CiteULike: cisevol's library [302 articles]

Gene expression variation in African and European populations of Drosophila melanogaster

Stephan Hutter — 2008-01-22T11:12:30-00:00

Genome Biology, Vol. 9 (21 January 2008), R12.

The yeast coexpression network has a small-world, scale-free architecture and can be explained by a simple model.

V van Noort — 2008-07-23T08:00:52-00:00

EMBO reports, Vol. 5, No. 3. (March 2004), pp. 280-284.

We investigated the gene coexpression network in Saccharomyces cerevisiae, in which genes are linked when they are coregulated. This network is shown to have a scale-free, small-world architecture. Such architecture is typical of biological networks in which the nodes are connected when they are involved in the same biological process. Current models for the evolution of intracellular networks do not adequately reproduce the features that we observe in the network. We therefore derive a new model for its evolution based on the observation that there is a positive correlation between the sequence similarity of paralogues and their probability of coexpression or sharing of transcription factor binding sites (TFBSs). The simple, neutralist's model consists of (1) coduplication of genes with their TFBSs, (2) deletion and duplication of individual TFBSs and (3) gene loss. A network is constructed by connecting genes that share multiple TFBSs. Our model reproduces the scale-free, small-world architecture of the coregulation network and the homology relations between coregulated genes without the need for selection either at the level of the network structure or at the level of gene regulation.

Gene co-regulation is highly conserved in the evolution of eukaryotes and prokaryotes.

B Snel — 2005-09-20T07:06:21-00:00

Nucleic Acids Res, Vol. 32, No. 16. (2004), pp. 4725-4731.

Differences between species have been suggested to largely reside in the network of connections among the genes. Nevertheless, the rate at which these connections evolve has not been properly quantified. Here, we measure the extent to which co-regulation between pairs of genes is conserved over large phylogenetic distances; between two eukaryotes Caenorhabditis elegans and Saccharomyces cerevisiae, and between two prokaryotes Escherichia coli and Bacillus subtilis. We first construct a reliable set of co-regulated genes by combining various functional genomics data from yeast, and subsequently determine conservation of co-regulation in worm from the distribution of co-expression values. For B.subtilis and E.coli, we use known operons and regulons. We find that between 76 and 80% of the co-regulatory connections are conserved between orthologous pairs of genes, which is very high compared with previous estimates and expectations regarding network evolution. We show that in the case of gene duplication after speciation, one of the two inparalogous genes tends to retain its original co-regulatory relationship, while the other loses this link and is presumably free for differentiation or sub-functionalization. The high level of co-regulation conservation implies that reliably predicted functional relationships from functional genomics data in one species can be transferred with high accuracy to another species when that species also harbours the associated genes.

Multiple rounds of speciation associated with reciprocal gene loss in polyploid yeasts

Devin Scannell — 2006-03-15T23:36:34-00:00

Nature, Vol. 440, No. 7082., pp. 341-345.

Functional Analysis of Gene Duplications in Saccharomyces cerevisiae

Yuanfang Guan — 2007-03-19T08:45:07-00:00

Genetics, Vol. 175, No. 2. (1 February 2007), pp. 933-943.

Gene duplication can occur on two scales: whole-genome duplications (WGD) and smaller-scale duplications (SSD) involving individual genes or genomic segments. Duplication may result in functionally redundant genes or diverge in function through neofunctionalization or subfunctionalization. The effect of duplication scale on functional evolution has not yet been explored, probably due to the lack of global knowledge of protein function and different times of duplication events. To address this question, we used integrated Bayesian analysis of diverse functional genomic data to accurately evaluate the extent of functional similarity and divergence between paralogs on a global scale. We found that paralogs resulting from the whole-genome duplication are more likely to share interaction partners and biological functions than smaller-scale duplicates, independent of sequence similarity. In addition, WGD paralogs show lower frequency of essential genes and higher synthetic lethality rate, but instead diverge more in expression pattern and upstream regulatory region. Thus, our analysis demonstrates that WGD paralogs generally have similar compensatory functions but diverging expression patterns, suggesting a potential of distinct evolutionary scenarios for paralogs that arose through different duplication mechanisms. Furthermore, by identifying these functional disparities between the two types of duplicates, we reconcile previous disputes on the relationship between sequence divergence and expression divergence or essentiality. 10.1534/genetics.106.064329

