CiteULike: gjuggler's library [211 articles]

Dynamic complex formation during the yeast cell cycle.

U de Lichtenberg — 2005-12-12T18:23:43-00:00

Science, Vol. 307, No. 5710. (4 February 2005), pp. 724-727.

To analyze the dynamics of protein complexes during the yeast cell cycle, we integrated data on protein interactions and gene expression. The resulting time-dependent interaction network places both periodically and constitutively expressed proteins in a temporal cell cycle context, thereby revealing previously unknown components and modules. We discovered that most complexes consist of both periodically and constitutively expressed subunits, which suggests that the former control complex activity by a mechanism of just-in-time assembly. Consistent with this, we show that additional regulation through targeted degradation and phosphorylation by Cdc28p (Cdk1) specifically affects the periodically expressed proteins.

The impact of recombination on nucleotide substitutions in the human genome.

L Duret — 2008-05-15T14:45:42-00:00

PLoS genetics, Vol. 4, No. 5. (May 2008)

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R2 = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp.

Phylogeny-Aware Gap Placement Prevents Errors in Sequence Alignment and Evolutionary Analysis

Ari Loytynoja — 2008-06-20T03:07:52-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1632-1635.

Genetic sequence alignment is the basis of many evolutionary and comparative studies, and errors in alignments lead to errors in the interpretation of evolutionary information in genomes. Traditional multiple sequence alignment methods disregard the phylogenetic implications of gap patterns that they create and infer systematically biased alignments with excess deletions and substitutions, too few insertions, and implausible insertion-deletion-event histories. We present a method that prevents these systematic errors by recognizing insertions and deletions as distinct evolutionary events. We show theoretically and practically that this improves the quality of sequence alignments and downstream analyses over a wide range of realistic alignment problems. These results suggest that insertions and sequence turnover are more common than is currently thought and challenge the conventional picture of sequence evolution and mechanisms of functional and structural changes. 10.1126/science.1158395

Use and misuse of the gene ontology annotations

Seung Rhee — 2008-05-15T05:58:28-00:00

Nature reviews. Genetics (13 May 2008)

The Gene Ontology (GO) project is a collaboration among model organism databases to describe gene products from all organisms using a consistent and computable language. GO produces sets of explicitly defined, structured vocabularies that describe biological processes, molecular functions and cellular components of gene products in both a computer- and human-readable manner. Here we describe key aspects of GO, which, when overlooked, can cause erroneous results, and address how these pitfalls can be avoided.

Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios.

AG Clark — 2006-05-24T23:42:14-00:00

Science, Vol. 302, No. 5652. (12 December 2003), pp. 1960-1963.

Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution. This evolutionary approach revealed an informative set of genes with significantly different patterns of substitution on the human lineage compared with the chimpanzee and mouse lineages. Partitions of genes into inferred biological classes identified accelerated evolution in several functional classes, including olfaction and nuclear transport. In addition to suggesting adaptive physiological differences between chimps and humans, human-accelerated genes are significantly more likely to underlie major known Mendelian disorders.

A comparison of normalization methods for high density oligonucleotide array data based on variance and bias.

BM Bolstad — 2005-07-31T21:52:43-00:00

Bioinformatics, Vol. 19, No. 2. (22 January 2003), pp. 185-193.

MOTIVATION: When running experiments that involve multiple high density oligonucleotide arrays, it is important to remove sources of variation between arrays of non-biological origin. Normalization is a process for reducing this variation. It is common to see non-linear relations between arrays and the standard normalization provided by Affymetrix does not perform well in these situations. RESULTS: We present three methods of performing normalization at the probe intensity level. These methods are called complete data methods because they make use of data from all arrays in an experiment to form the normalizing relation. These algorithms are compared to two methods that make use of a baseline array: a one number scaling based algorithm and a method that uses a non-linear normalizing relation by comparing the variability and bias of an expression measure. Two publicly available datasets are used to carry out the comparisons. The simplest and quickest complete data method is found to perform favorably. AVAILABILITY: Software implementing all three of the complete data normalization methods is available as part of the R package Affy, which is a part of the Bioconductor project http://www.bioconductor.org. SUPPLEMENTARY INFORMATION: Additional figures may be found at http://www.stat.berkeley.edu/~bolstad/normalize/index.html

Relating tissue specialisation to the differentiation of expression of singleton and duplicate mouse proteins

Shiri Freilich — 2006-10-09T11:37:22-00:00

Genome Biology, Vol. 7 (09 October 2006), R89.

A gene atlas of the mouse and human protein-encoding transcriptomes.

AI Su — 2006-03-03T12:15:01-00:00

Proc Natl Acad Sci U S A, Vol. 101, No. 16. (20 April 2004), pp. 6062-6067.

