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1.  PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium 
Nucleic Acids Research  2009;38(Database issue):D204-D210.
Protein Analysis THrough Evolutionary Relationships (PANTHER) is a comprehensive software system for inferring the functions of genes based on their evolutionary relationships. Phylogenetic trees of gene families form the basis for PANTHER and these trees are annotated with ontology terms describing the evolution of gene function from ancestral to modern day genes. One of the main applications of PANTHER is in accurate prediction of the functions of uncharacterized genes, based on their evolutionary relationships to genes with functions known from experiment. The PANTHER website, freely available at http://www.pantherdb.org, also includes software tools for analyzing genomic data relative to known and inferred gene functions. Since 2007, there have been several new developments to PANTHER: (i) improved phylogenetic trees, explicitly representing speciation and gene duplication events, (ii) identification of gene orthologs, including least diverged orthologs (best one-to-one pairs), (iii) coverage of more genomes (48 genomes, up to 87% of genes in each genome; see http://www.pantherdb.org/panther/summaryStats.jsp), (iv) improved support for alternative database identifiers for genes, proteins and microarray probes and (v) adoption of the SBGN standard for display of biological pathways. In addition, PANTHER trees are being annotated with gene function as part of the Gene Ontology Reference Genome project, resulting in an increasing number of curated functional annotations.
doi:10.1093/nar/gkp1019
PMCID: PMC2808919  PMID: 20015972
2.  QuartetS: a fast and accurate algorithm for large-scale orthology detection 
Nucleic Acids Research  2011;39(13):e88.
The unparalleled growth in the availability of genomic data offers both a challenge to develop orthology detection methods that are simultaneously accurate and high throughput and an opportunity to improve orthology detection by leveraging evolutionary evidence in the accumulated sequenced genomes. Here, we report a novel orthology detection method, termed QuartetS, that exploits evolutionary evidence in a computationally efficient manner. Based on the well-established evolutionary concept that gene duplication events can be used to discriminate homologous genes, QuartetS uses an approximate phylogenetic analysis of quartet gene trees to infer the occurrence of duplication events and discriminate paralogous from orthologous genes. We used function- and phylogeny-based metrics to perform a large-scale, systematic comparison of the orthology predictions of QuartetS with those of four other methods [bi-directional best hit (BBH), outgroup, OMA and QuartetS-C (QuartetS followed by clustering)], involving 624 bacterial genomes and >2 million genes. We found that QuartetS slightly, but consistently, outperformed the highly specific OMA method and that, while consuming only 0.5% additional computational time, QuartetS predicted 50% more orthologs with a 50% lower false positive rate than the widely used BBH method. We conclude that, for large-scale phylogenetic and functional analysis, QuartetS and QuartetS-C should be preferred, respectively, in applications where high accuracy and high throughput are required.
doi:10.1093/nar/gkr308
PMCID: PMC3141274  PMID: 21572104
3.  Identification of mammalian orthologs using local synteny 
BMC Genomics  2009;10:630.
Background
Accurate determination of orthology is central to comparative genomics. For vertebrates in particular, very large gene families, high rates of gene duplication and loss, multiple mechanisms of gene duplication, and high rates of retrotransposition all combine to make inference of orthology between genes difficult. Many methods have been developed to identify orthologous genes, mostly based upon analysis of the inferred protein sequence of the genes. More recently, methods have been proposed that use genomic context in addition to protein sequence to improve orthology assignment in vertebrates. Such methods have been most successfully implemented in fungal genomes and have long been used in prokaryotic genomes, where gene order is far less variable than in vertebrates. However, to our knowledge, no explicit comparison of synteny and sequence based definitions of orthology has been reported in vertebrates, or, more specifically, in mammals.
Results
We test a simple method for the measurement and utilization of gene order (local synteny) in the identification of mammalian orthologs by investigating the agreement between coding sequence based orthology (Inparanoid) and local synteny based orthology. In the 5 mammalian genomes studied, 93% of the sampled inter-species pairs were found to be concordant between the two orthology methods, illustrating that local synteny is a robust substitute to coding sequence for identifying orthologs. However, 7% of pairs were found to be discordant between local synteny and Inparanoid. These cases of discordance result from evolutionary events including retrotransposition and genome rearrangements.
