CiteULike: Tag genome

Genome instability: a mechanistic view of its causes and consequences.

Andrés Aguilera — 2008-02-01T10:36:05-00:00

Nat Rev Genet (29 January 2008)

Genomic instability in the form of mutations and chromosome rearrangements is usually associated with pathological disorders, and yet it is also crucial for evolution. Two types of elements have a key role in instability leading to rearrangements: those that act in trans to prevent instability - among them are replication, repair and S-phase checkpoint factors - and those that act in cis - chromosomal hotspots of instability such as fragile sites and highly transcribed DNA sequences. Taking these elements as a guide, we review the causes and consequences of instability with the aim of providing a mechanistic perspective on the origin of genomic instability.

The evolution of genome compression and genomic novelty in RNA viruses.

Robert Belshaw — 2007-09-07T05:21:32-00:00

Genome Res (4 September 2007)

The genomes of RNA viruses are characterized by their extremely small size and extremely high mutation rates (typically 10 kb and 10(-4)/base/replication cycle, respectively), traits that are thought to be causally linked. One aspect of their small size is the genome compression caused by the use of overlapping genes (where some nucleotides code for two genes). Using a comparative analysis of all known RNA viral species, we show that viruses with larger genomes tend to have less gene overlap. We provide a numerical model to show how a high mutation rate could lead to gene overlap, and we discuss the factors that might explain the observed relationship between gene overlap and genome size. We also propose a model for the evolution of gene overlap based on the co-opting of previously unused ORFs, which gives rise to two types of overlap: (1) the creation of novel genes inside older genes, predominantly via +1 frameshifts, and (2) the incremental increase in overlap between originally contiguous genes, with no frameshift preference. Both types of overlap are viewed as the creation of genomic novelty under pressure for genome compression. Simulations based on our model generate the empirical size distributions of overlaps and explain the observed frameshift preferences. We suggest that RNA viruses are a good model system for the investigation of general evolutionary relationship between genome attributes such as mutational robustness, mutation rate, and size.

A Genome-wide RNA Interference Screen Reveals that Variant Histones Are Necessary for Replication-Dependent Histone Pre-mRNA Processing

Eric Wagner — 2007-12-10T05:02:30-00:00

Molecular Cell, Vol. 28, No. 4. (30 November 2007), pp. 692-699.

Summary Metazoan replication-dependent histone mRNAs are not polyadenylated and instead end in a conserved stem loop that is the cis element responsible for coordinate posttranscriptional regulation of these mRNAs. Using biochemical approaches, only a limited number of factors required for cleavage of histone pre-mRNA have been identified. We therefore performed a genome-wide RNA interference screen in Drosophila cells using a GFP reporter that is expressed only when histone pre-mRNA processing is disrupted. Four of the 24 genes identified encode proteins also necessary for cleavage/polyadenylation, indicating mechanistic conservation in formation of different mRNA 3' ends. We also unexpectedly identified the histone variants H2Av and H3.3A/B. In H2Av mutant cells, U7 snRNP remains active but fails to accumulate at the histone locus, suggesting there is a regulatory pathway that coordinates the production of variant and canonical histones that acts via localization of essential histone pre-mRNA processing factors.

Predicting Protein Function with Hierarchical Phylogenetic Profiles: The Gene3D Phylo-Tuner Method Applied to Eukaryotic Genomes

Juan Ranea — 2007-12-10T04:43:16-00:00

PLoS Computational Biology, Vol. 3, No. 11. (1 November 2007), e237.

“Phylogenetic profiling” is based on the hypothesis that during evolution functionally or physically interacting genes are likely to be inherited or eliminated in a codependent manner. Creating presence–absence profiles of orthologous genes is now a common and powerful way of identifying functionally associated genes. In this approach, correctly determining orthology, as a means of identifying functional equivalence between two genes, is a critical and nontrivial step and largely explains why previous work in this area has mainly focused on using presence–absence profiles in prokaryotic species. Here, we demonstrate that eukaryotic genomes have a high proportion of multigene families whose phylogenetic profile distributions are poor in presence–absence information content. This feature makes them prone to orthology mis-assignment and unsuited to standard profile-based prediction methods. Using CATH structural domain assignments from the Gene3D database for 13 complete eukaryotic genomes, we have developed a novel modification of the phylogenetic profiling method that uses genome copy number of each domain superfamily to predict functional relationships. In our approach, superfamilies are subclustered at ten levels of sequence identity—from 30% to 100%—and phylogenetic profiles built at each level. All the profiles are compared using normalised Euclidean distances to identify those with correlated changes in their domain copy number. We demonstrate that two protein families will “auto-tune” with strong co-evolutionary signals when their profiles are compared at the similarity levels that capture their functional relationship. Our method finds functional relationships that are not detectable by the conventional presence–absence profile comparisons, and it does not require a priori any fixed criteria to define orthologous genes.

Evolutionary Genomics: Transdomain Gene Transfers

Seth Bordenstein — 2007-11-16T06:42:04-00:00

Current Biology, Vol. 17, No. 21. (6 November 2007), pp. R935-R936.

Summary Biologists have until now conceded that bacterial gene transfer to multicellular animals is relatively uncommon in Nature. A new study showing promiscuous insertions of bacterial endosymbiont genes into invertebrate genomes ushers in a shift in this paradigm.

Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome

Daniel Gibson — 2008-01-25T23:30:03-00:00

Science (24 January 2008), 1151721.

We have synthesized a 582,970 bp Mycoplasma genitalium genome. This synthetic genome, named M. genitalium JCVI-1.0, contains all the genes of wild-type M. genitalium G37 except MG408, which was disrupted by an antibiotic marker to block pathogenicity and to allow for selection. To identify the genome as synthetic, we inserted "watermarks" at intergenic sites known to tolerate transposon insertions. Overlapping "cassettes" of 5 to 7 kb, assembled from chemically synthesized oligonucleotides, were joined by in vitro recombination to produce intermediate assemblies of approximately 24 kb, 72 kb ("1/8 genome"), and 144 kb ("1/4 genome"), which were all cloned as bacterial artificial chromosomes (BACs) in Escherichia coli. Most of these intermediate clones were sequenced, and clones of all four 1/4 genomes with the correct sequence were identified. The complete synthetic genome was assembled by transformation-associated recombination (TAR) cloning in the yeast Saccharomyces cerevisiae, then isolated and sequenced. A clone with the correct sequence was identified. The methods described here will be generally useful for constructing large DNA molecules from chemically synthesized pieces and also from combinations of natural and synthetic DNA segments. 10.1126/science.1151721

Single-Molecule DNA Sequencing of a Viral Genome

Timothy Harris — 2008-04-04T15:36:18-00:00

Science, Vol. 320, No. 5872. (4 April 2008), pp. 106-109.

The full promise of human genomics will be realized only when the genomes of thousands of individuals can be sequenced for comparative analysis. A reference sequence enables the use of short read length. We report an amplification-free method for determining the nucleotide sequence of more than 280,000 individual DNA molecules simultaneously. A DNA polymerase adds labeled nucleotides to surface-immobilized primer-template duplexes in stepwise fashion, and the asynchronous growth of individual DNA molecules was monitored by fluorescence imaging. Read lengths of >25 bases and equivalent phred software program quality scores approaching 30 were achieved. We used this method to sequence the M13 virus to an average depth of >150x and with 100% coverage; thus, we resequenced the M13 genome with high-sensitivity mutation detection. This demonstrates a strategy for high-throughput low-cost resequencing. 10.1126/science.1150427

Networks of genomic co-occurrence capture characteristics of human influenza A (H3N2) evolution

Xiangjun Du — 2007-11-27T17:25:40-00:00

Genome Res. (21 November 2007), gr.6969007.

The recent availability of full genomic sequence data for a large number of human influenza A (H3N2) virus isolates over many years provides us an opportunity to analyze human influenza virus evolution by considering all gene segments simultaneously. However, such analysis requires development of new computational models that can capture the complex evolutionary features over the entire genome. By analyzing nucleotide co-occurrence over the entire genome of human H3N2 viruses, we have developed a network model to describe H3N2 virus evolutionary patterns and dynamics. The network model effectively captures the evolutionary antigenic features of H3N2 virus at the whole-genome level and accurately describes the complex evolutionary patterns between individual gene segments. Our analyses show that the co-occurring nucleotide modules apparently underpin the dynamics of human H3N2 evolution and that amino acid substitutions corresponding to nucleotide co-changes cluster preferentially in known antigenic regions of the viral HA. Therefore, our study demonstrates that nucleotide co-occurrence networks represent a powerful method for tracking influenza A virus evolution and that cooperative genomic interaction is a major force underlying influenza virus evolution. 10.1101/gr.6969007

Assessing the Significance of Conserved Genomic Aberrations Using High Resolution Genomic Microarrays

Mitchell Guttman — 2007-08-27T09:22:33-00:00

PLoS Genetics, Vol. 3, No. 8. (1 August 2007), e143.

Genomic aberrations recurrent in a particular cancer type can be important prognostic markers for tumor progression. Typically in early tumorigenesis, cells incur a breakdown of the DNA replication machinery that results in an accumulation of genomic aberrations in the form of duplications, deletions, translocations, and other genomic alterations. Microarray methods allow for finer mapping of these aberrations than has previously been possible; however, data processing and analysis methods have not taken full advantage of this higher resolution. Attention has primarily been given to analysis on the single sample level, where multiple adjacent probes are necessarily used as replicates for the local region containing their target sequences. However, regions of concordant aberration can be short enough to be detected by only one, or very few, array elements. We describe a method called Multiple Sample Analysis for assessing the significance of concordant genomic aberrations across multiple experiments that does not require a-priori definition of aberration calls for each sample. If there are multiple samples, representing a class, then by exploiting the replication across samples our method can detect concordant aberrations at much higher resolution than can be derived from current single sample approaches. Additionally, this method provides a meaningful approach to addressing population-based questions such as determining important regions for a cancer subtype of interest or determining regions of copy number variation in a population. Multiple Sample Analysis also provides single sample aberration calls in the locations of significant concordance, producing high resolution calls per sample, in concordant regions. The approach is demonstrated on a dataset representing a challenging but important resource: breast tumors that have been formalin-fixed, paraffin-embedded, archived, and subsequently UV-laser capture microdissected and hybridized to two-channel BAC arrays using an amplification protocol. We demonstrate the accurate detection on simulated data, and on real datasets involving known regions of aberration within subtypes of breast cancer at a resolution consistent with that of the array. Similarly, we apply our method to previously published datasets, including a 250K SNP array, and verify known results as well as detect novel regions of concordant aberration. The algorithm has been fully implemented and tested and is freely available as a Java application at http://www.cbil.upenn.edu/MSA.

