CiteULike: indigoviolet's library [368 articles]

Prospects for whole-genome linkage disequilibrium mapping of common disease genes.

L Kruglyak — 2007-07-10T02:34:44-00:00

Nat Genet, Vol. 22, No. 2. (June 1999), pp. 139-144.

Recently, attention has focused on the use of whole-genome linkage disequilibrium (LD) studies to map common disease genes. Such studies would employ a dense map of single nucleotide polymorphisms (SNPs) to detect association between a marker and disease. Construction of SNP maps is currently underway. An essential issue yet to be settled is the required marker density of such maps. Here, I use population simulations to estimate the extent of LD surrounding common gene variants in the general human population as well as in isolated populations. Two main conclusions emerge from these investigations. First, a useful level of LD is unlikely to extend beyond an average distance of roughly 3 kb in the general population, which implies that approximately 500,000 SNPs will be required for whole-genome studies. Second, the extent of LD is similar in isolated populations unless the founding bottleneck is very narrow or the frequency of the variant is low (<5%).

Advances in Genetics http://www.sciencedirect.com/science/bookseries/00652660

2007-07-09T09:11:56-00:00

A gene-centric approach to genome-wide association studies

Eric Jorgenson — 2006-10-18T20:14:27-00:00

Nature Reviews Genetics, Vol. 7, No. 11., pp. 885-891.

Genome-wide association studies: theoretical and practical concerns

William Wang — 2005-02-15T07:22:39-00:00

Nature Reviews Genetics, Vol. 6, No. 2. (01 February 2005), pp. 109-118.

Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis.

S Mooney — 2007-04-03T09:54:06-00:00

Brief Bioinform, Vol. 6, No. 1. (March 2005), pp. 44-56.

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation between individuals. Predicting and understanding the downstream effects of genetic variation using computational methods are becoming increasingly important for single nucleotide polymorphism (SNP) selection in genetics studies and understanding the molecular basis of disease. According to the NIH, there are now more than four million validated SNPs in the human genome. The volume of known genetic variations lends itself well to an informatics approach. Bioinformaticians have become very good at functional inference methods derived from functional and structural genomics. This review will present a broad overview of the tools and resources available to collect and understand functional variation from the perspective of structure, expression, evolution and phenotype. Additionally, public resources available for SNP identification and characterisation are summarised.

Genome-wide association studies for common diseases and complex traits

Joel Hirschhorn — 2005-02-15T07:22:40-00:00

Nature Reviews Genetics, Vol. 6, No. 2. (01 February 2005), pp. 95-108.

Linkage disequilibrium maps and association mapping.

NE Morton — 2007-06-10T09:32:41-00:00

J Clin Invest, Vol. 115, No. 6. (June 2005), pp. 1425-1430.

The causal chain between a gene and its effect on disease susceptibility cannot be understood until the effect has been localized in the DNA sequence. Recently, polymorphisms incorporated in the HapMap Project have made linkage disequilibrium (LD) the most powerful tool for localization. The genetics of LD, the maps and databases that it provides, and their use for association mapping, as well as alternative methods for gene localization, are briefly described.

Strategies for the detection of copy number and other structural variants in the human genome.

AR Carson — 2006-08-10T17:12:32-00:00

Hum Genomics, Vol. 2, No. 6. (June 2006), pp. 403-414.

Advances in genome scanning technologies are revealing that copy number variants (CNVs) and polymorphisms, ranging from a few kilobases to several megabases in size, are present in genomes at frequencies much greater than previously known. Discoveries of additional forms of genomic variation, including inversions, insertions, deletions and complex rearrangements, are also occurring at an increased rate. Along with CNVs, these sequence alterations are collectively known as structural variants, and their discovery has had an immediate impact on the interpretation of basic research and clinical diagnostic data. This paper discusses different methods, experimental strategies and technologies that are currently available to study copy number variation and other structural variants in the human genome.

Clinical applications of whole-genome association studies: future applications at the bedside

Motsinger — 2006-07-13T04:30:22-00:00

Expert Review of Molecular Diagnostics, Vol. 6, No. 4. (July 2006), pp. 551-565.

Phylogenomics: the beginning of incongruence?

Olivier Jeffroy — 2006-03-07T15:51:27-00:00

Trends Genet (18 February 2006)

Until recently, molecular phylogenies based on a single or few orthologous genes often yielded contradictory results. Using multiple genes in a large concatenation was proposed to end these incongruences. Here we show that single-gene phylogenies often produce incongruences, albeit ones lacking statistically significant support. By contrast, the use of different tree reconstruction methods on different partitions of the concatenated supergene leads to well-resolved, but real (i.e. statistically significant) incongruences. Gathering a large amount of data is not sufficient to produce reliable trees, given the current limitation of tree reconstruction methods, especially when the quality of data is poor. We propose that selecting only data that contain minimal nonphylogenetic signals takes full advantage of phylogenomics and markedly reduces incongruence.

Genome-Wide Prediction of C. elegans Genetic Interactions

Weiwei Zhong — 2006-03-10T03:13:41-00:00

Science, Vol. 311, No. 5766. (10 March 2006), pp. 1481-1484.