Conclusions
By analyzing cases of discordance between local synteny and Inparanoid we show that local synteny can distinguish between true orthologs and recent retrogenes, can resolve ambiguous many-to-many orthology relationships into one-to-one ortholog pairs, and might be used to identify cases of non-orthologous gene displacement by retroduplicated paralogs.
doi:10.1186/1471-2164-10-630
PMCID: PMC2807883  PMID: 20030836
4.  Evola: Ortholog database of all human genes in H-InvDB with manual curation of phylogenetic trees 
Nucleic Acids Research  2007;36(Database issue):D787-D792.
Orthologs are genes in different species that evolved from a common ancestral gene by speciation. Currently, with the rapid growth of transcriptome data of various species, more reliable orthology information is prerequisite for further studies. However, detection of orthologs could be erroneous if pairwise distance-based methods, such as reciprocal BLAST searches, are utilized. Thus, as a sub-database of H-InvDB, an integrated database of annotated human genes (http://h-invitational.jp/), we constructed a fully curated database of evolutionary features of human genes, called ‘Evola’. In the process of the ortholog detection, computational analysis based on conserved genome synteny and transcript sequence similarity was followed by manual curation by researchers examining phylogenetic trees. In total, 18 968 human genes have orthologs among 11 vertebrates (chimpanzee, mouse, cow, chicken, zebrafish, etc.), either computationally detected or manually curated orthologs. Evola provides amino acid sequence alignments and phylogenetic trees of orthologs and homologs. In ‘dN/dS view’, natural selection on genes can be analyzed between human and other species. In ‘Locus maps’, all transcript variants and their exon/intron structures can be compared among orthologous gene loci. We expect the Evola to serve as a comprehensive and reliable database to be utilized in comparative analyses for obtaining new knowledge about human genes. Evola is available at http://www.h-invitational.jp/evola/.
doi:10.1093/nar/gkm878
PMCID: PMC2238928  PMID: 17982176
5.  PhyloTreePruner: A Phylogenetic Tree-Based Approach for Selection of Orthologous Sequences for Phylogenomics 
Molecular phylogenetics relies on accurate identification of orthologous sequences among the taxa of interest. Most orthology inference programs available for use in phylogenomics rely on small sets of pre-defined orthologs from model organisms or phenetic approaches such as all-versus-all sequence comparisons followed by Markov graph-based clustering. Such approaches have high sensitivity but may erroneously include paralogous sequences. We developed PhyloTreePruner, a software utility that uses a phylogenetic approach to refine orthology inferences made using phenetic methods. PhyloTreePruner checks single-gene trees for evidence of paralogy and generates a new alignment for each group containing only sequences inferred to be orthologs. Importantly, PhyloTreePruner takes into account support values on the tree and avoids unnecessarily deleting sequences in cases where a weakly supported tree topology incorrectly indicates paralogy. A test of PhyloTreePruner on a dataset generated from 11 completely sequenced arthropod genomes identified 2,027 orthologous groups sampled for all taxa. Phylogenetic analysis of the concatenated supermatrix yielded a generally well-supported topology that was consistent with the current understanding of arthropod phylogeny. PhyloTreePruner is freely available from http://sourceforge.net/projects/phylotreepruner/.
doi:10.4137/EBO.S12813
PMCID: PMC3825643  PMID: 24250218
phylogenomic; orthology; paralogy; gene tree
6.  RIO: Analyzing proteomes by automated phylogenomics using resampled inference of orthologs 
BMC Bioinformatics  2002;3:14.
Background
When analyzing protein sequences using sequence similarity searches, orthologous sequences (that diverged by speciation) are more reliable predictors of a new protein's function than paralogous sequences (that diverged by gene duplication). The utility of phylogenetic information in high-throughput genome annotation ("phylogenomics") is widely recognized, but existing approaches are either manual or not explicitly based on phylogenetic trees.