Heterosis and the Evolution of Duplications

Janice Spofford — 2008-07-22T19:11:28-00:00

The American Naturalist, Vol. 103, No. 932. (1969), pp. 407-432.

Single locus heterosis affords a sufficient drive for the incorporation of a newly arisen duplication into a species gene pool. Heterosis is here assumed to result from the formation of heterodimers between polypeptides specified by alleles. In consequence, the normal homologue of the duplication-bearing chromosome is eliminated rapidly unless the product of the locus is regulated in amount and recombination occurs so infrequently as to approximate mutation rates. In the latter case, the duplication comes to a frequency that is the higher, the fewer alleles initially present. This frequency would then continue until the slower processes such as mutation or recombination between adjacent cistrons permit a renewed climb to fixation. The allele included in the duplication will be lost at the original site unless the original number of alleles is low and it forms homozygotes of fitness nearly equal to the heterozygote. In general, segregation would be expected to continue for at least two alleles in nearly equal proportions at the original site. Recombination above a certain minimal value delays the attainment of selective equilibrium. This mechanism would be operative in haploid species as well, although heterosis-maintained segregation would of course not provide either initial or final polymorphism. Although only an arbitrarily simple model was investigated thoroughly, the general conclusions appear unperturbed by various relaxations of the restrictions built into it. Further diversification at the duplication site would be expected to follow its fixation.

Evolution of genetic redundancy.

MA Nowak — 2008-07-22T19:06:53-00:00

Nature, Vol. 388, No. 6638. (10 July 1997), pp. 167-171.

Genetic redundancy means that two or more genes are performing the same function and that inactivation of one of these genes has little or no effect on the biological phenotype. Redundancy seems to be widespread in genomes of higher organisms. Examples of apparently redundant genes come from numerous studies of developmental biology, immunology, neurobiology and the cell cycle. Yet there is a problem: genes encoding functional proteins must be under selection pressure. If a gene was truly redundant then it would not be protected against the accumulation of deleterious mutations. A widespread view is therefore that such redundancy cannot be evolutionarily stable. Here we develop a simple genetic model to analyse selection pressures acting on redundant genes. We present four cases that can explain why genetic redundancy is common. In three cases, redundancy is even evolutionarily stable. Our theory provides a framework for exploring the evolution of genetic organization.

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

Integration of Horizontally Transferred Genes into Regulatory Interaction Networks Takes Many Million Years

Martin Lercher — 2007-12-25T12:02:33-00:00

Mol Biol Evol (24 December 2007), msm283.

Adaptation of bacteria to new or changing environments is often associated with the uptake of foreign genes through horizontal gene transfer. However, it has remained unclear how (and how fast) new genes are integrated into their host's cellular networks. Combining the regulatory and protein-interaction networks of Escherichia coli with comparative genomics tools, we provide the first systematic analysis of this issue. Recently transferred genes have fewer interaction partners compared to non-transferred genes in both regulatory and protein-interaction networks. Thus, horizontally transferred genes involved in complex regulatory and protein-protein interactions are rarely favoured by selection . Only few protein-protein interactions are gained after the initial integration of genes following the transfer event. In contrast, transferred genes are gradually integrated into the regulatory network of their host over evolutionary time. During adaptation to the host cellular environment, horizontally transferred genes recruit existing transcription factors of the host, reflected in the fast evolutionary rates of the cis-regulatory regions of transferred genes. Further, genes resulting from increasingly ancient transfer events show increasing numbers of transcriptional regulators as well as improved co-regulation with interacting proteins. Fine-tuned integration of horizontally transferred genes into the regulatory network spans more than 8-22 million years, and encompasses accelerated evolution of regulatory regions, stabilization of protein-protein interactions, and changes in codon usage. 10.1093/molbev/msm283

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

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

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

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.