To obtain a global view of functional interactions among genes in a metazoan genome, we computationally integrated interactome data, gene expression data, phenotype data, and functional annotation data from three model organisms--Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster--and predicted genome-wide genetic interactions in C. elegans. The resulting genetic interaction network (consisting of 18,183 interactions) provides a framework for system-level understanding of gene functions. We experimentally tested the predicted interactions for two human disease-related genes and identified 14 new modifiers.

X chromosomes and autosomes evolve at similar rates in Drosophila: No evidence for faster-X protein evolution.

Kevin Thornton — 2006-03-09T01:44:05-00:00

Genome Res (6 March 2006)

Recent data from Drosophila suggest that a substantial fraction of amino acid substitutions observed between species are beneficial. If these beneficial mutations are on average partially recessive, then the rate of protein evolution is predicted to be faster for X-linked genes compared to autosomal genes (the "faster-X" hypothesis). We test this prediction by comparing rates of protein substitutions between orthologous genes, taking advantage of variations in chromosome fusions within the genus Drosophila. In members of the Drosophila melanogaster species group, the chromosomal arm 3L segregates as an ordinary autosome (i.e., two homologous copies in both males and females). However, in the Drosophila pseudoobscura species group, this chromosomal arm has become fused to the ancestral X chromosome and is hemizygous in males. The faster-X hypothesis predicts that protein evolution should be faster for genes on this chromosomal arm in the D. pseudoobscura lineage, relative to the D. melanogaster lineage. Here we combine new sequence data for 202 gene fragments in Drosophila miranda (in the pseudoobscura species group) with the completed genomes of D. melanogaster, D. pseudoobscura, and Drosophila yakuba to show that there are no detectable differences in rates of amino acid evolution for orthologous X-linked and autosomal genes. Our results imply that the contribution of the faster-X (if any) to the large-X effect on reproductive isolation in Drosophila is not due to a generally faster rate of protein evolution. The lack of a detectable faster-X effect in these species suggests either that beneficial amino acids are not partially recessive on average, or that adaptive evolution does not often use newly arising amino acid mutations.

Evolution of exon-intron structure and alternative splicing in fruit flies and malarial mosquito genomes.

Dmitry B Malko — 2006-03-09T01:43:35-00:00

Genome Res (6 March 2006)

Comparative analysis of alternative splicing of orthologous genes from fruit flies (Drosophila melanogaster and Drosophila pseudoobscura) and mosquito (Anopheles gambiae) demonstrated that both in the fruit fly genes and in fruit fly-mosquito comparisons, constitutive exons and splicing sites are more conserved than alternative ones. While >97% of constitutive D. melanogaster exons are conserved in D. pseudoobscura, only approximately 80% of alternative exons are conserved. Similarly, 77% of constitutive fruit fly exons are conserved in the mosquito genes, compared with <50% of alternative exons. Internal alternatives are more conserved than terminal ones. Retained introns are the least conserved, alternative acceptor sites are slightly more conserved than donor sites, and mutually exclusive exons are almost as conserved as constitutive exons. Cassette and mutually exclusive exons experience almost no intron insertions. We also observed cases of interconversion of various elementary alternatives, e.g., transformation of cassette exons into alternative sites. These results agree with the observations made earlier in human-mouse comparisons and demonstrate that the phenomenon of relatively low conservation of alternatively spliced regions may be universal, as it has been observed in different taxonomic groups (mammals and insects) and at various evolutionary distances.

A Map of Recent Positive Selection in the Human Genome.

Benjamin F Voight — 2006-03-08T03:25:45-00:00

PLoS Biol, Vol. 4, No. 3. (7 March 2006)

The identification of signals of very recent positive selection provides information about the adaptation of modern humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide polymorphism (SNP) data for signals of recent selection, and apply this to data from the International HapMap Project. In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific, though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest approximately 250 signals of recent selection in each population.

Large-Scale Trends in the Evolution of Gene Structures within 11 Animal Genomes.

Mark Yandell — 2006-03-08T00:50:31-00:00

PLoS Comput Biol, Vol. 2, No. 3. (3 March 2006)

We have used the annotations of six animal genomes (Homo sapiens, Mus musculus, Ciona intestinalis, Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans) together with the sequences of five unannotated Drosophila genomes to survey changes in protein sequence and gene structure over a variety of timescales-from the less than 5 million years since the divergence of D. simulans and D. melanogaster to the more than 500 million years that have elapsed since the Cambrian explosion. To do so, we have developed a new open-source software library called CGL (for "Comparative Genomics Library"). Our results demonstrate that change in intron-exon structure is gradual, clock-like, and largely independent of coding-sequence evolution. This means that genome annotations can be used in new ways to inform, corroborate, and test conclusions drawn from comparative genomics analyses that are based upon protein and nucleotide sequence similarities.

The Origins of Eukaryotic Gene Structure

Michael Lynch — 2006-01-09T12:13:41-00:00

Mol Biol Evol, Vol. 23, No. 2. (1 February 2006), pp. 450-468.