Results
Here we present RIO (Resampled Inference of Orthologs), a procedure for automated phylogenomics using explicit phylogenetic inference. RIO analyses are performed over bootstrap resampled phylogenetic trees to estimate the reliability of orthology assignments. We also introduce supplementary concepts that are helpful for functional inference. RIO has been implemented as Perl pipeline connecting several C and Java programs. It is available at http://www.genetics.wustl.edu/eddy/forester/. A web server is at http://www.rio.wustl.edu/. RIO was tested on the Arabidopsis thaliana and Caenorhabditis elegans proteomes.
Conclusion
The RIO procedure is particularly useful for the automated detection of first representatives of novel protein subfamilies. We also describe how some orthologies can be misleading for functional inference.
doi:10.1186/1471-2105-3-14
PMCID: PMC116988  PMID: 12028595
7.  Orthology prediction at scalable resolution by phylogenetic tree analysis 
BMC Bioinformatics  2007;8:83.
Background
Orthology is one of the cornerstones of gene function prediction. Dividing the phylogenetic relations between genes into either orthologs or paralogs is however an oversimplification. Already in two-species gene-phylogenies, the complicated, non-transitive nature of phylogenetic relations results in inparalogs and outparalogs. For situations with more than two species we lack semantics to specifically describe the phylogenetic relations, let alone to exploit them. Published procedures to extract orthologous groups from phylogenetic trees do not allow identification of orthology at various levels of resolution, nor do they document the relations between the orthologous groups.
Results
We introduce "levels of orthology" to describe the multi-level nature of gene relations. This is implemented in a program LOFT (Levels of Orthology From Trees) that assigns hierarchical orthology numbers to genes based on a phylogenetic tree. To decide upon speciation and gene duplication events in a tree LOFT can be instructed either to perform classical species-tree reconciliation or to use the species overlap between partitions in the tree. The hierarchical orthology numbers assigned by LOFT effectively summarize the phylogenetic relations between genes. The resulting high-resolution orthologous groups are depicted in colour, facilitating visual inspection of (large) trees. A benchmark for orthology prediction, that takes into account the varying levels of orthology between genes, shows that the phylogeny-based high-resolution orthology assignments made by LOFT are reliable.
Conclusion
The "levels of orthology" concept offers high resolution, reliable orthology, while preserving the relations between orthologous groups. A Windows as well as a preliminary Java version of LOFT is available from the LOFT website .
doi:10.1186/1471-2105-8-83
PMCID: PMC1838432  PMID: 17346331
8.  Inferring angiosperm phylogeny from EST data with widespread gene duplication 
BMC Evolutionary Biology  2007;7(Suppl 1):S3.
Background
Most studies inferring species phylogenies use sequences from single copy genes or sets of orthologs culled from gene families. For taxa such as plants, with very high levels of gene duplication in their nuclear genomes, this has limited the exploitation of nuclear sequences for phylogenetic studies, such as those available in large EST libraries. One rarely used method of inference, gene tree parsimony, can infer species trees from gene families undergoing duplication and loss, but its performance has not been evaluated at a phylogenomic scale for EST data in plants.
Results
A gene tree parsimony analysis based on EST data was undertaken for six angiosperm model species and Pinus, an outgroup. Although a large fraction of the tentative consensus sequences obtained from the TIGR database of ESTs was assembled into homologous clusters too small to be phylogenetically informative, some 557 clusters contained promising levels of information. Based on maximum likelihood estimates of the gene trees obtained from these clusters, gene tree parsimony correctly inferred the accepted species tree with strong statistical support. A slight variant of this species tree was obtained when maximum parsimony was used to infer the individual gene trees instead.
Conclusion
Despite the complexity of the EST data and the relatively small fraction eventually used in inferring a species tree, the gene tree parsimony method performed well in the face of very high apparent rates of duplication.
doi:10.1186/1471-2148-7-S1-S3
PMCID: PMC1796612  PMID: 17288576
9.  Detecting non-orthology in the COGs database and other approaches grouping orthologs using genome-specific best hits 
Nucleic Acids Research  2006;34(11):3309-3316.