The words of the regulatory code are arranged in a variable manner in highly conserved enhancers.

Sepand Rastegar — 2008-05-06T22:56:41-00:00

Developmental biology (4 April 2008)

The cis-regulatory regions of many developmental regulators and transcription factors are believed to be highly conserved in the genomes of vertebrate species, suggesting specific regulatory mechanisms for these gene classes. We functionally characterized five notochord enhancers, whose sequence is highly conserved, and systematically mutated two of them. Two subregions were identified to be essential for expression in the notochord of the zebrafish embryo. Synthetic enhancers containing the two essential regions in front of a TATA-box drive expression in the notochord while concatemerization of the subregions alone is not sufficient, indicating that the combination of the two sequence elements is required for notochord expression. Both regions are present in the five functionally characterized notochord enhancers. However, the position, the distance and relative orientation of the two sequence motifs can vary substantially within the enhancer sequences. This suggests that the regulatory grammar itself does not dictate the high evolutionary conservation between these orthologous cis-regulatory sequences. Rather, it represents a less well-conserved layer of sequence organization within these sequences.

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.

Evolutionary changes in gene regulation from a comparative analysis of multiple Drosophila species.

L Hu — 2008-06-12T20:57:18-00:00

Genome informatics. International Conference on Genome Informatics, Vol. 18 (2007), pp. 12-21.

Exploiting the ortholog/homolog information now available from the complete genomic sequences of twelve species of Drosophila, we have investigated the ability of regulatory site recognition methods to find regulatory changes for orthologs linked to chromosomal rearrangements. This has made use of the wealth of synteny information among these species. By comparing orthologs in multiple species, we found that the breakpoint of chromosomal rearrangements could have had an impact on regulatory changes of genes next to it with respect to the gene function and location. Extensions of our approach could be used to shed light on the role of gene regulation in the evolutionary adaptation to different environmental conditions.

CSMET: Comparative Genomic Motif Detection via Multi-Resolution Phylogenetic Shadowing

Pradipta Ray — 2008-06-07T18:41:30-00:00

PLoS Comput Biol, Vol. 4, No. 6. (6 June 2008), e1000090.

Functional turnover of transcription factor binding sites (TFBSs), such as whole-motif loss or gain, are common events during genome evolution. Conventional probabilistic phylogenetic shadowing methods model the evolution of genomes only at nucleotide level, and lack the ability to capture the evolutionary dynamics of functional turnover of aligned sequence entities. As a result, comparative genomic search of non-conserved motifs across evolutionarily related taxa remains a difficult challenge, especially in higher eukaryotes, where the cis-regulatory regions containing motifs can be long and divergent; existing methods rely heavily on specialized pattern-driven heuristic search or sampling algorithms, which can be difficult to generalize and hard to interpret based on phylogenetic principles. We propose a new method: Conditional Shadowing via Multi-resolution Evolutionary Trees, or CSMET, which uses a context-dependent probabilistic graphical model that allows aligned sites from different taxa in a multiple alignment to be modeled by either a background or an appropriate motif phylogeny conditioning on the functional specifications of each taxon. The functional specifications themselves are the output of a phylogeny which models the evolution not of individual nucleotides, but of the overall functionality (e.g., functional retention or loss) of the aligned sequence segments over lineages. Combining this method with a hidden Markov model that autocorrelates evolutionary rates on successive sites in the genome, CSMET offers a principled way to take into consideration lineage-specific evolution of TFBSs during motif detection, and a readily computable analytical form of the posterior distribution of motifs under TFBS turnover. On both simulated and real Drosophila cis-regulatory modules, CSMET outperforms other state-of-the-art comparative genomic motif finders.