Most of the phenotypic diversity that we perceive in the natural world is directly attributable to the peculiar structure of the eukaryotic gene, which harbors numerous embellishments relative to the situation in prokaryotes. The most profound changes include introns that must be spliced out of precursor mRNAs, transcribed but untranslated leader and trailer sequences (untranslated regions), modular regulatory elements that drive patterns of gene expression, and expansive intergenic regions that harbor additional diffuse control mechanisms. Explaining the origins of these features is difficult because they each impose an intrinsic disadvantage by increasing the genic mutation rate to defective alleles. To address these issues, a general hypothesis for the emergence of eukaryotic gene structure is provided here. Extensive information on absolute population sizes, recombination rates, and mutation rates strongly supports the view that eukaryotes have reduced genetic effective population sizes relative to prokaryotes, with especially extreme reductions being the rule in multicellular lineages. The resultant increase in the power of random genetic drift appears to be sufficient to overwhelm the weak mutational disadvantages associated with most novel aspects of the eukaryotic gene, supporting the idea that most such changes are simple outcomes of semi-neutral processes rather than direct products of natural selection. However, by establishing an essentially permanent change in the population-genetic environment permissive to the genome-wide repatterning of gene structure, the eukaryotic condition also promoted a reliable resource from which natural selection could secondarily build novel forms of organismal complexity. Under this hypothesis, arguments based on molecular, cellular, and/or physiological constraints are insufficient to explain the disparities in gene, genomic, and phenotypic complexity between prokaryotes and eukaryotes.

Defining the sequence-recognition profile of DNA-binding molecules

Christopher Warren — 2006-01-26T22:16:34-00:00

PNAS, Vol. 103, No. 4. (24 January 2006), pp. 867-872.

Determining the sequence-recognition properties of DNA-binding proteins and small molecules remains a major challenge. To address this need, we have developed a high-throughput approach that provides a comprehensive profile of the binding properties of DNA-binding molecules. The approach is based on displaying every permutation of a duplex DNA sequence (up to 10 positional variants) on a microfabricated array. The entire sequence space is interrogated simultaneously, and the affinity of a DNA-binding molecule for every sequence is obtained in a rapid, unbiased, and unsupervised manner. Using this platform, we have determined the full molecular recognition profile of an engineered small molecule and a eukaryotic transcription factor. The approach also yielded unique insights into the altered sequence-recognition landscapes as a result of cooperative assembly of DNA-binding molecules in a ternary complex. Solution studies strongly corroborated the sequence preferences identified by the array analysis.

Noncoding RNAs of Trithorax Response Elements Recruit Drosophila Ash1 to Ultrabithorax.

T Sanchez-Elsner — 2006-02-26T00:50:06-00:00

Science, Vol. 311, No. 5764. (24 February 2006), pp. 1118-1123.

Homeotic genes contain cis-regulatory trithorax response elements (TREs) that are targeted by epigenetic activators and transcribed in a tissue-specific manner. We show that the transcripts of three TREs located in the Drosophila homeotic gene Ultrabithorax (Ubx) mediate transcription activation by recruiting the epigenetic regulator Ash1 to the template TREs. TRE transcription coincides with Ubx transcription and recruitment of Ash1 to TREs in Drosophila. The SET domain of Ash1 binds all three TRE transcripts, with each TRE transcript hybridizing with and recruiting Ash1 only to the corresponding TRE in chromatin. Transgenic transcription of TRE transcripts restores recruitment of Ash1 to Ubx TREs and restores Ubx expression in Drosophila cells and tissues that lack endogenous TRE transcripts. Small interfering RNA-induced degradation of TRE transcripts attenuates Ash1 recruitment to TREs and Ubx expression, which suggests that noncoding TRE transcripts play an important role in epigenetic activation of gene expression.

Gene structure conservation aids similarity based gene prediction.

IM Meyer — 2005-11-15T11:08:54-00:00

Nucleic Acids Res, Vol. 32, No. 2. (2004), pp. 776-783.

One of the primary tasks in deciphering the functional contents of a newly sequenced genome is the identification of its protein coding genes. Existing computational methods for gene prediction include ab initio methods which use the DNA sequence itself as the only source of information, comparative methods using multiple genomic sequences, and similarity based methods which employ the cDNA or protein sequences of related genes to aid the gene prediction. We present here an algorithm implemented in a computer program called Projector which combines comparative and similarity approaches. Projector employs similarity information at the genomic DNA level by directly using known genes annotated on one DNA sequence to predict the corresponding related genes on another DNA sequence. It therefore makes explicit use of the conservation of the exon-intron structure between two related genes in addition to the similarity of their encoded amino acid sequences. We evaluate the performance of Projector by comparing it with the program Genewise on a test set of 491 pairs of independently confirmed mouse and human genes. It is more accurate than Genewise for genes whose proteins are <80% identical, and is suitable for use in a combined gene prediction system where other methods identify well conserved and non-conserved genes, and pseudogenes.

The Case for Selection at CCR5-Delta32.

Pardis C Sabeti — 2005-11-01T13:04:40-00:00

PLoS Biol, Vol. 3, No. 11. (1 November 2005)

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen atCCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.

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

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

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

Adaptive Protein Evolution and Regulatory Divergence in Drosophila.