Correct orthology assignment is a critical prerequisite of numerous comparative genomics procedures, such as function prediction, construction of phylogenetic species trees and genome rearrangement analysis. We present an algorithm for the detection of non-orthologs that arise by mistake in current orthology classification methods based on genome-specific best hits, such as the COGs database. The algorithm works with pairwise distance estimates, rather than computationally expensive and error-prone tree-building methods. The accuracy of the algorithm is evaluated through verification of the distribution of predicted cases, case-by-case phylogenetic analysis and comparisons with predictions from other projects using independent methods. Our results show that a very significant fraction of the COG groups include non-orthologs: using conservative parameters, the algorithm detects non-orthology in a third of all COG groups. Consequently, sequence analysis sensitive to correct orthology assignments will greatly benefit from these findings.
doi:10.1093/nar/gkl433
PMCID: PMC1500873  PMID: 16835308
10.  Genome trees constructed using five different approaches suggest new major bacterial clades 
Background
The availability of multiple complete genome sequences from diverse taxa prompts the development of new phylogenetic approaches, which attempt to incorporate information derived from comparative analysis of complete gene sets or large subsets thereof. Such attempts are particularly relevant because of the major role of horizontal gene transfer and lineage-specific gene loss, at least in the evolution of prokaryotes.
Results
Five largely independent approaches were employed to construct trees for completely sequenced bacterial and archaeal genomes: i) presence-absence of genomes in clusters of orthologous genes; ii) conservation of local gene order (gene pairs) among prokaryotic genomes; iii) parameters of identity distribution for probable orthologs; iv) analysis of concatenated alignments of ribosomal proteins; v) comparison of trees constructed for multiple protein families. All constructed trees support the separation of the two primary prokaryotic domains, bacteria and archaea, as well as some terminal bifurcations within the bacterial and archaeal domains. Beyond these obvious groupings, the trees made with different methods appeared to differ substantially in terms of the relative contributions of phylogenetic relationships and similarities in gene repertoires caused by similar life styles and horizontal gene transfer to the tree topology. The trees based on presence-absence of genomes in orthologous clusters and the trees based on conserved gene pairs appear to be strongly affected by gene loss and horizontal gene transfer. The trees based on identity distributions for orthologs and particularly the tree made of concatenated ribosomal protein sequences seemed to carry a stronger phylogenetic signal. The latter tree supported three potential high-level bacterial clades,: i) Chlamydia-Spirochetes, ii) Thermotogales-Aquificales (bacterial hyperthermophiles), and ii) Actinomycetes-Deinococcales-Cyanobacteria. The latter group also appeared to join the low-GC Gram-positive bacteria at a deeper tree node. These new groupings of bacteria were supported by the analysis of alternative topologies in the concatenated ribosomal protein tree using the Kishino-Hasegawa test and by a census of the topologies of 132 individual groups of orthologous proteins. Additionally, the results of this analysis put into question the sister-group relationship between the two major archaeal groups, Euryarchaeota and Crenarchaeota, and suggest instead that Euryarchaeota might be a paraphyletic group with respect to Crenarchaeota.
Conclusions
We conclude that, the extensive horizontal gene flow and lineage-specific gene loss notwithstanding, extension of phylogenetic analysis to the genome scale has the potential of uncovering deep evolutionary relationships between prokaryotic lineages.
doi:10.1186/1471-2148-1-8
PMCID: PMC60490  PMID: 11734060
11.  Prokaryotic Phylogenies Inferred from Whole-Genome Sequence and Annotation Data 
BioMed Research International  2013;2013:409062.