Genome Analysis of Minibacterium massiliensis Highlights the Convergent Evolution of Water-Living Bacteria

Stéphane Audic — 2007-09-03T14:15:57-00:00

PLoS Genetics, Vol. 3, No. 8. (1 August 2007), e138.

Filtration usually eliminates water-living bacteria. Here, we report on the complete genome sequence of Minibacterium massiliensis, a β-proteobacteria that was recovered from 0.22-μm filtered water used for patients in the hospital. The unexpectedly large 4,110,251-nucleotide genome sequence of M. massiliensis was determined using the traditional shotgun sequencing approach. Bioinformatic analyses shows that the M. massiliensis genome sequence illustrates characteristic features of water-living bacteria, including overrepresentation of genes encoding transporters and transcription regulators. Phylogenomic analysis based on the gene content of available bacterial genome sequences displays a congruent evolution of water-living bacteria from various taxonomic origins, principally for genes involved in energy production and conversion, cell division, chromosome partitioning, and lipid metabolism. This phylogenomic clustering partially results from lateral gene transfer, which appears to be more frequent in water than in other environments. The M. massiliensis genome analyses strongly suggest that water-living bacteria are a common source for genes involved in heavy-metal resistance, antibiotics resistance, and virulence factors.

Identification and Characterization of Cell Type-Specific and Ubiquitous Chromatin Regulatory Structures in the Human Genome.

Hualin Xi — 2007-08-25T09:20:43-00:00

PLoS Genet, Vol. 3, No. 8. (17 August 2007)

The identification of regulatory elements from different cell types is necessary for understanding the mechanisms controlling cell type-specific and housekeeping gene expression. Mapping DNaseI hypersensitive (HS) sites is an accurate method for identifying the location of functional regulatory elements. We used a high throughput method called DNase-chip to identify 3,904 DNaseI HS sites from six cell types across 1% of the human genome. A significant number (22%) of DNaseI HS sites from each cell type are ubiquitously present among all cell types studied. Surprisingly, nearly all of these ubiquitous DNaseI HS sites correspond to either promoters or insulator elements: 86% of them are located near annotated transcription start sites and 10% are bound by CTCF, a protein with known enhancer-blocking insulator activity. We also identified a large number of DNaseI HS sites that are cell type specific (only present in one cell type); these regions are enriched for enhancer elements and correlate with cell type-specific gene expression as well as cell type-specific histone modifications. Finally, we found that approximately 8% of the genome overlaps a DNaseI HS site in at least one the six cell lines studied, indicating that a significant percentage of the genome is potentially functional.

Integrating physical and genetic maps: from genomes to interaction networks

Andreas Beyer — 2007-08-18T01:43:38-00:00

Nature Reviews Genetics, Vol. 8, No. 9., pp. 699-710.

An in Vivo Map of the Yeast Protein Interactome

Kirill Tarassov — 2008-06-13T17:39:23-00:00

Science, Vol. 320, No. 5882. (13 June 2008), pp. 1465-1470.

Protein interactions regulate the systems-level behavior of cells; thus, deciphering the structure and dynamics of protein interaction networks in their cellular context is a central goal in biology. We have performed a genome-wide in vivo screen for protein-protein interactions in Saccharomyces cerevisiae by means of a protein-fragment complementation assay (PCA). We identified 2770 interactions among 1124 endogenously expressed proteins. Comparison with previous studies confirmed known interactions, but most were not known, revealing a previously unexplored subspace of the yeast protein interactome. The PCA detected structural and topological relationships between proteins, providing an 8-nanometer-resolution map of dynamically interacting complexes in vivo and extended networks that provide insights into fundamental cellular processes, including cell polarization and autophagy, pathways that are evolutionarily conserved and central to both development and human health. 10.1126/science.1153878

Genome-Wide Mapping of in Vivo Protein-DNA Interactions

David Johnson — 2007-06-04T11:05:50-00:00

Science (31 May 2007), 1141319.

In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultra-high-throughput DNA sequencing. This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element-1 silencing transcription factor) to 1946 locations in the human genome. The data display sharp resolution of binding position [+/-50 base pairs (bp)], which facilitated our finding motifs and allowed us to identify noncanonical NRSF-binding motifs. These ChIPSeq data also have high sensitivity and specificity [ROC (receiver operator characteristic) area =0.96] and statistical confidence (P <10-4), properties that were important for inferring new candidate interactions. These include key transcription factors in the gene network that regulates pancreatic islet cell development. 10.1126/science.1141319

The neoselectionist theory of genome evolution

Giorgio Bernardi — 2007-05-29T01:40:21-00:00

PNAS, Vol. 104, No. 20. (15 May 2007), pp. 8385-8390.