The tissue-specific pattern of mRNA expression can indicate important clues about gene function. High-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale. Toward this end, we have designed custom arrays that interrogate the expression of the vast majority of protein-encoding human and mouse genes and have used them to profile a panel of 79 human and 61 mouse tissues. The resulting data set provides the expression patterns for thousands of predicted genes, as well as known and poorly characterized genes, from mice and humans. We have explored this data set for global trends in gene expression, evaluated commonly used lines of evidence in gene prediction methodologies, and investigated patterns indicative of chromosomal organization of transcription. We describe hundreds of regions of correlated transcription and show that some are subject to both tissue and parental allele-specific expression, suggesting a link between spatial expression and imprinting.

Assessing the conservation of mammalian gene expression using high-density exon arrays.

Y Xing — 2008-02-13T10:30:41-00:00

Mol Biol Evol, Vol. 24, No. 6. (June 2007), pp. 1283-1285.

Microarray data from multiple species have been used to study evolutionary constraints on gene expression. Expression measurements from conventional microarray platforms such as the 3' expression arrays are strongly affected by platform-dependent probe effects that may introduce apparent but misleading discrepancies between species. In this manuscript, we assess the conservation of mammalian gene expression in adult tissues using data from a high-density exon array platform. The exon arrays have more than 6 million probes on a single array targeting all exons in a genome. We find that, unlike 3' array data, gene expression measurements from exon arrays reveal patterns of gene expression that are highly conserved between humans and mice in multiple tissues. Our analysis provides strong evidence for widespread stabilizing selection pressure on transcript abundance during mammalian evolution.

Synonymous Codon Usage in Escherichia coli: Selection for Translational Accuracy

Stoletzki — 2007-02-04T11:18:59-00:00

Molecular Biology and Evolution, Vol. 24, No. 2. (February 2007), pp. 374-381.

Transition-Transversion Bias Is Not Universal: A Counter Example from Grasshopper Pseudogenes

Irene Keller — 2008-06-15T09:37:49-00:00

PLoS Genet, Vol. 3, No. 2. (2 February 2007), e22.

Comparisons of the DNA sequences of metazoa show an excess of transitional over transversional substitutions. Part of this bias is due to the relatively high rate of mutation of methylated cytosines to thymine. Postmutation processes also introduce a bias, particularly selection for codon-usage bias in coding regions. It is generally assumed, however, that there is a universal bias in favour of transitions over transversions, possibly as a result of the underlying chemistry of mutation. Surprisingly, this underlying trend has been evaluated only in two types of metazoan, namely Drosophila and the Mammalia. Here, we investigate a third group, and find no such bias. We characterize the point substitution spectrum in Podisma pedestris, a grasshopper species with a very large genome. The accumulation of mutations was surveyed in two pseudogene families, nuclear mitochondrial and ribosomal DNA sequences. The cytosine-guanine (CpG) dinucleotides exhibit the high transition frequencies expected of methylated sites. The transition rate at other cytosine residues is significantly lower. After accounting for this methylation effect, there is no significant difference between transition and transversion rates. These results contrast with reports from other taxa and lead us to reject the hypothesis of a universal transition/transversion bias. Instead we suggest fundamental interspecific differences in point substitution processes.

The distribution of fitness effects of new mutations

Adam Walker — 2007-07-18T23:16:35-00:00

Nature Reviews Genetics, Vol. 8, No. 8., pp. 610-618.

The Global Circulation of Seasonal Influenza A (H3N2) Viruses

Colin Russell — 2008-04-18T15:04:24-00:00

Science, Vol. 320, No. 5874. (18 April 2008), pp. 340-346.

Antigenic and genetic analysis of the hemagglutinin of [~]13,000 human influenza A (H3N2) viruses from six continents during 20022007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network of temporally overlapping epidemics and that epidemics in the temperate regions were seeded from this network each year. Seed strains generally first reached Oceania, North America, and Europe, and later South America. This evidence suggests that once A (H3N2) viruses leave E-SE Asia, they are unlikely to contribute to long-term viral evolution. If the trends observed during this period are an accurate representation of overall patterns of spread, then the antigenic characteristics of A (H3N2) viruses outside E-SE Asia may be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection. 10.1126/science.1154137

Uncertainty in homology inferences: Assessing and improving genomic sequence alignment

Gerton Lunter — 2008-02-01T19:13:08-00:00

Genome Res., Vol. 18, No. 2. (1 February 2008), pp. 298-309.