Jeffrey M Good — 2006-03-20T01:08:00-00:00

Mol Biol Evol (14 March 2006)

Two recent studies demonstrated a positive correlation between divergence in gene expression and protein sequence in Drosophila. This correlation could be driven by positive selection or variation in functional constraint. To distinguish between these alternatives we compared patterns of molecular evolution for 1,862 genes with two previously reported estimates of expression divergence in Drosophila. We found a slight negative trend (nonsignifcant) between positive selection on protein sequence and divergence in expression levels between D. melanogaster and D. simulans. Conversely, shifts in expression patterns during Drosophila development showed a positive association with adaptive protein evolution, though as before the relationship was weak and not significant. Overall, we found no strong evidence for an increase in the incidence of positive selection on protein coding regions in genes with divergent expression in Drosophila, suggesting the previously reported positive association between protein and regulatory divergence primarily reflects variation in functional constraint.

Why most published research findings are false.

JP Ioannidis — 2005-08-31T19:31:16-00:00

PLoS Med, Vol. 2, No. 8. (August 2005)

SUMMARY: There is increasing concern that most current published research findings are false. The probability that a research claim is true may depend on study power and bias, the number of other studies on the same question, and, importantly, the ratio of true to no relationships among the relationships probed in each scientific field. In this framework, a research finding is less likely to be true when the studies conducted in a field are smaller; when effect sizes are smaller; when there is a greater number and lesser preselection of tested relationships; where there is greater flexibility in designs, definitions, outcomes, and analytical modes; when there is greater financial and other interest and prejudice; and when more teams are involved in a scientific field in chase of statistical significance. Simulations show that for most study designs and settings, it is more likely for a research claim to be false than true. Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias. In this essay, I discuss the implications of these problems for the conduct and interpretation of research.

"Genome design" model: Evidence from conserved intronic sequence in human-mouse comparison

Alexander Vinogradov — 2006-03-02T06:59:36-00:00

Genome Res., Vol. 16, No. 3. (1 March 2006), pp. 347-354.

Introns are shorter in housekeeping genes than in tissue- or development-specific genes. Differing explanations have been offered for this phenomenon: selection for economy (in housekeeping genes), mutation bias or "genomic design." The large-scale implementation in this present paper of a rigorous local sequence alignment algorithm revealed an unprecedented fraction of evolutionarily conserved DNA in human-mouse introns ([~]60% of human and [~]70% of mouse intron length remained after masking for lineage-specific repeats). The length distributions of both conserved and nonconserved regions are very broad but show peaks close to nucleosomal and dinucleosomal DNA. Both the fraction of conserved sequence and its absolute length were higher in introns of tissue-specific genes than housekeeping genes. This difference remained after control for between-species identity of the conserved fraction, mutation rate, and GC content. In a more direct control, the product of the conserved sequence fraction and the between-species identity of this fraction (which can be considered to be the fraction of conserved nucleotides) was greater in introns of tissue-specific genes than housekeeping genes. Neither the fraction of intron length covered by repeats nor the balance of small insertions and deletions (indels) can explain the greater length of introns in tissue-specific genes. The length of the conserved intronic DNA in a gene is correlated with the number of functional domains in the protein encoded by that gene. These results suggest that the greater length of introns in tissue-specific genes is not due to selection for economy or mutation bias but instead is related to functional complexity (probably mediated by chromatin condensation), and that the evolution of the bulk of noncoding DNA is not completely neutral.

Engineering gene networks to emulate Drosophila embryonic pattern formation.

M Isalan — 2005-03-30T02:56:21-00:00

PLoS Biol, Vol. 3, No. 3. (March 2005)

Pattern formation is essential in the development of higher eukaryotes. For example, in the Drosophila embryo, maternal morphogen gradients establish gap gene expression domain patterning along the anterior-posterior axis, through linkage with an elaborate gene network. To understand the evolution and behaviour of such systems better, it is important to establish the minimal determinants required for patterning. We have therefore engineered artificial transcription-translation networks that generate simple patterns, crudely analogous to the Drosophila gap gene system. The Drosophila syncytium was modelled using DNA-coated paramagnetic beads fixed by magnets in an artificial chamber, forming a gene expression network. Transient expression domain patterns were generated using various levels of network connectivity. Generally, adding more transcription repression interactions increased the "sharpness" of the pattern while reducing overall expression levels. An accompanying computer model for our system allowed us to search for parameter sets compatible with patterning. While it is clear that the Drosophila embryo is far more complex than our simplified model, several features of interest emerge. For example, the model suggests that simple diffusion may be too rapid for Drosophila-scale patterning, implying that sublocalisation, or "trapping," is required. Second, we find that for pattern formation to occur under the conditions of our in vitro reaction-diffusion system, the activator molecules must propagate faster than the inhibitors. Third, adding controlled protease degradation to the system stabilizes pattern formation over time. We have reconstituted transcriptional pattern formation from purified substances, including phage RNA polymerases, ribonucleotides, and an eukaryotic translation extract. We anticipate that the system described here will be generally applicable to the study of any biological network with a spatial component.

Localized maternal orthodenticle patterns anterior and posterior in the long germ wasp Nasonia

Jeremy Lynch — 2006-02-08T20:37:53-00:00

Nature, Vol. 439, No. 7077. (February 2006), pp. 728-732.