The vertebrate genome is a mosaic of GC-poor and GC-rich isochores, megabase-sized DNA regions of fairly homogeneous base composition that differ in relative amount, gene density, gene expression, replication timing, and recombination frequency. At the emergence of warm-blooded vertebrates, the gene-rich, moderately GC-rich isochores of the cold-blooded ancestors underwent a GC increase. This increase was similar in mammals and birds and was maintained during the evolution of mammalian and avian orders. Neither the GC increase nor its conservation can be accounted for by the random fixation of neutral or nearly neutral single-nucleotide changes (i.e., the vast majority of nucleotide substitutions) or by a biased gene conversion process occurring at random genome locations. Both phenomena can be explained, however, by the neoselectionist theory of genome evolution that is presented here. This theory fully accepts Ohta's nearly neutral view of point mutations but proposes in addition (i) that the AT-biased mutational input present in vertebrates pushes some DNA regions below a certain GC threshold; (ii) that these lower GC levels cause regional changes in chromatin structure that lead to deleterious effects on replication and transcription; and (iii) that the carriers of these changes undergo negative (purifying) selection, the final result being a compositional conservation of the original isochore pattern in the surviving population. Negative selection may also largely explain the GC increase accompanying the emergence of warm-blooded vertebrates. In conclusion, the neoselectionist theory not only provides a solution to the neutralist/selectionist debate but also introduces an epigenomic component in genome evolution. 10.1073/pnas.0701652104

The evolution of human influenza A viruses from 1999 to 2006 - a complete genome study

Karoline Bragstad — 2008-03-07T17:03:37-00:00

Virology Journal, Vol. 5 (07 March 2008), 40.

Comparing whole genomes using DNA microarrays

David Gresham — 2008-03-19T16:25:02-00:00

Nat Rev Genet, Vol. 9, No. 4. (April 2008), pp. 291-302.

Approaches to comparative sequence analysis: towards a functional view of vertebrate genomes

Elliott Margulies — 2008-03-19T01:24:04-00:00

Nat Rev Genet, Vol. 9, No. 4. (April 2008), pp. 303-313.

PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome

Michael Stiffler — 2007-07-23T06:11:29-00:00

Science, Vol. 317, No. 5836. (20 July 2007), pp. 364-369.

PDZ domains have long been thought to cluster into discrete functional classes defined by their peptide-binding preferences. We used protein microarrays and quantitative fluorescence polarization to characterize the binding selectivity of 157 mouse PDZ domains with respect to 217 genome-encoded peptides. We then trained a multidomain selectivity model to predict PDZ domainpeptide interactions across the mouse proteome with an accuracy that exceeds many large-scale, experimental investigations of protein-protein interactions. Contrary to the current paradigm, PDZ domains do not fall into discrete classes; instead, they are evenly distributed throughout selectivity space, which suggests that they have been optimized across the proteome to minimize cross-reactivity. We predict that focusing on families of interaction domains, which facilitates the integration of experimentation and modeling, will play an increasingly important role in future investigations of protein function. 10.1126/science.1144592

Improvisation in evolution of genes and genomes: whose structure is it anyway?

Boris E Shakhnovich — 2008-05-22T09:43:34-00:00

Current opinion in structural biology (17 May 2008)

Significant progress has been made in recent years in a variety of seemingly unrelated fields such as sequencing, protein structure prediction, and high-throughput transcriptomics and metabolomics. At the same time, new microscopic models have been developed that made it possible to analyze the evolution of genes and genomes from first principles. The results from these efforts enable, for the first time, a comprehensive insight into the evolution of complex systems and organisms on all scales - from sequences to organisms and populations. Every newly sequenced genome uncovers new genes, families, and folds. Where do these new genes come from? How do gene duplication and subsequent divergence of sequence and structure affect the fitness of the organism? What role does regulation play in the evolution of proteins and folds? Emerging synergism between data and modeling provides first robust answers to these questions.

A Computational Approach to the Functional Screening of Genomes

Davide Chiarugi — 2007-10-30T10:02:12-00:00

PLoS Computational Biology, Vol. 3, No. 9. (1 September 2007), e174.

Comparative genomics usually involves managing the functional aspects of genomes, by simply comparing gene-by-gene functions. Following this approach, Mushegian and Koonin proposed a hypothetical minimal genome, Minimal Gene Set (MGS), aiming for a possible oldest ancestor genome. They obtained MGS by comparing the genomes of two simple bacteria and eliminating duplicated or functionally identical genes. The authors raised the fundamental question of whether a hypothetical organism possessing MGS is able to live or not. We attacked this viability problem specifying in silico the metabolic pathways of the MGS-based prokaryote. We then performed a dynamic simulation of cellular metabolic activities in order to check whether the MGS-prokaryote reaches some equilibrium state and produces the necessary biomass. We assumed these two conditions to be necessary for a living organism. Our simulations clearly show that the MGS does not express an organism that is able to live. We then iteratively proceeded with functional replacements in order to obtain a genome composition that gives rise to equilibrium. We ruled out 76 of the original 254 genes in the MGS, because they resulted in duplication from a functional point of view. We also added seven genes not present in the MGS. These genes encode for enzymes involved in critical nodes of the metabolic network. These modifications led to a genome composed of 187 elements expressing a virtually living organism, Virtual Cell (ViCe), that exhibits homeostatic capabilities and produces biomass. Moreover, the steady-state distribution of the concentrations of virtual metabolites that resulted was similar to that experimentally measured in bacteria. We conclude then that ViCe is able to “live in silico.”

Organization and Evolution of Primate Centromeric DNA from Whole-Genome Shotgun Sequence Data

Can Alkan — 2007-11-02T08:08:29-00:00

PLoS Computational Biology, Vol. 3, No. 9. (1 September 2007), e181.