Sequence alignment underpins all of comparative genomics, yet it remains an incompletely solved problem. In particular, the statistical uncertainty within inferred alignments is often disregarded, while parametric or phylogenetic inferences are considered meaningless without confidence estimates. Here, we report on a theoretical and simulation study of pairwise alignments of genomic DNA at humanmouse divergence. We find that >15% of aligned bases are incorrect in existing whole-genome alignments, and we identify three types of alignment error, each leading to systematic biases in all algorithms considered. Careful modeling of the evolutionary process improves alignment quality; however, these improvements are modest compared with the remaining alignment errors, even with exact knowledge of the evolutionary model, emphasizing the need for statistical approaches to account for uncertainty. We develop a new algorithm, Marginalized Posterior Decoding (MPD), which explicitly accounts for uncertainties, is less biased and more accurate than other algorithms we consider, and reduces the proportion of misaligned bases by a third compared with the best existing algorithm. To our knowledge, this is the first nonheuristic algorithm for DNA sequence alignment to show robust improvements over the classic NeedlemanWunsch algorithm. Despite this, considerable uncertainty remains even in the improved alignments. We conclude that a probabilistic treatment is essential, both to improve alignment quality and to quantify the remaining uncertainty. This is becoming increasingly relevant with the growing appreciation of the importance of noncoding DNA, whose study relies heavily on alignments. Alignment errors are inevitable, and should be considered when drawing conclusions from alignments. Software and alignments to assist researchers in doing this are provided at http://genserv.anat.ox.ac.uk/grape/. 10.1101/gr.6725608

Detecting amino acid sites under positive selection and purifying selection.

Tim Massingham — 2005-03-29T20:16:05-00:00

Genetics (16 January 2005)

An excess of nonsynonymous over synonymous substitution at individual amino acid sites is an important indicator that positive selection has affected the evolution of a protein between the extant sequences under study and their most recent common ancestor. Several methods exist to detect the presence, and sometimes location, of positively selected sites in alignments of protein coding sequences. This paper describes the novel 'Sitewise Likelihood Ratio' (SLR) method for detecting non-neutral evolution, a statistical test that can identify sites that are unusually conserved as well as those that are unusually variable. We show that the SLR method can be more powerful than currently published methods for detecting the location of positive selection, especially in difficult cases where the strength of selection is low. The increase in power is achieved whilst relaxing assumptions about how the strength of selection varies over sites and without elevated rates of false positive results that have been reported with some other methods. We also show that the SLR method performs well even under circumstances where the results from some previous methods can be misleading.

Contrasting evolution of expression differences in the testis between species and subspecies of the house mouse

Christian Voolstra — 2008-05-22T16:20:52-00:00

Genome Res., Vol. 17, No. 1. (1 January 2007), pp. 42-49.

Regulatory changes in genes involved in reproduction are thought to be prime targets for divergence during speciation, since they are expected to play an important role in sexual selection and sexual conflict. We used microarray analysis of RNA from different wild populations of house mouse subspecies (including Mus m. musculus, Mus m. domesticus, and Mus m. castaneus) and from the sister species Mus spretus to test this assumption. A comparison of expression divergence in brain, liver/kidney, and testis shows a major difference in the evolutionary dynamics of testis-related genes. While the comparison between species confirms an excess in divergence in testis genes, we find that all comparisons between subspecies yield only a very small number of genes with significantly different expression levels in the testis. These results suggest that the early phase of the speciation process may not be driven by regulatory changes in genes that are potential targets of sexual selection, and that the divergence in these genes is only established during a later phase of the speciation process. 10.1101/gr.5683806

Regulatory changes underlying expression differences within and between Drosophila species.

Patricia Wittkopp — 2008-02-24T04:20:19-00:00

Nat Genet (17 February 2008)

Differences in gene expression are an important source of phenotypic variation, and can be caused by changes in cis and/or trans regulation. cis-regulatory variants alter allele-specific expression, whereas trans-regulatory variants influence expression of both alleles in a diploid cell. Because of this difference, we hypothesize that natural selection may favor one type of change over the other. Here, we investigate contributions of cis- and trans-regulatory changes to variable intra- and interspecific gene expression using four strains of Drosophila melanogaster, three strains of D. simulans and a total of 78 genes. We show that cis-regulatory changes account for a greater proportion of the expression differences observed between rather than within species. These data are inconsistent with a neutral model assuming equal probabilities of fixation for cis- and trans-regulatory polymorphisms, suggesting that natural selection influences the molecular mechanisms underlying divergent gene expression. Specifically, cis-regulatory changes seem to accumulate preferentially over time.

Evaluating the role of natural selection in the evolution of gene regulation

JC Fay — 2007-05-24T01:28:47-00:00

Heredity, Vol. aop, No. current.

Clustering of phosphorylation site recognition motifs can be exploited to predict the targets of cyclin-dependent kinase.

Alan Moses — 2007-02-22T18:48:09-00:00

Genome Biology, Vol. 8 (22 February 2007), R23.

The McDonald-Kreitman Test and Slightly Deleterious Mutations

Jane Charlesworth — 2008-05-09T23:25:21-00:00

Mol Biol Evol, Vol. 25, No. 6. (1 June 2008), pp. 1007-1015.