Genome Biology | Full text | The design of transcription-factor binding sites is affected by combinatorial regulation

2005-12-06T03:51:10-00:00

Using hexamers to predict cis-regulatory modules in Drosophila.

Bob Chan — 2005-11-18T06:29:46-00:00

BMC Bioinformatics, Vol. 6, No. 1. (27 October 2005)

BACKGROUND: Cis-regulatory modules (CRMs) are short stretches of DNA that help regulate gene expression in higher eukaryotes. They have been found up to one megabase away from the genes they regulate and can be located upstream, downstream, and even within their target genes. Due to the difficulty of finding CRMs using biological and computational techniques, even well-studied regulatory systems may contain CRMs that have not yet been discovered. RESULTS: We present a simple, efficient method (HexDiff) based only on hexamer frequencies of known CRMs and non-CRM sequence to predict novel CRMs in regulatory systems. On a data set of 16 gap and pair-rule genes containing 52 known CRMs, predictions made by HexDiff had a higher correlation with the known CRMs than several existing CRM prediction algorithms: Ahab, Cluster Buster, MSCAN, MCAST, and LWF. After combining the results of the different algorithms, 10 putative CRMs were identified and are strong candidates for future study. The hexamers used by HexDiff to distinguish between CRMs and non-CRM sequence were also analyzed and were shown to be enriched in regulatory elements. CONCLUSION: HexDiff provides an efficient and effective means for finding new CRMs based on known CRMs, rather than known binding sites.

Divergent selection and the evolution of signal traits and mating preferences.

HD Rundle — 2005-11-15T04:31:01-00:00

PLoS Biol, Vol. 3, No. 11. (November 2005)

Mating preferences are common in natural populations, and their divergence among populations is considered an important source of reproductive isolation during speciation. Although mechanisms for the divergence of mating preferences have received substantial theoretical treatment, complementary experimental tests are lacking. We conducted a laboratory evolution experiment, using the fruit fly Drosophila serrata, to explore the role of divergent selection between environments in the evolution of female mating preferences. Replicate populations of D. serrata were derived from a common ancestor and propagated in one of three resource environments: two novel environments and the ancestral laboratory environment. Adaptation to both novel environments involved changes in cuticular hydrocarbons, traits that predict mating success in these populations. Furthermore, female mating preferences for these cuticular hydrocarbons also diverged among populations. A component of this divergence occurred among treatment environments, accounting for at least 17.4% of the among-population divergence in linear mating preferences and 17.2% of the among-population divergence in nonlinear mating preferences. The divergence of mating preferences in correlation with environment is consistent with the classic by-product model of speciation in which premating isolation evolves as a side effect of divergent selection adapting populations to their different environments.

GeneWise and Genomewise

Ewan Birney — 2005-11-15T00:32:21-00:00

Genome Res., Vol. 14, No. 5. (1 May 2004), pp. 988-995.

We present two algorithms in this paper: GeneWise, which predicts gene structure using similar protein sequences, and Genomewise, which provides a gene structure final parse across cDNA- and EST-defined spliced structure. Both algorithms are heavily used by the Ensembl annotation system. The GeneWise algorithm was developed from a principled combination of hidden Markov models (HMMs). Both algorithms are highly accurate and can provide both accurate and complete gene structures when used with the correct evidence.

Sex- and segment-specific modulation of gene expression profiles in Drosophila.

Olga Barmina — 2005-11-14T20:11:50-00:00

Dev Biol (31 October 2005)

Homeotic and sex-determining genes control a wide range of morphological traits by regulating the expression of different target genes in different tissues. The identity of most of these target genes remains unknown, and it is not even clear what fraction of the genome is regulated in a segment- and sex-specific manner. In this report, we examine segment- and sex-specific gene expression in Drosophila pupal legs. The first and second legs in Drosophila have clearly distinguishable bristle patterns. Bristle pattern in the first leg also differs between males and females, whereas the second leg has no overt sexual dimorphism. To identify the genes responsible for these differences, we compared transcriptional profiles between male and female first and second legs during early pupal development. The extent of sexually dimorphic gene expression parallels morphological differences: over 100 genes are expressed sex specifically in the first leg, whereas no sexual differences are seen in the second leg. Segmental differences are less extensive than sexual dimorphism and involve fewer than 14 genes. We have identified a novel gene, CG13857, that is expressed exclusively in the first leg in a pattern that suggests this gene may play an important role in specifying segment- and sex-specific bristle patterns.

Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans.

Matthew V Rockman — 2005-11-14T19:50:57-00:00

PLoS Biol, Vol. 3, No. 12. (15 November 2005)

Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee-human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.

Bicoid determines sharp and precise target gene expression in the Drosophila embryo.

O Crauk — 2005-11-14T04:17:39-00:00

Curr Biol, Vol. 15, No. 21. (8 November 2005), pp. 1888-1898.