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

Regulatory divergence modifies limb length between mammals

Chris Cretekos — 2008-01-16T12:31:44-00:00

Genes Dev., Vol. 22, No. 2. (15 January 2008), pp. 141-151.

Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation. We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls because of endochondral bone formation alterations. Surprisingly, deletion of the mouse Prx1 limb enhancer results in normal forelimb length and Prx1 expression, revealing regulatory redundancy. These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations. 10.1101/gad.1620408

Co-evolution of transcription factors and their targets depends on mode of regulation

Ruth Hershberg — 2006-07-20T03:30:50-00:00

Genome Biology, Vol. 7 (19 July 2006), R62.

Evolutionary origin of regulatory regions of retrogenes in Drosophila

Yongsheng Bai — 2008-05-23T16:03:42-00:00

BMC Genomics, Vol. 9 (22 May 2008), 241.

Resurrection of DNA function in vivo from an extinct genome.

AJ Pask — 2008-05-23T18:08:29-00:00

PLoS ONE, Vol. 3, No. 5. (2008)

There is a burgeoning repository of information available from ancient DNA that can be used to understand how genomes have evolved and to determine the genetic features that defined a particular species. To assess the functional consequences of changes to a genome, a variety of methods are needed to examine extinct DNA function. We isolated a transcriptional enhancer element from the genome of an extinct marsupial, the Tasmanian tiger (Thylacinus cynocephalus or thylacine), obtained from 100 year-old ethanol-fixed tissues from museum collections. We then examined the function of the enhancer in vivo. Using a transgenic approach, it was possible to resurrect DNA function in transgenic mice. The results demonstrate that the thylacine Col2A1 enhancer directed chondrocyte-specific expression in this extinct mammalian species in the same way as its orthologue does in mice. While other studies have examined extinct coding DNA function in vitro, this is the first example of the restoration of extinct non-coding DNA and examination of its function in vivo. Our method using transgenesis can be used to explore the function of regulatory and protein-coding sequences obtained from any extinct species in an in vivo model system, providing important insights into gene evolution and diversity.

Microevolutionary divergence pattern of the segmentation gene hunchback in Drosophila.

D Tautz — 2008-01-20T21:38:27-00:00

Mol Biol Evol, Vol. 15, No. 11. (November 1998), pp. 1403-1411.

To study the microevolutionary processes shaping the evolution of the segmentation gene hunchback (hb) from Drosophila melanogaster, we cloned and sequenced the gene from 12 isofemale lines representing wild-type populations of D. melanogaster, as well as from the closely related species Drosophila sechellia, Drosophila orena, and Drosophila yakuba. We find a relatively low degree of sequence variation in D. melanogaster (theta = 0.0017), which is, however, consistent with its chromosomal location in a region of low recombination. Tests of neutrality do not reject a neutral-evolution model for the whole region. However, pairwise tests with different subregions indicate that there is a relative excess of polymorphic sites in the leader and the intron. Codon usage pattern analysis shows a particularly biased codon usage in the highly conserved regions, which is in line with the hypothesis that selection on translational accuracy is the driving force behind such a bias. A comparison of the expression pattern of hb in different sibling species of D. melanogaster reveals some regulatory changes in D. yakuba, which could be interpreted as changes in the timing of secondary expression domains.

A comparison of homologous developmental genes from Drosophila and Tribolium reveals major differences in length and trinucleotide repeat content.

KJ Schmid — 2008-05-22T13:21:53-00:00

Journal of molecular evolution, Vol. 49, No. 5. (November 1999), pp. 558-566.