It is possible to estimate the proportion of substitutions that are due to adaptive evolution using the numbers of silent and nonsilent polymorphisms and substitutions in a McDonald and Kreitman-type analysis. Unfortunately, this estimate of adaptive evolution is biased downward by the segregation of slightly deleterious mutations. It has been suggested that 1 way to cope with the effects of these slightly deleterious mutations is to remove low-frequency polymorphisms from the analysis. We investigate the performance of this method theoretically. We show that although removing low-frequency polymorphisms does indeed reduce the bias in the estimate of adaptive evolution, the estimate is always downwardly biased, often to the extent that one would not be able to detect adaptive evolution, even if it existed. The method is reasonably satisfactory, only if the rate of adaptive evolution is high and the distribution of fitness effects for slightly deleterious mutations is very leptokurtic. Our analysis suggests that adaptive evolution could be quite prevalent in humans (>8%) and still not be detectable using current methodologies. Our analysis also suggests that the level of adaptive evolution has probably been underestimated, possibly substantially, in both bacteria and Drosophila. 10.1093/molbev/msn005

Differentiated evolutionary rates in alternative exons and the implications for splicing regulation

Mireya Plass — 2006-06-22T18:12:14-00:00

BMC Evolutionary Biology, Vol. 6 (22 June 2006), 50.

Widespread Evolutionary Conservation of Alternatively Spliced Exons in Caenorhabditis

Manuel Irimia — 2008-05-22T16:12:11-00:00

Mol Biol Evol, Vol. 25, No. 2. (1 February 2008), pp. 375-382.

Alternative splicing (AS) contributes to increased transcriptome and proteome diversity in various eukaryotic lineages. Previous studies showed low levels of conservation of alternatively spliced (cassette) exons within mammals and within dipterans. We report a strikingly different pattern in Caenorhabditis nematodes--more than 92% of cassette exons from Caenorhabditis elegans are conserved in Caenorhabditis briggsae and/or Caenorhabditis remanei. High levels of conservation extend to minor-form exons (present in a minority of transcripts) and are particularly pronounced for exons showing complex patterns of splicing. The functionality of the vast majority of cassette exons is underscored by various other features. We suggest that differences in conservation between lineages reflect differences in levels of functionality and further suggest that these differences are due to differences in intron length and the strength of consensus boundaries across lineages. Finally, we demonstrate an inverse relationship between AS and gene duplication, suggesting that the latter may be primarily responsible for the emergence of new functional transcripts in nematodes. 10.1093/molbev/msm262

Spliceosomal introns as tools for genomic and evolutionary analysis

Manuel Irimia — 2008-05-22T16:10:11-00:00

Nucl. Acids Res., Vol. 36, No. 5. (1 March 2008), pp. 1703-1712.

Over the past 5 years, the availability of dozens of whole genomic sequences from a wide variety of eukaryotic lineages has revealed a very large amount of information about the dynamics of intron loss and gain through eukaryotic history, as well as the evolution of intron sequences. Implicit in these advances is a great deal of information about the structure and evolution of surrounding sequences. Here, we review the wealth of ways in which structures of spliceosomal introns as well as their conservation and change through evolution may be harnessed for evolutionary and genomic analysis. First, we discuss uses of intron length distributions and positions in sequence assembly and annotation, and for improving alignment of homologous regions. Second, we review uses of introns in evolutionary studies, including the utility of introns as indicators of rates of sequence evolution, for inferences about molecular evolution, as signatures of orthology and paralogy, and for estimating rates of nucleotide substitution. We conclude with a discussion of phylogenetic methods utilizing intron sequences and positions. 10.1093/nar/gkn012

Intron mis-splicing: no alternative?

Scott Roy — 2008-02-20T01:39:44-00:00

Genome Biology, Vol. 9 (19 February 2008), 208.

Refined analysis of genetic variability parameters in hepatitis C virus and the ability to predict antiviral treatment response

JM Cuevas — 2008-05-22T16:07:33-00:00

Journal of Viral Hepatitis, Vol. 0, No. 0. (0), pp. ???-???.