The major DNA constituent of primate centromeres is alpha satellite DNA. As much as 2%–5% of sequence generated as part of primate genome sequencing projects consists of this material, which is fragmented or not assembled as part of published genome sequences due to its highly repetitive nature. Here, we develop computational methods to rapidly recover and categorize alpha-satellite sequences from previously uncharacterized whole-genome shotgun sequence data. We present an algorithm to computationally predict potential higher-order array structure based on paired-end sequence data and then experimentally validate its organization and distribution by experimental analyses. Using whole-genome shotgun data from the human, chimpanzee, and macaque genomes, we examine the phylogenetic relationship of these sequences and provide further support for a model for their evolution and mutation over the last 25 million years. Our results confirm fundamental differences in the dispersal and evolution of centromeric satellites in the Old World monkey and ape lineages of evolution.

A Universal Framework for Regulatory Element Discovery across All Genomes and Data Types.

O Elemento — 2007-10-31T12:12:38-00:00

Mol Cell, Vol. 28, No. 2. (26 October 2007), pp. 337-350.

Deciphering the noncoding regulatory genome has proved a formidable challenge. Despite the wealth of available gene expression data, there currently exists no broadly applicable method for characterizing the regulatory elements that shape the rich underlying dynamics. We present a general framework for detecting such regulatory DNA and RNA motifs that relies on directly assessing the mutual information between sequence and gene expression measurements. Our approach makes minimal assumptions about the background sequence model and the mechanisms by which elements affect gene expression. This provides a versatile motif discovery framework, across all data types and genomes, with exceptional sensitivity and near-zero false-positive rates. Applications from yeast to human uncover putative and established transcription-factor binding and miRNA target sites, revealing rich diversity in their spatial configurations, pervasive co-occurrences of DNA and RNA motifs, context-dependent selection for motif avoidance, and the strong impact of posttranscriptional processes on eukaryotic transcriptomes.

Integration of Genome and Chromatin Structure with Gene Expression Profiles To Predict c-MYC Recognition Site Binding and Function.

Yili Chen — 2007-04-08T07:53:59-00:00

PLoS Comput Biol, Vol. 3, No. 4. (6 April 2007)

The MYC genes encode nuclear sequence specific-binding DNA-binding proteins that are pleiotropic regulators of cellular function, and the c-MYC proto-oncogene is deregulated and/or mutated in most human cancers. Experimental studies of MYC binding to the genome are not fully consistent. While many c-MYC recognition sites can be identified in c-MYC responsive genes, other motif matches-even experimentally confirmed sites-are associated with genes showing no c-MYC response. We have developed a computational model that integrates multiple sources of evidence to predict which genes will bind and be regulated by MYC in vivo. First, a Bayesian network classifier is used to predict those c-MYC recognition sites that are most likely to exhibit high-occupancy binding in chromatin immunoprecipitation studies. This classifier incorporates genomic sequence, experimentally determined genomic chromatin acetylation islands, and predicted methylation status from a computational model estimating the likelihood of genomic DNA methylation. We find that the predictions from this classifier are also applicable to other transcription factors, such as cAMP-response element-binding protein, whose binding sites are sensitive to DNA methylation. Second, the MYC binding probability is combined with the gene expression profile data from nine independent microarray datasets in multiple tissues. Finally, we may consider gene function annotations in Gene Ontology to predict the c-MYC targets. We assess the performance of our prediction results by comparing them with the c-myc targets identified in the biomedical literature. In total, we predict 460 likely c-MYC target genes in the human genome, of which 67 have been reported to be both bound and regulated by MYC, 68 are bound by MYC, and another 80 are MYC-regulated. The approach thus successfully identifies many known c-MYC targets and suggests many novel sites. Our findings suggest that to identify c-MYC genomic targets, integration of different data sources helps to improve the accuracy.

The Chlamydomonas Genome Reveals the Evolution of Key Animal and Plant Functions

Sabeeha Merchant — 2007-10-14T18:48:53-00:00

Science, Vol. 318, No. 5848. (12 October 2007), pp. 245-250.

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the [~]120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella. 10.1126/science.1143609

High-Resolution Profiling of Histone Methylations in the Human Genome

Artem Barski — 2007-06-14T01:06:51-00:00

Cell, Vol. 129, No. 4. (18 May 2007), pp. 823-837.

Summary Histone modifications are implicated in influencing gene expression. We have generated high-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology. Typical patterns of histone methylations exhibited at promoters, insulators, enhancers, and transcribed regions are identified. The monomethylations of H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations of H3K27, H3K9, and H3K79 are linked to repression. H2A.Z associates with functional regulatory elements, and CTCF marks boundaries of histone methylation domains. Chromosome banding patterns are correlated with unique patterns of histone modifications. Chromosome breakpoints detected in T cell cancers frequently reside in chromatin regions associated with H3K4 methylations. Our data provide new insights into the function of histone methylation and chromatin organization in genome function.

Principles of Genome Evolution in the Drosophila melanogaster Species Group

José Ranz — 2007-06-14T01:02:58-00:00

PLoS Biology, Vol. 5, No. 6. (1 June 2007), e152.