The flour beetle Tribolium castaneum has become an important model organism for comparative studies of insect development. Many developmentally important genes have now been cloned from both Tribolium and Drosophila and their expression characteristics were studied. We analyze here the complete coding sequences of 17 homologous gene pairs from D. melanogaster and T. castaneum, most of which encode transcription factors. We find that the Tribolium genes are on average 30% shorter than their Drosophila homologues. This appears to be due largely to the almost-complete absence of trinucleotide repeats in the coding sequences of Tribolium as well as the generally lower degree of internal repetitiveness. Clusters of polar and other amino acids such as glutamine, proline, and serine, which are often considered to be important for transcriptional activation domains in Drosophila, are almost completely absent in Tribolium. Codon usage is generally less biased in Tribolium, although we find a similar tendency for the preference of G- or C-ending codons and a higher bias in conserved subregions of the proteins as in Drosophila. Most of the aminoacid substitutions in the DNA-binding domains of the transcription factors occur at residues that do not make a specific contact to DNA, suggesting that the recognition sequences are likely to be conserved between the two species.

A test for adaptive change in DNA sequences controlling transcription.

DL Jenkins — 2008-05-22T13:18:14-00:00

Proceedings. Biological sciences / The Royal Society, Vol. 261, No. 1361. (22 August 1995), pp. 203-207.

Spatial and temporal differences in gene expression in early development result from the interaction of transcription factors with enhancer and silencer sequences in DNA. The evolution of the developmental process thus involves changes in the DNA sequences that bind transcription factors. Here we advocate a non-parametric statistical test-comparing levels of polymorphism and fixed substitutions between species -to look for evidence of adaptive evolution in sequences controlling gene expression. The test is illustrated by DNA sequence changes in the proximal part of the 'zebra' elements in the fushi terazu gene of the Drosophila melanogaster species group, which yield significant evidence for adaptive substitutions. (This is despite highly significant evidence that all parts of the sequence have been subject to strong selective constraint). The test can be applied generally to investigate adaptive evolution in the control of gene expression.

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.

Fast Evolution of Core Promoters in Primate Genomes

Han Liang — 2008-05-13T16:24:18-00:00

Mol Biol Evol, Vol. 25, No. 6. (1 June 2008), pp. 1239-1244.

Despite much interest in regulatory evolution, how promoters have evolved remains poorly studied, mainly owing to paucity of data on promoter regions. Using a new set of high-quality experimentally determined core promoters of the human genome, we conducted a comparative analysis of 2,492 human and rhesus macaque promoters and their neighboring nearly neutral regions. We found that the core promoters have an average rate of nucleotide substitution substantially higher than that at 4-fold degenerate sites and only slightly lower than that for the assumed neutral controls of neighboring noncoding regions, suggesting that core promoters are subject to very weak selective constraints. Interestingly, we identified 24 core promoters (at false discovery rate = 50%) that have evolved at an accelerated rate compared with the neutral controls, suggesting that they may have undergone positive selection. The inferred positively selected genes show strong bias in molecular function. We also used population genetic approaches to examine the evolution of core promoters in human populations and found evidence of positive selection at some loci. Taken together, our results suggest that positive selection has played a substantial role in the evolution of transcriptional regulation in primates. 10.1093/molbev/msn072

Retrotransposition as a Source of New Promoters.

Kohji Okamura — 2008-03-31T09:07:48-00:00

Mol Biol Evol (25 March 2008)

The fact that promoters are essential for the function of all genes presents the basis of the general idea that retrotranspositions give rise to processed pseudogenes. However, recent studies have demonstrated that some retrotransposed genes are transcriptionally active. Because promoters are not thought to be retrotransposed along with exonic sequences, these transcriptionally active genes must have acquired a functional promoter by mechanisms that are yet to be determined. Hence, comparison between a retrotransposed gene and its source gene appears to provide a unique opportunity to investigate the promoter creation for a new gene. Here, we identified 29 gene pairs in the human genome, consisting of a functional retrotransposed gene and its parental gene, and compared their respective promoters. In more than half of these cases, we unexpectedly found that a large part of the core promoter had been transcribed, reverse-transcribed, and then integrated to be operative at the transposed locus. This observation can be ascribed to the recent discovery that transcription start sites tend to be interspersed rather than situated at one specific site. This propensity could confer retrotransposability to promoters per se. Accordingly, the retrotransposability can explain the genesis of some alternative promoters.