Summary. Hepatitis C virus (HCV) infects approximately 3% of the world population. The chronicity of hepatitis C seems to depend on the level of genetic variability. We have recently (Torres-Puente et al., J Viral Hepat, 2008; 15: 188) reported genetic variability estimates from a large-scale sequence analysis of 67 patients infected with HCV subtypes 1a (23 patients) and 1b (44 patients) and related them to response, or lack of, to alpha-interferon plus ribavirin treatment.. Two HCV genome regions were analysed in samples prior to antiviral therapy, one compressing the three hypervariable regions of the E2 glycoprotein and another one including the interferon sensitive determining region and the V3 domain of the NS5A protein. Haplotype and nucleotide diversity measures showed a clear tendency to higher genetic variability levels in nonresponder than in responder patients. Here, we have refined the analysis of genetic variability (haplotype and nucleotide diversity, number of haplotypes and mutations) by considering their distribution in each of the biologically meaningful subregions mentioned above, as well as in their surrounding and intervening regions. Variability levels are very heterogeneous among the different subregions, being higher for nonresponder patients. Interestingly, significant differences were detected in the biologically relevant regions, but also in the surrounding regions, suggesting that the level of variability of the whole HCV genome, rather than exclusively that from the hypervariable regions, is the main indicator of the treatment response. Finally, the number of haplotypes and mutations seem to be better discriminators than haplotype and nucleotide diversity, especially in the NS5A region.

Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila

Cathy Liautard — 2007-01-03T19:15:13-00:00

Nature, Vol. 445, No. 7123. (4 January 2007), pp. 82-85.

Mutation Accumulation Studies in Evolutionary Genetics

Peter Keightley — 2008-05-22T16:05:54-00:00

Annual Review of Ecology, Evolution, and Systematics, Vol. 39, No. 1. (2008)

Evolution of Multicellularity (Choanflagelates)

Antonis Rokas — 2008-05-22T16:04:48-00:00

Annual Review of Genetics, Vol. 42, No. 1. (2008)

GENOMICS: Lining Up to Avoid Bias

Antonis Rokas — 2008-01-25T06:50:52-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 416-417.

10.1126/science.1153156

The Inverse Relationship Between Evolutionary Rate and Age of Mammalian Genes Is an Artifact of Increased Genetic Distance with Rate of Evolution and Time of Divergence

Eran Elhaik — 2005-12-11T22:49:22-00:00

Molecular Biology and Evolution, Vol. 23, No. 1. (January 2006), pp. 1-3.

Global analysis of alternative splicing differences between humans and chimpanzees

John Calarco — 2007-11-13T03:42:29-00:00

Genes Dev. (31 October 2007), gad.1606907.

Alternative splicing is a powerful mechanism affording extensive proteomic and regulatory diversity from a limited repertoire of genes. However, the extent to which alternative splicing has contributed to the evolution of primate species-specific characteristics has not been assessed previously. Using comparative genomics and quantitative microarray profiling, we performed the first global analysis of alternative splicing differences between humans and chimpanzees. Surprisingly, 6%8% of profiled orthologous exons display pronounced splicing level differences in the corresponding tissues from the two species. Little overlap is observed between the genes associated with alternative splicing differences and the genes that display steady-state transcript level differences, indicating that these layers of regulation have evolved rapidly to affect distinct subsets of genes in humans and chimpanzees. The alternative splicing differences we detected are predicted to affect diverse functions including gene expression, signal transduction, cell death, immune defense, and susceptibility to diseases. Differences in expression at the protein level of the major splice variant of Glutathione S-transferase omega-2 (GSTO2), which functions in the protection against oxidative stress and is associated with human aging-related diseases, suggests that this enzyme is less active in human cells compared with chimpanzee cells. The results of this study thus support an important role for alternative splicing in establishing differences between humans and chimpanzees. 10.1101/gad.1606907

PhylomeDB: a database for genome-wide collections of gene phylogenies.

Huerta Cepas — 2008-05-22T15:59:32-00:00

Nucleic acids research, Vol. 36, No. Database issue. (January 2008)

The complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.

A genome-wide approach to identifying novel-imprinted genes.

KS Pollard — 2008-02-03T22:30:25-00:00

Hum Genet, Vol. 122, No. 6. (January 2008), pp. 625-634.

Genomic imprinting is an epigenetic process in which the copy of a gene inherited from one parent (maternal or paternal) is consistently silenced or expressed at a significantly lower level than the copy from the other parent. In an effort to begin a systematic genome-wide screen for imprinted genes, we assayed differential allelic expression (DAE) at 3,877 bi-allelic protein-coding sites located in 2,625 human genes in 67 unrelated individuals using genotyping microarrays. We used the presence of both over- and under-expression of the reference allele compared to the alternate allele to identify candidate-imprinted genes. We found 61 genes with at least twofold DAE plus "flipping" of the more highly expressed allele between reference and alternate across heterozygous samples. Sixteen flipping genes were genotyped and assayed for DAE in an independent data set of lymphoblastoid cell lines from two CEPH pedigrees. We confirmed that PEG10 is paternally expressed, identified one gene (ZNF331) with multiple lines of data indicating it is imprinted, and predicted several additional imprinting candidate genes. Our findings suggest that there are at most several hundred genes in the human genome that are universally imprinted. With samples of mRNA from appropriate tissues and a collection of informative cSNPs, a genome-wide search using this methodology could expand the list of genes that undergo genomic imprinting in a tissue- or temporal-specific manner.