Phylogenetic trees are used to represent the evolutionary relationship among various groups of species. In this paper, a novel method for inferring prokaryotic phylogenies using multiple genomic information is proposed. The method is called CGCPhy and based on the distance matrix of orthologous gene clusters between whole-genome pairs. CGCPhy comprises four main steps. First, orthologous genes are determined by sequence similarity, genomic function, and genomic structure information. Second, genes involving potential HGT events are eliminated, since such genes are considered to be the highly conserved genes across different species and the genes located on fragments with abnormal genome barcode. Third, we calculate the distance of the orthologous gene clusters between each genome pair in terms of the number of orthologous genes in conserved clusters. Finally, the neighbor-joining method is employed to construct phylogenetic trees across different species. CGCPhy has been examined on different datasets from 617 complete single-chromosome prokaryotic genomes and achieved applicative accuracies on different species sets in agreement with Bergey's taxonomy in quartet topologies. Simulation results show that CGCPhy achieves high average accuracy and has a low standard deviation on different datasets, so it has an applicative potential for phylogenetic analysis.
doi:10.1155/2013/409062
PMCID: PMC3773407  PMID: 24073404
12.  Improving the specificity of high-throughput ortholog prediction 
BMC Bioinformatics  2006;7:270.
Background
Orthologs (genes that have diverged after a speciation event) tend to have similar function, and so their prediction has become an important component of comparative genomics and genome annotation. The gold standard phylogenetic analysis approach of comparing available organismal phylogeny to gene phylogeny is not easily automated for genome-wide analysis; therefore, ortholog prediction for large genome-scale datasets is typically performed using a reciprocal-best-BLAST-hits (RBH) approach. One problem with RBH is that it will incorrectly predict a paralog as an ortholog when incomplete genome sequences or gene loss is involved. In addition, there is an increasing interest in identifying orthologs most likely to have retained similar function.
Results
To address these issues, we present here a high-throughput computational method named Ortholuge that further evaluates previously predicted orthologs (including those predicted using an RBH-based approach) – identifying which orthologs most closely reflect species divergence and may more likely have similar function. Ortholuge analyzes phylogenetic distance ratios involving two comparison species and an outgroup species, noting cases where relative gene divergence is atypical. It also identifies some cases of gene duplication after species divergence. Through simulations of incomplete genome data/gene loss, we show that the vast majority of genes falsely predicted as orthologs by an RBH-based method can be identified. Ortholuge was then used to estimate the number of false-positives (predominantly paralogs) in selected RBH-predicted ortholog datasets, identifying approximately 10% paralogs in a eukaryotic data set (mouse-rat comparison) and 5% in a bacterial data set (Pseudomonas putida – Pseudomonas syringae species comparison). Higher quality (more precise) datasets of orthologs, which we term "ssd-orthologs" (supporting-species-divergence-orthologs), were also constructed. These datasets, as well as Ortholuge software that may be used to characterize other species' datasets, are available at (software under GNU General Public License).
Conclusion
The Ortholuge method reported here appears to significantly improve the specificity (precision) of high-throughput ortholog prediction for both bacterial and eukaryotic species. This method, and its associated software, will aid those performing various comparative genomics-based analyses, such as the prediction of conserved regulatory elements upstream of orthologous genes.
doi:10.1186/1471-2105-7-270
PMCID: PMC1524997  PMID: 16729895
13.  Phylogenomics of plant genomes: a methodology for genome-wide searches for orthologs in plants 
BMC Genomics  2008;9:183.
Background
Gene ortholog identification is now a major objective for mining the increasing amount of sequence data generated by complete or partial genome sequencing projects. Comparative and functional genomics urgently need a method for ortholog detection to reduce gene function inference and to aid in the identification of conserved or divergent genetic pathways between several species. As gene functions change during evolution, reconstructing the evolutionary history of genes should be a more accurate way to differentiate orthologs from paralogs. Phylogenomics takes into account phylogenetic information from high-throughput genome annotation and is the most straightforward way to infer orthologs. However, procedures for automatic detection of orthologs are still scarce and suffer from several limitations.
Results
We developed a procedure for ortholog prediction between Oryza sativa and Arabidopsis thaliana. Firstly, we established an efficient method to cluster A. thaliana and O. sativa full proteomes into gene families. Then, we developed an optimized phylogenomics pipeline for ortholog inference. We validated the full procedure using test sets of orthologs and paralogs to demonstrate that our method outperforms pairwise methods for ortholog predictions.