That closely related species often differ by chromosomal inversions was discovered by Sturtevant and Plunkett in 1926. Our knowledge of how these inversions originate is still very limited, although a prevailing view is that they are facilitated by ectopic recombination events between inverted repetitive sequences. The availability of genome sequences of related species now allows us to study in detail the mechanisms that generate interspecific inversions. We have analyzed the breakpoint regions of the 29 inversions that differentiate the chromosomes of Drosophila melanogaster and two closely related species, D. simulans and D. yakuba, and reconstructed the molecular events that underlie their origin. Experimental and computational analysis revealed that the breakpoint regions of 59% of the inversions (17/29) are associated with inverted duplications of genes or other nonrepetitive sequences. In only two cases do we find evidence for inverted repetitive sequences in inversion breakpoints. We propose that the presence of inverted duplications associated with inversion breakpoint regions is the result of staggered breaks, either isochromatid or chromatid, and that this, rather than ectopic exchange between inverted repetitive sequences, is the prevalent mechanism for the generation of inversions in the melanogaster species group. Outgroup analysis also revealed evidence for widespread breakpoint recycling. Lastly, we have found that expression domains in D. melanogaster may be disrupted in D. yakuba, bringing into question their potential adaptive significance.

The Functional Genomics Experiment model (FuGE): an extensible framework for standards in functional genomics

Andrew Jones — 2007-10-11T16:03:11-00:00

Nat Biotech, Vol. 25, No. 10. (October 2007), pp. 1127-1133.

Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen

Abraham Brass — 2008-01-11T15:34:09-00:00

Science (10 January 2008), 1152725.

HIV-1 exploits multiple host proteins during infection. We performed a large-scale siRNA screen to identify host factors required by HIV-1 and identified over 250 HIV-dependency factors (HDFs). These proteins participate in a broad array of cellular functions and implicate new pathways in the viral life cycle. Further analysis revealed previously unknown roles for retrograde Golgi transport proteins (Rab6 and Vps53) in viral entry, a karyopherin (TNPO3) in viral integration, and the Mediator complex (Med28) in viral transcription. Transcriptional analysis revealed that HDF genes were enriched for high expression in immune cells suggesting that viruses evolve in host cells that optimally perform the functions required for their life cycle. This effort illustrates the power with which RNA interference and forward genetics can be used to expose the dependencies of human pathogens such as HIV, and in so doing identify potential targets for therapy. 10.1126/science.1152725

InPrePPI: an integrated evaluation method based on genomic context for predicting protein-protein interactions in prokaryotic genomes

Jingchun Sun — 2007-10-26T20:30:46-00:00

BMC Bioinformatics, Vol. 8 (26 October 2007), 414.

Life-history traits drive the evolutionary rates of mammalian coding and noncoding genomic elements

Sergey Nikolaev — 2007-12-12T10:23:23-00:00

Proceedings of the National Academy of Sciences (11 December 2007), 0705658104.

A comprehensive phylogenetic framework is indispensable for investigating the evolution of genomic features in mammals as a whole, and particularly in humans. Using the ENCODE sequence data, we estimated mammalian neutral evolutionary rates and selective pressures acting on conserved coding and noncoding elements. We show that neutral evolutionary rates can be explained by the generation time (GT) hypothesis. Accordingly, primates (especially humans), having longer GTs than other mammals, display slower rates of neutral evolution. The evolution of constrained elements, particularly of nonsynonymous sites, is in agreement with the expectations of the nearly neutral theory of molecular evolution. We show that rates of nonsynonymous substitutions (dN) depend on the population size of a species. The results are robust to the exclusion of hypermutable CpG prone sites. The average rate of evolution in conserved noncoding sequences (CNCs) is 1.7 times higher than in nonsynonymous sites. Despite this, CNCs evolve at similar or even lower rates than nonsynonymous sites in the majority of basal branches of the eutherian tree. This observation could be the result of an overall gradual or, alternatively, lineage-specific relaxation of CNCs. The latter hypothesis was supported by the finding that 3 of the 20 longest CNCs displayed significant relaxation of individual branches. This observation may explain why the evolution of CNCs fits the expectations of the nearly neutral theory less well than the evolution of nonsynonymous sites. 10.1073/pnas.0705658104

Evolution of genes and genomes on the Drosophila phylogeny

2007-11-07T19:25:43-00:00

Nature, Vol. 450, No. 7167. (November 2007), pp. 203-218.

Human disease classification in the postgenomic era: A complex systems approach to human pathobiology

Joseph Loscalzo — 2007-07-11T18:26:11-00:00

Mol Syst Biol, Vol. 3 (10 July 2007)

Molecular and Genomic Data Identify the Closest Living Relative of Primates

Jan Janecka — 2007-11-02T21:42:33-00:00

Science, Vol. 318, No. 5851. (2 November 2007), pp. 792-794.

A full understanding of primate morphological and genomic evolution requires the identification of their closest living relative. In order to resolve the ancestral relationships among primates and their closest relatives, we searched multispecies genome alignments for phylogenetically informative rare genomic changes within the superordinal group Euarchonta, which includes the orders Primates, Dermoptera (colugos), and Scandentia (treeshrews). We also constructed phylogenetic trees from 14 kilobases of nuclear genes for representatives from most major primate lineages, both extant colugos, and multiple treeshrews, including the pentail treeshrew, Ptilocercus lowii, the only living member of the family Ptilocercidae. A relaxed molecular clock analysis including Ptilocercus suggests that treeshrews arose approximately 63 million years ago. Our data show that colugos are the closest living relatives of primates and indicate that their divergence occurred in the Cretaceous. 10.1126/science.1147555

Complete genome sequence of the myxobacterium Sorangium cellulosum

Susanne Schneiker — 2007-11-09T06:46:58-00:00

Nature Biotechnology, Vol. 25, No. 11. (28 October 2007), pp. 1281-1289.