Deciphering Human Immunodeficiency Virus Type 1 Transmission and Early Envelope Diversification by Single-Genome Amplification and Sequencing

Jesus — 2008-05-22T15:55:33-00:00

J. Virol., Vol. 82, No. 8. (15 April 2008), pp. 3952-3970.

Accurate identification of the transmitted virus and sequences evolving from it could be instrumental in elucidating the transmission of human immunodeficiency virus type 1 (HIV-1) and in developing vaccines, drugs, or microbicides to prevent infection. Here we describe an experimental approach to analyze HIV-1 env genes as intact genetic units amplified from plasma virion RNA by single-genome amplification (SGA), followed by direct sequencing of uncloned DNA amplicons. We show that this strategy precludes in vitro artifacts caused by Taq-induced nucleotide substitutions and template switching, provides an accurate representation of the env quasispecies in vivo, and has an overall error rate (including nucleotide misincorporation, insertion, and deletion) of less than 8 x 10-5. Applying this method to the analysis of virus in plasma from 12 Zambian subjects from whom samples were obtained within 3 months of seroconversion, we show that transmitted or early founder viruses can be identified and that molecular pathways and rates of early env diversification can be defined. Specifically, we show that 8 of the 12 subjects were each infected by a single virus, while 4 others acquired more than one virus; that the rate of virus evolution in one subject during an 80-day period spanning seroconversion was 1.7 x 10-5 substitutions per site per day; and that evidence of strong immunologic selection can be seen in Env and overlapping Rev sequences based on nonrandom accumulation of nonsynonymous mutations. We also compared the results of the SGA approach with those of more-conventional bulk PCR amplification methods performed on the same patient samples and found that the latter is associated with excessive rates of Taq-induced recombination, nucleotide misincorporation, template resampling, and cloning bias. These findings indicate that HIV-1 env genes, other viral genes, and even full-length viral genomes responsible for productive clinical infection can be identified by SGA analysis of plasma virus sampled at intervals typical in large-scale vaccine trials and that pathways of viral diversification and immune escape can be determined accurately. 10.1128/JVI.02660-07

Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome

Michael Weber — 2007-03-29T09:59:17-00:00

Nature Genetics, Vol. 39, No. 4. (04 March 2007), pp. 457-466.

A rescue strategy for multimapping short sequence tags refines surveys of transcriptional activity by CAGE.

GJ Faulkner — 2008-05-16T14:18:29-00:00

Genomics, Vol. 91, No. 3. (March 2008), pp. 281-288.

Cap analysis gene expression (CAGE) is a high-throughput, tag-based method designed to survey the 5' end of capped full-length cDNAs. CAGE has previously been used to define global transcription start site usage and monitor gene activity in mammals. A drawback of the CAGE approach thus far has been the removal of as many as 40% of CAGE sequence tags due to their mapping to multiple genomic locations. Here, we address the origins of multimap tags and present a novel strategy to assign CAGE tags to their most likely source promoter region. When this approach was applied to the FANTOM3 CAGE libraries, the percentage of protein-coding mouse transcriptional frameworks detected by CAGE improved from 42.9 to 57.8% (an increase of 5516 frameworks) with no reduction in CAGE to microarray correlation. These results suggest that the multimap tags produced by high-throughput, short sequence tag-based approaches can be rescued to augment greatly the transcriptome coverage provided by single-map tags alone.

Discovering sequence motifs with arbitrary insertions and deletions.

MC Frith — 2008-05-08T14:33:21-00:00

PLoS computational biology, Vol. 4, No. 4. (April 2008)

BIOLOGY IS ENCODED IN MOLECULAR SEQUENCES: deciphering this encoding remains a grand scientific challenge. Functional regions of DNA, RNA, and protein sequences often exhibit characteristic but subtle motifs; thus, computational discovery of motifs in sequences is a fundamental and much-studied problem. However, most current algorithms do not allow for insertions or deletions (indels) within motifs, and the few that do have other limitations. We present a method, GLAM2 (Gapped Local Alignment of Motifs), for discovering motifs allowing indels in a fully general manner, and a companion method GLAM2SCAN for searching sequence databases using such motifs. glam2 is a generalization of the gapless Gibbs sampling algorithm. It re-discovers variable-width protein motifs from the PROSITE database significantly more accurately than the alternative methods PRATT and SAM-T2K. Furthermore, it usefully refines protein motifs from the ELM database: in some cases, the refined motifs make orders of magnitude fewer overpredictions than the original ELM regular expressions. GLAM2 performs respectably on the BAliBASE multiple alignment benchmark, and may be superior to leading multiple alignment methods for "motif-like" alignments with N- and C-terminal extensions. Finally, we demonstrate the use of GLAM2 to discover protein kinase substrate motifs and a gapped DNA motif for the LIM-only transcriptional regulatory complex: using GLAM2SCAN, we identify promising targets for the latter. GLAM2 is especially promising for short protein motifs, and it should improve our ability to identify the protein cleavage sites, interaction sites, post-translational modification attachment sites, etc., that underlie much of biology. It may be equally useful for arbitrarily gapped motifs in DNA and RNA, although fewer examples of such motifs are known at present. GLAM2 is public domain software, available for download at http://bioinformatics.org.au/glam2.