Conclusion
Our procedure achieved a high level of accuracy in predicting ortholog and paralog relationships. Phylogenomic predictions for all validated gene families in both species were easily achieved and we can conclude that our methodology outperforms similarly based methods.
doi:10.1186/1471-2164-9-183
PMCID: PMC2377279  PMID: 18426584
14.  MetaPhOrs: orthology and paralogy predictions from multiple phylogenetic evidence using a consistency-based confidence score 
Nucleic Acids Research  2010;39(5):e32.
Reliable prediction of orthology is central to comparative genomics. Approaches based on phylogenetic analyses closely resemble the original definition of orthology and paralogy and are known to be highly accurate. However, the large computational cost associated to these analyses is a limiting factor that often prevents its use at genomic scales. Recently, several projects have addressed the reconstruction of large collections of high-quality phylogenetic trees from which orthology and paralogy relationships can be inferred. This provides us with the opportunity to infer the evolutionary relationships of genes from multiple, independent, phylogenetic trees. Using such strategy, we combine phylogenetic information derived from different databases, to predict orthology and paralogy relationships for 4.1 million proteins in 829 fully sequenced genomes. We show that the number of independent sources from which a prediction is made, as well as the level of consistency across predictions, can be used as reliable confidence scores. A webserver has been developed to easily access these data (http://orthology.phylomedb.org), which provides users with a global repository of phylogeny-based orthology and paralogy predictions.
doi:10.1093/nar/gkq953
PMCID: PMC3061081  PMID: 21149260
15.  A Tight Link between Orthologs and Bidirectional Best Hits in Bacterial and Archaeal Genomes 
Genome Biology and Evolution  2012;4(12):1286-1294.
Orthologous relationships between genes are routinely inferred from bidirectional best hits (BBH) in pairwise genome comparisons. However, to our knowledge, it has never been quantitatively demonstrated that orthologs form BBH. To test this “BBH-orthology conjecture,” we take advantage of the operon organization of bacterial and archaeal genomes and assume that, when two genes in compared genomes are flanked by two BBH show statistically significant sequence similarity to one another, these genes are bona fide orthologs. Under this assumption, we tested whether middle genes in “syntenic orthologous gene triplets” form BBH. We found that this was the case in more than 95% of the syntenic gene triplets in all genome comparisons. A detailed examination of the exceptions to this pattern, including maximum likelihood phylogenetic tree analysis, showed that some of these deviations involved artifacts of genome annotation, whereas very small fractions represented random assignment of the best hit to one of closely related in-paralogs, paralogous displacement in situ, or even less frequent genuine violations of the BBH–orthology conjecture caused by acceleration of evolution in one of the orthologs. We conclude that, at least in prokaryotes, genes for which independent evidence of orthology is available typically form BBH and, conversely, BBH can serve as a strong indication of gene orthology.
doi:10.1093/gbe/evs100
PMCID: PMC3542571  PMID: 23160176
orthology; bidirectional best hit; genome comparison; synteny
16.  Ortholog identification in the presence of domain architecture rearrangement 
Briefings in Bioinformatics  2011;12(5):413-422.
Ortholog identification is used in gene functional annotation, species phylogeny estimation, phylogenetic profile construction and many other analyses. Bioinformatics methods for ortholog identification are commonly based on pairwise protein sequence comparisons between whole genomes. Phylogenetic methods of ortholog identification have also been developed; these methods can be applied to protein data sets sharing a common domain architecture or which share a single functional domain but differ outside this region of homology. While promiscuous domains represent a challenge to all orthology prediction methods, overall structural similarity is highly correlated with proximity in a phylogenetic tree, conferring a degree of robustness to phylogenetic methods. In this article, we review the issues involved in orthology prediction when data sets include sequences with structurally heterogeneous domain architectures, with particular attention to automated methods designed for high-throughput application, and present a case study to illustrate the challenges in this area.
doi:10.1093/bib/bbr036
PMCID: PMC3178056  PMID: 21712343
phylogenomics; orthology; promiscuous domains; multi-domain architecture; function prediction; super-ortholog
17.  DODO: an efficient orthologous genes assignment tool based on domain architectures. Domain based ortholog detection 
BMC Bioinformatics  2010;11(Suppl 7):S6.