Background: The activity of the Bicoid (Bcd) transcription factor is a useful example of how quantitative information contained in a smooth morphogen gradient is transformed into discrete and precise patterns of target gene expression. There are two distinct and important aspects to this process: the "sharpening" of the posterior borders of the expression domains and the "precision" of where the target genes are expressed along the length of the embryo as the syncytial embryo begins to cellularize. Although the sharpening phenomenon was observed over a decade ago, it is still poorly understood. Results: Here, we show that a Bcd reporter gene containing binding sites only for Bcd is expressed, like natural targets of Bcd, in a precise domain with a sharp boundary. Analysis of embryos expressing deleted forms of Bcd indicates that the sharpness of the Bcd target gene hunchback's expression involves the glutamine-rich and C-terminal activation domains of Bcd. Furthermore, several artificial Gal4-derived transcription factors expressed as gradients in the embryo share Bcd's ability to drive precise target gene expression with sharp boundaries. Conclusion: Thus, contrary to recent reports proposing that the Bcd gradient is not sufficient to establish precise positional information, we show that Bcd drives precise and sharp expression of its target genes through a process that depends exclusively on its ability to activate transcription.

PLoS Computational Biology: Selective constraint on noncoding regions of hominid genomes

2005-11-14T04:08:59-00:00

The Making of a Fly: The Genetics of Animal Design

Peter Lawrence — 2007-12-15T03:00:46-00:00

(15 April 1992)

Understanding how a multicellular animal develops from a single cell (the fertilized egg) poses one of the greatest challenges in biology today. Development from egg to adult involves the sequential expression of virtually the whole of an organism's genetic instructions both in the mother as she lays down developmental cues in the egg, and in the embryo itself. Most of our present information on the role of genes in development comes from the invertebrate fruit fly, Drosophila. The two authors of this text (amongst the foremost authorities in the world) follow the developmental process from fertilization through the primitive structural development of the body plan of the fly after cleavage into the differentiation of the variety of tissues, organs and body parts that together define the fly. The developmental processes are fully explained throughout the text in the modern language of molecular biology and genetics. This text represents the vital synthesis of the subject that many have been waiting for and it will enable many specific courses in developmental biology and molecular genetics to focus on it. It will appeali to 2nd and 3rd year students in these disciplines as well as in biochemistry, neurobiology and zoology. It will also have widespread appeal among researchers. <ul> <li>Authored by one of the foremost authorities in the world. <li>A unique synthesis of the developmental cycle of Drosophila - our major source of information on the role of genes in development. <li>Designed to provide the basis of new courses in developmental biology and molecular genetics at senior undergraduate level. <li>A lucid explanation in the modern language of the science.</li></ul>

WebLogo: A Sequence Logo Generator

Gavin Crooks — 2005-11-24T10:24:28-00:00

Genome Res., Vol. 14, No. 6. (1 June 2004), pp. 1188-1190.

WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment. Sequence logos provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive. Each logo consists of stacks of letters, one stack for each position in the sequence. The overall height of each stack indicates the sequence conservation at that position (measured in bits), whereas the height of symbols within the stack reflects the relative frequency of the corresponding amino or nucleic acid at that position. WebLogo has been enhanced recently with additional features and options, to provide a convenient and highly configurable sequence logo generator. A command line interface and the complete, open WebLogo source code are available for local installation and customization.

Sequence logos: a new way to display consensus sequences.

TD Schneider — 2005-11-24T10:26:51-00:00

Nucleic Acids Res, Vol. 18, No. 20. (25 October 1990), pp. 6097-6100.

A graphical method is presented for displaying the patterns in a set of aligned sequences. The characters representing the sequence are stacked on top of each other for each position in the aligned sequences. The height of each letter is made proportional to its frequency, and the letters are sorted so the most common one is on top. The height of the entire stack is then adjusted to signify the information content of the sequences at that position. From these 'sequence logos', one can determine not only the consensus sequence but also the relative frequency of bases and the information content (measured in bits) at every position in a site or sequence. The logo displays both significant residues and subtle sequence patterns.

Selection of DNA binding sites by regulatory proteins. Statistical-mechanical theory and application to operators and promoters.

OG Berg — 2007-05-03T16:39:34-00:00

J Mol Biol, Vol. 193, No. 4. (20 February 1987), pp. 723-750.

We present a statistical-mechanical selection theory for the sequence analysis of a set of specific DNA regulatory sites that makes it possible to predict the relationship between individual base-pair choices in the site and specific activity (affinity). The theory is based on the assumption that specific DNA sequences have been selected to conform to some requirement for protein binding (or activity), and that all sequences that can fulfil this requirement are equally likely to occur. In most cases, the number of specific DNA sequences that are known for a certain DNA-binding protein is very small, and we discuss in detail the small-sample uncertainties that this leads to. When applied to the binding sites for cro repressor in phage lambda, the theory can predict, from the sequence statistics alone, their rank order binding affinities in reasonable agreement with measured values. However, the statistical uncertainty generated by such a small sample (only 6 sites known) limits the result to order-of-magnitude comparisons. When applied to the much larger sample of Escherichia coli promoter sequences, the theory predicts the correlation between in vitro activity (k2KB values) and homology score (closeness to the consensus sequence) observed by Mulligan et al. (1984). The analysis of base-pair frequencies in the promoter sample is consistent with the assumption that base-pairs at different positions in the sites contribute independently to the specific activity, except in a few marginal cases that are discussed. When the promoter sites are ordered according to predicted activities, they seem to conform to the Gaussian distribution that results from a requirement for maximal sequence variability within the constraint of providing a certain average activity. The theory allows us to compare the number of specific sites with a certain activity to the number that would be expected from random occurrence in the genome. While strong promoters are "overspecified", in the sense that their probability of random occurrence is very low, random sequences with weak promoter-like properties are expected to occur in very large numbers. This leads to the conclusion that functional specificity is based on other properties in addition to primary sequence recognition; some possibilities are discussed. Finally, we show that the sequence information, as defined by Schneider et al. (1986), can be used directly (at least in the case of equilibrium binding sites) to estimate the number of protein molecules that are specifically bound at random "pseudosites" in the genome.(ABSTRACT TRUNCATED AT 400 WORDS)

An overview of the structures of protein-DNA complexes.