Towards multidimensional genome annotation

Jennifer Reed — 2006-01-18T16:36:02-00:00

Nature Reviews Genetics, Vol. 7, No. 2., pp. 130-141.

CpG Island Mapping by Epigenome Prediction.

Christoph Bock — 2007-06-17T06:58:42-00:00

PLoS Comput Biol, Vol. 3, No. 6. (8 June 2007)

CpG islands were originally identified by epigenetic and functional properties, namely, absence of DNA methylation and frequent promoter association. However, this concept was quickly replaced by simple DNA sequence criteria, which allowed for genome-wide annotation of CpG islands in the absence of large-scale epigenetic datasets. Although widely used, the current CpG island criteria incur significant disadvantages: (1) reliance on arbitrary threshold parameters that bear little biological justification, (2) failure to account for widespread heterogeneity among CpG islands, and (3) apparent lack of specificity when applied to the human genome. This study is driven by the idea that a quantitative score of "CpG island strength" that incorporates epigenetic and functional aspects can help resolve these issues. We construct an epigenome prediction pipeline that links the DNA sequence of CpG islands to their epigenetic states, including DNA methylation, histone modifications, and chromatin accessibility. By training support vector machines on epigenetic data for CpG islands on human Chromosomes 21 and 22, we identify informative DNA attributes that correlate with open versus compact chromatin structures. These DNA attributes are used to predict the epigenetic states of all CpG islands genome-wide. Combining predictions for multiple epigenetic features, we estimate the inherent CpG island strength for each CpG island in the human genome, i.e., its inherent tendency to exhibit an open and transcriptionally competent chromatin structure. We extensively validate our results on independent datasets, showing that the CpG island strength predictions are applicable and informative across different tissues and cell types, and we derive improved maps of predicted "bona fide" CpG islands. The mapping of CpG islands by epigenome prediction is conceptually superior to identifying CpG islands by widely used sequence criteria since it links CpG island detection to their characteristic epigenetic and functional states. And it is superior to purely experimental epigenome mapping for CpG island detection since it abstracts from specific properties that are limited to a single cell type or tissue. In addition, using computational epigenetics methods we could identify high correlation between the epigenome and characteristics of the DNA sequence, a finding which emphasizes the need for a better understanding of the mechanistic links between genome and epigenome.

Adaptive Mutations in Bacteria: High Rate and Small Effects

Lilia Perfeito — 2007-08-15T02:21:34-00:00

Science, Vol. 317, No. 5839. (10 August 2007), pp. 813-815.

Evolution by natural selection is driven by the continuous generation of adaptive mutations. We measured the genomic mutation rate that generates beneficial mutations and their effects on fitness in Escherichia coli under conditions in which the effect of competition between lineages carrying different beneficial mutations is minimized. We found a rate on the order of 105 per genome per generation, which is 1000 times as high as previous estimates, and a mean selective advantage of 1%. Such a high rate of adaptive evolution has implications for the evolution of antibiotic resistance and pathogenicity. 10.1126/science.1142284

Alignment Uncertainty and Genomic Analysis

Karen Wong — 2008-01-25T07:09:02-00:00

Science, Vol. 319, No. 5862. (25 January 2008), pp. 473-476.

The statistical methods applied to the analysis of genomic data do not account for uncertainty in the sequence alignment. Indeed, the alignment is treated as an observation, and all of the subsequent inferences depend on the alignment being correct. This may not have been too problematic for many phylogenetic studies, in which the gene is carefully chosen for, among other things, ease of alignment. However, in a comparative genomics study, the same statistical methods are applied repeatedly on thousands of genes, many of which will be difficult to align. Using genomic data from seven yeast species, we show that uncertainty in the alignment can lead to several problems, including different alignment methods resulting in different conclusions. 10.1126/science.1151532

Widespread Lateral Gene Transfer from Intracellular Bacteria to Multicellular Eukaryotes

Julie Hotopp — 2007-08-31T00:38:44-00:00

Science (30 August 2007), 1142490.

Although common among bacteria, lateral gene transferthe movement of genes between distantly related organismsis thought to occur only rarely between bacteria and multicellular eukaryotes. However, the presence of endosymbionts, such as Wolbachia pipientis, within some eukaryotic germlines may facilitate bacterial gene transfers to eukaryotic host genomes. We therefore examined host genomes for evidence of gene transfer events from Wolbachia bacteria to their hosts. We found and confirmed transfers into the genomes of 4 insect and 4 nematode species that range from nearly the entire Wolbachia genome (>1 megabase) to short (<500 base pairs) insertions. Potential Wolbachia to host transfers were also detected computationally in three additional sequenced insect genomes. We also show that some of these inserted Wolbachia genes are transcribed within eukaryotic cells lacking endosymbionts. Therefore, heritable lateral gene transfer occurs into eukaryotic hosts from their prokaryote symbionts, potentially providing a mechanism for acquisition of new genes and functions. 10.1126/science.1142490

Identifying clusters of functionally related genes in genomes.