Background
Orthologs are genes derived from the same ancestor gene loci after speciation events. Orthologous proteins usually have similar sequences and perform comparable biological functions. Therefore, ortholog identification is useful in annotations of newly sequenced genomes. With rapidly increasing number of sequenced genomes, constructing or updating ortholog relationship between all genomes requires lots of effort and computation time. In addition, elucidating ortholog relationships between distantly related genomes is challenging because of the lower sequence similarity. Therefore, an efficient ortholog detection method that can deal with large number of distantly related genomes is desired.
Results
An efficient ortholog detection pipeline DODO (DOmain based Detection of Orthologs) is created on the basis of domain architectures in this study. Supported by domain composition, which usually directly related with protein function, DODO could facilitate orthologs detection across distantly related genomes. DODO works in two main steps. Starting from domain information, it first assigns protein groups according to their domain architectures and further identifies orthologs within those groups with much reduced complexity. Here DODO is shown to detect orthologs between two genomes in considerably shorter period of time than traditional methods of reciprocal best hits and it is more significant when analyzed a large number of genomes. The output results of DODO are highly comparable with other known ortholog databases.
Conclusions
DODO provides a new efficient pipeline for detection of orthologs in a large number of genomes. In addition, a database established with DODO is also easier to maintain and could be updated relatively effortlessly. The pipeline of DODO could be downloaded from http://140.109.42.19:16080/dodo_web/home.htm
doi:10.1186/1471-2105-11-S7-S6
PMCID: PMC2957689  PMID: 21106128
18.  Factors affecting the concordance between orthologous gene trees and species tree in bacteria 
Background
As originally defined, orthologous genes implied a reflection of the history of the species. In recent years, many studies have examined the concordance between orthologous gene trees and species trees in bacteria. These studies have produced contradictory results that may have been influenced by orthologous gene misidentification and artefactual phylogenetic reconstructions. Here, using a method that allows the detection and exclusion of false positives during identification of orthologous genes, we address the question of whether putative orthologous genes within bacteria really reflect the history of the species.
Results
We identified a set of 370 orthologous genes from the bacterial order Rhizobiales. Although manifesting strong vertical signal, almost every orthologous gene had a distinct phylogeny, and the most common topology among the orthologous gene trees did not correspond with the best estimate of the species tree. However, each orthologous gene tree shared an average of 70% of its bipartitions with the best estimate of the species tree. Stochastic error related to gene size affected the concordance between the best estimated of the species tree and the orthologous gene trees, although this effect was weak and distributed unevenly among the functional categories. The nodes showing the greatest discordance were those defined by the shortest internal branches in the best estimated of the species tree. Moreover, a clear bias was evident with respect to the function of the orthologous genes, and the degree of divergence among the orthologous genes appeared to be related to their functional classification.
Conclusion
Orthologous genes do not reflect the history of the species when taken as individual markers, but they do when taken as a whole. Stochastic error affected the concordance of orthologous genes with the species tree, albeit weakly. We conclude that two important biological causes of discordance among orthologous genes are incomplete lineage sorting and functional restriction.
doi:10.1186/1471-2148-8-300
PMCID: PMC2614993  PMID: 18973688
19.  PhylomeDB v4: zooming into the plurality of evolutionary histories of a genome 
Nucleic Acids Research  2013;42(D1):D897-D902.