Genome analysis of the platypus reveals unique signatures of evolution

2008-05-07T23:43:22-00:00

Nature, Vol. 453, No. 7192. (May 2008), pp. 175-183.

Combining Statistical Alignment and Phylogenetic Footprinting to Detect Regulatory Elements.

R Satija — 2008-03-21T18:29:17-00:00

Bioinformatics (18 March 2008)

MOTIVATION: Traditional alignment-based phylogenetic footprinting approaches make predictions on the basis of a single assumed alignment. The predictions are therefore highly sensitive to alignment errors or regions of alignment uncertainty. Alternatively, statistical alignment methods provide a framework for performing phylogenetic analyses by examining a distribution of alignments. RESULTS: We developed a novel algorithm for predicting functional elements by combining statistical alignment and phylogenetic footprinting (SAPF). SAPF simultaneously performs both alignment and annotation by combining phylogenetic footprinting techniques with an HMM transducer-based multiple alignment model, and can analyze sequence data from multiple sequences. We assessed SAPF's predictive performance on two simulated datasets and three well-annotated cis-regulatory modules from newly sequenced Drosophila genomes. The results demonstrate that removing the traditional dependence on a single alignment can significantly augment the predictive performance, especially when there is uncertainty in the alignment of functional regions. AVAILABILITY: SAPF is freely available to download online at http://www.stats.ox.ac.uk/~satija/SAPF/ CONTACT: satija@stats.ox.ac.uk.

The Transcriptional Landscape of the Yeast Genome Defined by RNA Sequencing

Ugrappa Nagalakshmi — 2008-05-01T22:47:26-00:00

Science (1 May 2008), 1158441.

The identification of untranslated regions (UTRs), introns, and coding regions within an organism remains challenging. We developed a quantitative sequencing-based method for mapping transcribed regions called RNA-Seq in which cDNA fragments are subjected to high throughput sequencing and mapped to the genome. We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed. We confirmed many known and predicted introns and demonstrated that others are not actively used. Alternative initiation codons and upstream open reading frames were also identified for many yeast genes. We also found unexpected 3' end heterogeneity and the presence of many overlapping genes. These results indicate that the yeast transcriptome is more complex than previously appreciated. 10.1126/science.1158441

Designating eukaryotic orthology via processed transcription units.

Meng — 2008-05-02T08:32:23-00:00

Nucleic acids research (29 April 2008)

Orthology is a widely used concept in comparative and evolutionary genomics. In addition to prokaryotic orthology, delineating eukaryotic orthology has provided insight into the evolution of higher organisms. Indeed, many eukaryotic ortholog databases have been established for this purpose. However, unlike prokaryotes, alternative splicing (AS) has hampered eukaryotic orthology assignments. Therefore, existing databases likely contain ambiguous eukaryotic ortholog relationships and possibly misclassify alternatively spliced protein isoforms as in-paralogs, which are duplicated genes that arise following speciation. Here, we propose a new approach for designating eukaryotic orthology using processed transcription units, and we present an orthology database prototype using the human and mouse genomes. Currently existing programs cover less than 69% of the human reference sequences when assigning human/mouse orthologs. In contrast, our method encompasses up to 80% of the human reference sequences. Moreover, the ortholog database presented herein is more than 92% consistent with the existing databases. In addition to managing AS, this approach is capable of identifying orthologs of embedded genes and fusion genes using syntenic evidence. In summary, this new approach is sensitive, specific and can generate a more comprehensive and accurate compilation of eukaryotic orthologs.

High Guanine and Cytosine Content Increases mRNA Levels in Mammalian Cells

Grzegorz Kudla — 2006-05-24T20:58:27-00:00

PLoS Biology, Vol. 4, No. 6. (1 June 2006)

Mammalian genes are highly heterogeneous with respect to their nucleotide composition, but the functional consequences of this heterogeneity are not clear. In the previous studies, weak positive or negative correlations have been found between the silent-site guanine and cytosine (GC) content and expression of mammalian genes. However, previous studies disregarded differences in the genomic context of genes, which could potentially obscure any correlation between GC content and expression. In the present work, we directly compared the expression of GC-rich and GC-poor genes placed in the context of identical promoters and UTR sequences. We performed transient and stable transfections of mammalian cells with GC-rich and GC-poor versions of Hsp70, green fluorescent protein, and IL2 genes. The GC-rich genes were expressed several-fold to over a 100-fold more efficiently than their GC-poor counterparts. This effect was not due to different translation rates of GC-rich and GC-poor mRNA. On the contrary, the efficient expression of GC-rich genes resulted from their increased steady-state mRNA levels. mRNA degradation rates were not correlated with GC content, suggesting that efficient transcription or mRNA processing is responsible for the high expression of GC-rich genes. We conclude that silent-site GC content correlates with gene expression efficiency in mammalian cells.