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.

Studying the functional conservation of cis-regulatory modules and their transcriptional output

Denis Bauer — 2008-04-29T09:23:48-00:00

BMC Bioinformatics, Vol. 9 (29 April 2008), 220.

Transposable element fragments in protein-coding regions and their contributions to human functional proteins

Ming Wu — 2007-09-05T10:10:14-00:00

Gene, Vol. 401, No. 1-2. (15 October 2007), pp. 165-171.

Transposable elements (TEs) and their contributions to protein-coding regions are of particular interest. Here we searched for TE fragments in Homo sapiens at both the transcript and protein levels. We found evidence in support of TE exonization and its association with alternative splicing. Despite recent findings that long evolutionary times are required to incorporate TE into proteins, we found many functional proteins with translated TE cassettes derived from young TEs. Analyses of two Bcl-family proteins and Alu-encoded segments suggest the coding and functional potential of TE sequences.

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.

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.

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.

How many human genes can be defined as housekeeping with current expression data?

Jiang Zhu — 2008-04-16T11:53:22-00:00

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

BACKGROUND:Housekeeping (HK) genes are ubiquitously expressed in all tissue/cell types and constitute a basal transcriptome for the maintenance of basic cellular functions. Partitioning transcriptomes into HK and tissue-specific (TS) genes relatively is fundamental for studying gene expression and cellular differentiation. Although many studies have aimed at large-scale and thorough categorization of human HK genes, a meaningful consensus has yet to be reached.RESULTS:We collected two latest gene expression datasets (both EST and microarray data) from public databases and analyzed the gene expression profiles in 18 human tissues that have been well-documented by both two data types. Benchmarked by a manually-curated HK gene collection (HK408), we demonstrated that present data from EST sampling was far from saturated, and the inadequacy has limited the gene detectability and our understanding of TS expressions. Due to a likely over-stringent threshold, microarray data showed higher false negative rate compared with EST data, leading to a significant underestimation of HK genes. Based on EST data, we found that 40.0% of the currently annotated human genes were universally expressed in at least 16 of 18 tissues, as compared to only 5.1% specifically expressed in a single tissue. Our current EST-based estimate on human HK genes ranged from 3,140 to 6,909 in number, a ten-fold increase in comparison with previous microarray-based estimates.CONCLUSIONS:We concluded that a significant fraction of human genes, at least in the currently annotated data depositories, was broadly expressed. Our understanding of tissue-specific expression was still preliminary and required much more large-scale and high-quality transcriptomic data in future studies. The new HK gene list categorized in this study will be useful for genome-wide analyses on structural and functional features of HK genes.

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.

ReXSpecies - a tool for the analysis of the evolution of gene regulation across species

Stephan Struckmann — 2008-04-15T18:39:18-00:00

BMC Evolutionary Biology, Vol. 8 (14 April 2008), 111.

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.

[Reconstruction of ancestral regulatory signals along a transcription factor tree]

KIu Gorbunov — 2008-04-06T07:00:14-00:00

Molekuliarnaia biologiia, Vol. 41, No. 5. (t 2007), pp. 918-925.

A model and an algorithm are proposed to reconstruct ancestral regulatory signals, mostly of protein-DNA interaction, at inner nodes of the transcription factor phylogeny on the basis of contemporary signal distribution. The algorithm also infers an evolutionary scenario, i.e. a set of edges in the tree, along which the signal diverged the most. The model and algorithm were tested with artificial data and biological evidence on signals NrdR, MntR and factor LacI (for the last two cases data are not shown).

Weak correlation between sequence conservation in promoter regions and in protein-coding regions of human-mouse orthologous gene pairs

Hirokazu Chiba — 2008-04-03T18:26:01-00:00

BMC Genomics, Vol. 9 (02 April 2008), 152.

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.

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.