NM Luscombe — 2006-03-21T16:48:16-00:00

Genome Biol, Vol. 1, No. 1. (2000)

On the basis of a structural analysis of 240 protein-DNA complexes contained in the Protein Data Bank (PDB), we have classified the DNA-binding proteins involved into eight different structural/functional groups, which are further classified into 54 structural families. Here we present this classification and review the functions, structures and binding interactions of these protein-DNA complexes.

Drosophila DNase I footprint database: a systematic genome annotation of transcription factor binding sites in the fruitfly, Drosophila melanogaster.

CM Bergman — 2007-04-30T09:18:37-00:00

Bioinformatics, Vol. 21, No. 8. (15 April 2005), pp. 1747-1749.

SUMMARY: Despite increasing numbers of computational tools developed to predict cis-regulatory sequences, the availability of high-quality datasets of transcription factor binding sites limits advances in the bioinformatics of gene regulation. Here we present such a dataset based on a systematic literature curation and genome annotation of DNase I footprints for the fruitfly, Drosophila melanogaster. Using the experimental results of 201 primary references, we annotated 1367 binding sites from 87 transcription factors and 101 target genes in the D.melanogaster genome sequence. These data will provide a rich resource for future bioinformatics analyses of transcriptional regulation in Drosophila such as constructing motif models, training cis-regulatory module detectors, benchmarking alignment tools and continued text mining of the extensive literature on transcriptional regulation in this important model organism. AVAILABILITY: http://www.flyreg.org/ CONTACT: cbergman@gen.cam.ac.uk.

GOstat: find statistically overrepresented Gene Ontologies within a group of genes.

T Beissbarth — 2005-05-25T04:19:07-00:00

Bioinformatics, Vol. 20, No. 9. (12 June 2004), pp. 1464-1465.

SUMMARY: Modern experimental techniques, as for example DNA microarrays, as a result usually produce a long list of genes, which are potentially interesting in the analyzed process. In order to gain biological understanding from this type of data, it is necessary to analyze the functional annotations of all genes in this list. The Gene-Ontology (GO) database provides a useful tool to annotate and analyze the functions of a large number of genes. Here, we introduce a tool that utilizes this information to obtain an understanding of which annotations are typical for the analyzed list of genes. This program automatically obtains the GO annotations from a database and generates statistics of which annotations are overrepresented in the analyzed list of genes. This results in a list of GO terms sorted by their specificity. AVAILABILITY: Our program GOstat is accessible via the Internet at http://gostat.wehi.edu.au

Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

M Ashburner — 2005-05-27T12:30:22-00:00

Nat Genet, Vol. 25, No. 1. (May 2000), pp. 25-29.

Temporal patterns of fruit fly (Drosophila) evolution revealed by mutation clocks.

K Tamura — 2007-12-12T14:32:26-00:00

Mol Biol Evol, Vol. 21, No. 1. (January 2004), pp. 36-44.

Drosophila melanogaster has been a canonical model organism to study genetics, development, behavior, physiology, evolution, and population genetics for nearly a century. Despite this emphasis and the completion of its nuclear genome sequence, the timing of major speciation events leading to the origin of this fruit fly remain elusive because of the paucity of extensive fossil records and biogeographic data. Use of molecular clocks as an alternative has been fraught with non-clock-like accumulation of nucleotide and amino-acid substitutions. Here we present a novel methodology in which genomic mutation distances are used to overcome these limitations and to make use of all available gene sequence data for constructing a fruit fly molecular time scale. Our analysis of 2977 pairwise sequence comparisons from 176 nuclear genes reveals a long-term fruit fly mutation clock ticking at a rate of 11.1 mutations per kilobase pair per Myr. Genomic mutation clock-based timings of the landmark speciation events leading to the evolution of D. melanogaster show that it shared most recent common ancestry 5.4 MYA with D. simulans, 12.6 MYA with D. erecta+D. orena, 12.8 MYA with D. yakuba+D. teisseri, 35.6 MYA with the takahashii subgroup, 41.3 MYA with the montium subgroup, 44.2 MYA with the ananassae subgroup, 54.9 MYA with the obscura group, 62.2 MYA with the willistoni group, and 62.9 MYA with the subgenus Drosophila. These and other estimates are compatible with those known from limited biogeographic and fossil records. The inferred temporal pattern of fruit fly evolution shows correspondence with the cooling patterns of paleoclimate changes and habitat fragmentation in the Cenozoic.

Gene Recognition Via Spliced Sequence Alignment

Mikhail Gelfand — 2007-12-12T14:20:19-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 17. (1996), pp. 9061-9066.

