas.0603313103