The evolutionary advantage of recombination.

J Felsenstein — 2007-09-26T16:43:29-00:00

Genetics, Vol. 78, No. 2. (October 1974), pp. 737-756.

The controversy over the evolutionary advantage of recombination initially discovered by Fisher and by Muller is reviewed. Those authors whose models had finite-population effects found an advantage of recombination, and those whose models had infinite populations found none. The advantage of recombination is that it breaks down random linkage disequilibrium generated by genetic drift. Hill and Robertson found that the average effect of this randomly-generated linkage disequilibrium was to cause linked loci to interfere with each other's response to selection, even where there was no gene interaction between the loci. This effect is shown to be identical to the original argument of Fisher and Muller. It also predicts the "ratchet mechanism" discovered by Muller, who pointed out that deleterious mutants would more readily increase in a population without recombination. Computer simulations of substitution of favorable mutants and of the long-term increase of deleterious mutants verified the essential correctness of the original Fisher-Muller argument and the reality of the Muller ratchet mechanism. It is argued that these constitute an intrinsic advantage of recombination capable of accounting for its persistence in the face of selection for tighter linkage between interacting polymorphisms, and possibly capable of accounting for its origin.

THE EVOLUTIONARY ADVANTAGE OF RECOMBINATION. II. INDIVIDUAL SELECTION FOR RECOMBINATION

Joseph Felsenstein — 2008-05-01T12:28:37-00:00

Genetics, Vol. 83, No. 4. (1 August 1976), pp. 845-859.

Based on the Fisher-Muller theory of the evolution of recombination, an argument can be constructed predicting that a recessive allele favoring recombination will be favored, if there are either favorable or deleterious mutants occurring at other loci. In this case there is no clear distinction between individual and group selection. Computer simulation of populations segregating for recessive or dominant recombination alleles showed selection favoring recombination, except in the case of a dominant recombination allele with deleterious background mutants. The relationship of this work to parallel investigations by Williams and by Strobeck, Maynard Smith, and Charlesworth is explored. All seem to rely on the same phenomenon. There seems no reason to assume that the evolution of recombination must have occurred by group selection.

Positive selection drives a correlation between nonsynonymous/ synonymous divergence and functional divergence.

Jacob Tennessen — 2008-05-01T10:54:48-00:00

Bioinformatics (Oxford, England) (28 April 2008)

MOTIVATION: Functional divergence among proteins is often assumed to be strongly influenced by natural selection, as inferred from the ratio of nonsynonymous nucleotide divergence (d(N)) to synonymous nucleotide divergence (d(S)). That is, the more a mutation changes protein function, the more likely it is to be either selected against or selectively favored, and because the d(N)/d(S) ratio is a measure of natural selection, this ratio can be used to predict the degree of functional divergence (d(F)). However, these hypotheses have rarely been experimentally tested. RESULTS: I present a novel method to address this issue, and demonstrate that divergence in bacteria-killing activity among animal antimicrobial peptides is positively correlated with the log of the d(N)/d(S) ratio. The primary cause of this pattern appears to be that positively selected substitutions change protein function more than neutral substitutions do. Thus, the d(N)/d(S) ratio is an accurate estimator of adaptive functional divergence. CONTACT: tennessj@science.oregonstate.edu SUPPLEMENTARY INFORMATION: Supplementary data, including GenBank Accession numbers, are available at Bioinformatics Online.

Phylogenetic distribution of large-scale genome patchiness

Jose Oliver — 2008-04-12T18:37:25-00:00

BMC Evolutionary Biology, Vol. 8 (11 April 2008), 107.

Low Rates of Expression Profile Divergence in Highly Expressed Genes and Tissue-Specific Genes During Mammalian Evolution

Ben Liao — 2006-05-19T13:53:05-00:00

Molecular Biology and Evolution, Vol. 23, No. 6. (June 2006), pp. 1119-1128.

Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes

Toshiaki Watanabe — 2008-04-11T04:52:35-00:00

Nature (10 April 2008)

Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes

Oliver Tam — 2008-04-11T04:52:35-00:00

Nature (10 April 2008)

Multiple transcription start sites for FOXP2 with varying cellular specificities

Diane Schroeder — 2008-03-06T09:05:56-00:00

Gene, Vol. In Press, Accepted Manuscript