Gangman Yi — 2007-02-04T20:41:06-00:00

Bioinformatics (19 January 2007)

MOTIVATION: An increasing body of literature shows that genomes of eukaryotes can contain clusters of functionally related genes. Most approaches to identify gene clusters utilize microarray data or metabolic pathway databases to find groups of genes on chromosomes that are linked by common attributes. A generalized method that can find gene clusters regardless of the mechanism of origin would provide researchers with an unbiased method for finding clusters and studying the evolutionary forces that give rise to them. RESULTS: We present an algorithm to identify gene clusters in eukaryotic genomes that utilizes functional categories defined in graph-based vocabularies such as the Gene Ontology (GO). Clusters identified in this manner need only have a common function and are not constrained by gene expression or other properties. We tested the algorithm by analyzing genomes of a representative set of species. We identified species-specific variation in percentage of clustered genes as well as in properties of gene clusters including size distribution and functional annotation. These properties may be diagnostic of the evolutionary forces that lead to the formation of gene clusters. AVAILABILITY: A software implementation of the algorithm and example output files are available at http://fcg.tamu.edu/C_Hunter/.

Phylogenetic exploration of bacterial genomic rearrangements

Romain Fremez — 2007-05-10T07:12:47-00:00

Bioinformatics, Vol. 23, No. 9. (1 May 2007), pp. 1172-1174.

Summary: We present a graphical tool dedicated to the exploration of bacterial genome rearrangements. The principle of this exploration relies on the reconstruction of ancestral genomes at each internal node of a gene-order-based phylogenetic tree. This tool allows the selection of internal nodes to visualize the rearrangements between the inferred chromosome of this node and its direct descendant on the tree. Availability: PEGR is available at the Genopole Toulouse Bioinformatics platform. Supplementary information: Online supplementary data are available at PEGR web site: http://bioinfo.genopole-toulouse.prd.fr/pegr. 10.1093/bioinformatics/btm070

Phenotype ontologies: the bridge between genomics and evolution

Paula Mabee — 2007-08-18T07:56:25-00:00

Trends in Ecology & Evolution, Vol. 22, No. 7. (July 2007), pp. 345-350.

Understanding the developmental and genetic underpinnings of particular evolutionary changes has been hindered by inadequate databases of evolutionary anatomy and by the lack of a computational approach to identify underlying candidate genes and regulators. By contrast, model organism studies have been enhanced by ontologies shared among genomic databases. Here, we suggest that evolutionary and genomics databases can be developed to exchange and use information through shared phenotype and anatomy ontologies. This would facilitate computing on evolutionary questions pertaining to the genetic basis of evolutionary change, the genetic and developmental bases of correlated characters and independent evolution, biomedical parallels to evolutionary change, and the ecological and paleontological correlates of particular types of change in genes, gene networks and developmental pathways.

A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1

Jacques Fellay — 2007-08-18T07:36:10-00:00

Science, Vol. 317, No. 5840. (17 August 2007), pp. 944-947.

Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents. 10.1126/science.1143767

Viral Evolution in the Genomic Age

Edward Holmes — 2007-10-02T19:24:33-00:00

PLoS Biology, Vol. 5, No. 10. (1 October 2007), e278.

RNA-mediated epigenetic programming of a genome-rearrangement pathway

Mariusz Nowacki — 2007-11-29T05:38:48-00:00

Nature (28 November 2007)

Genome Transplantation in Bacteria: Changing One Species to Another

Carole Lartigue — 2007-06-30T05:37:35-00:00

Science (28 June 2007), 1144622.

As a step toward propagation of synthetic genomes, we completely replaced the genome of a bacterial cell with one from another species by transplanting a whole genome as naked DNA. Intact genomic DNA from Mycoplasma mycoides large colony (LC), virtually free of protein, was transplanted into Mycoplasma capricolum cells by polyethylene glycol-mediated transformation. Cells selected for tetracycline resistance, carried by the M. mycoides LC chromosome, contain the complete donor genome and are free of detectable recipient genomic sequences. These cells that result from genome transplantation are phenotypically identical to the M. mycoides LC donor strain as judged by several criteria. 10.1126/science.1144622

Genome Duplication, a Trait Shared by 22,000 Species of Ray-Finned Fish

John Taylor — 2007-01-17T14:56:22-00:00

Genome Res., Vol. 13, No. 3. (1 March 2003), pp. 382-390.

Through phylogeny reconstruction we identified 49 genes with a single copy in man, mouse, and chicken, one or two copies in the tetraploid frog Xenopus laevis, and two copies in zebrafish (Danio rerio). For 22 of these genes, both zebrafish duplicates had orthologs in the pufferfish (Takifugu rubripes). For another 20 of these genes, we found only one pufferfish ortholog but in each case it was more closely related to one of the zebrafish duplicates than to the other. Forty-three pairs of duplicated genes map to 24 of the 25 zebrafish linkage groups but they are not randomly distributed; we identified 10 duplicated regions of the zebrafish genome that each contain between two and five sets of paralogous genes. These phylogeny and synteny data suggest that the common ancestor of zebrafish and pufferfish, a fish that gave rise to [~]22,000 species, experienced a large-scale gene or complete genome duplication event and that the pufferfish has lost many duplicates that the zebrafish has retained. [Supplemental material is available online at www.genome.org.] 10.1101/gr.640303