Gene recognition is one of the most important problems in computational molecular biology. Previous attempts to solve this problem were based on statistics, and applications of combinatorial methods for gene recognition were almost unexplored. Recent advances in large-scale cDNA sequencing open a way toward a new approach to gene recognition that uses previously sequenced genes as a clue for recognition of newly sequenced genes. This paper describes a spliced alignment algorithm and software tool that explores all possible exon assemblies in polynomial time and finds the multiexon structure with the best fit to a related protein. Unlike other existing methods, the algorithm successfully recognizes genes even in the case of short exons or exons with unusual codon usage; we also report correct assemblies for genes with more than 10 exons. On a test sample of human genes with known mammalian relatives, the average correlation between the predicted and actual proteins was 99%. The algorithm correctly reconstructed 87% of genes and the rare discrepancies between the predicted and real exon-intron structures were caused either by short (less than 5 amino acids) initial/terminal exons or by alternative splicing. Moreover, the algorithm predicts human genes reasonably well when the homologous protein is nonvertebrate or even prokaryotic. The surprisingly good performance of the method was confirmed by extensive simulations: in particular, with target proteins at 160 accepted point mutations (PAM) (25% similarity), the correlation between the predicted and actual genes was still as high as 95%.

TRANSFAC: a database on transcription factors and their DNA binding sites.

E Wingender — 2006-09-28T21:13:40-00:00

Nucleic Acids Res, Vol. 24, No. 1. (1 January 1996), pp. 238-241.

TRANSFAC is a database about eukaryotic transcription regulating DNA sequence elements and the transcription factors binding to and acting through them. This report summarizes the present status of this database and accompanying retrieval tools.

Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase.

C Tuerk — 2006-11-01T16:58:40-00:00

Science, Vol. 249, No. 4968. (3 August 1990), pp. 505-510.

High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated and characterized. In particular one eight-base region of an RNA that interacts with the T4 DNA polymerase was chosen and randomized. Two different sequences were selected by this procedure from the calculated pool of 65,536 species. One is the wild-type sequence found in the bacteriophage mRNA; one is varied from wild type at four positions. The binding constants of these two RNA's to T4 DNA polymerase are equivalent. These protocols with minimal modification can yield high-affinity ligands for any protein that binds nucleic acids as part of its function; high-affinity ligands could conceivably be developed for any target molecule.

Identifying DNA and protein patterns with statistically significant alignments of multiple sequences

Gz Hertz — 2006-06-20T10:24:34-00:00

Bioinformatics, Vol. 15, No. 7. (1 July 1999), pp. 563-577.

10.1093/bioinformatics/15.7.563

A computational genomics approach to the identification of gene networks

A Wagner — 2007-12-12T11:04:50-00:00

Nucl. Acids Res., Vol. 25, No. 18. (15 September 1997), pp. 3594-3604.

10.1093/nar/25.18.3594

A graph-based motif detection algorithm models complex nucleotide dependencies in transcription factor binding sites.

BT Naughton — 2007-12-12T10:59:52-00:00

Nucleic Acids Res, Vol. 34, No. 20. (2006), pp. 5730-5739.

Given a set of known binding sites for a specific transcription factor, it is possible to build a model of the transcription factor binding site, usually called a motif model, and use this model to search for other sites that bind the same transcription factor. Typically, this search is performed using a position-specific scoring matrix (PSSM), also known as a position weight matrix. In this paper we analyze a set of eukaryotic transcription factor binding sites and show that there is extensive clustering of similar k-mers in eukaryotic motifs, owing to both functional and evolutionary constraints. The apparent limitations of probabilistic models in representing complex nucleotide dependencies lead us to a graph-based representation of motifs. When deciding whether a candidate k-mer is part of a motif or not, we base our decision not on how well the k-mer conforms to a model of the motif as a whole, but how similar it is to specific, known k-mers in the motif. We elucidate the reasons why we expect graph-based methods to perform well on motif data. Our MotifScan algorithm shows greatly improved performance over the prevalent PSSM-based method for the detection of eukaryotic motifs.

Combining evidence using p-values: application to sequence homology searches.

TL Bailey — 2007-12-12T10:57:21-00:00

Bioinformatics, Vol. 14, No. 1. (1998), pp. 48-54.

MOTIVATION: To illustrate an intuitive and statistically valid method for combining independent sources of evidence that yields a p-value for the complete evidence, and to apply it to the problem of detecting simultaneous matches to multiple patterns in sequence homology searches. RESULTS: In sequence analysis, two or more (approximately) independent measures of the membership of a sequence (or sequence region) in some class are often available. We would like to estimate the likelihood of the sequence being a member of the class in view of all the available evidence. An example is estimating the significance of the observed match of a macromolecular sequence (DNA or protein) to a set of patterns (motifs) that characterize a biological sequence family. An intuitive way to do this is to express each piece of evidence as a p-value, and then use the product of these p-values as the measure of membership in the family. We derive a formula and algorithm (QFAST) for calculating the statistical distribution of the product of n independent p-values. We demonstrate that sorting sequences by this p-value effectively combines the information present in multiple motifs, leading to highly accurate and sensitive sequence homology searches.