Phylogenetic trees representing the evolutionary relationships of homologous genes are the entry point for many evolutionary analyses. For instance, the use of a phylogenetic tree can aid in the inference of orthology and paralogy relationships, and in the detection of relevant evolutionary events such as gene family expansions and contractions, horizontal gene transfer, recombination or incomplete lineage sorting. Similarly, given the plurality of evolutionary histories among genes encoded in a given genome, there is a need for the combined analysis of genome-wide collections of phylogenetic trees (phylomes). Here, we introduce a new release of PhylomeDB (http://phylomedb.org), a public repository of phylomes. Currently, PhylomeDB hosts 120 public phylomes, comprising >1.5 million maximum likelihood trees and multiple sequence alignments. In the current release, phylogenetic trees are annotated with taxonomic, protein-domain arrangement, functional and evolutionary information. PhylomeDB is also a major source for phylogeny-based predictions of orthology and paralogy, covering >10 million proteins across 1059 sequenced species. Here we describe newly implemented PhylomeDB features, and discuss a benchmark of the orthology predictions provided by the database, the impact of proteome updates and the use of the phylome approach in the analysis of newly sequenced genomes and transcriptomes.
doi:10.1093/nar/gkt1177
PMCID: PMC3964985  PMID: 24275491
20.  Toward community standards in the quest for orthologs 
Bioinformatics  2012;28(6):900-904.
The identification of orthologs—genes pairs descended from a common ancestor through speciation, rather than duplication—has emerged as an essential component of many bioinformatics applications, ranging from the annotation of new genomes to experimental target prioritization. Yet, the development and application of orthology inference methods is hampered by the lack of consensus on source proteomes, file formats and benchmarks. The second ‘Quest for Orthologs’ meeting brought together stakeholders from various communities to address these challenges. We report on achievements and outcomes of this meeting, focusing on topics of particular relevance to the research community at large. The Quest for Orthologs consortium is an open community that welcomes contributions from all researchers interested in orthology research and applications.
Contact: dessimoz@ebi.ac.uk
doi:10.1093/bioinformatics/bts050
PMCID: PMC3307119  PMID: 22332236
21.  Efficient assembly and annotation of the transcriptome of catfish by RNA-Seq analysis of a doubled haploid homozygote 
BMC Genomics  2012;13:595.
Background
Upon the completion of whole genome sequencing, thorough genome annotation that associates genome sequences with biological meanings is essential. Genome annotation depends on the availability of transcript information as well as orthology information. In teleost fish, genome annotation is seriously hindered by genome duplication. Because of gene duplications, one cannot establish orthologies simply by homology comparisons. Rather intense phylogenetic analysis or structural analysis of orthologies is required for the identification of genes. To conduct phylogenetic analysis and orthology analysis, full-length transcripts are essential. Generation of large numbers of full-length transcripts using traditional transcript sequencing is very difficult and extremely costly.
Results
In this work, we took advantage of a doubled haploid catfish, which has two sets of identical chromosomes and in theory there should be no allelic variations. As such, transcript sequences generated from next-generation sequencing can be favorably assembled into full-length transcripts. Deep sequencing of the doubled haploid channel catfish transcriptome was performed using Illumina HiSeq 2000 platform, yielding over 300 million high-quality trimmed reads totaling 27 Gbp. Assembly of these reads generated 370,798 non-redundant transcript-derived contigs. Functional annotation of the assembly allowed identification of 25,144 unique protein-encoding genes. A total of 2,659 unique genes were identified as putative duplicated genes in the catfish genome because the assembly of the corresponding transcripts harbored PSVs or MSVs (in the form of pseudo-SNPs in the assembly). Of the 25,144 contigs with unique protein hits, around 20,000 contigs matched 50% length of reference proteins, and over 14,000 transcripts were identified as full-length with complete open reading frames. The characterization of consensus sequences surrounding start codon and the stop codon confirmed the correct assembly of the full-length transcripts.
Conclusions
The large set of transcripts assembled in this study is the most comprehensive set of genome resources ever developed from catfish, which will provide the much needed resources for functional genome research in catfish, serving as a reference transcriptome for genome annotation, analysis of gene duplication, gene family structures, and digital gene expression analysis. The putative set of duplicated genes provide a starting point for genome scale analysis of gene duplication in the catfish genome, and should be a valuable resource for comparative genome analysis, genome evolution, and genome function studies.
doi:10.1186/1471-2164-13-595
PMCID: PMC3582483  PMID: 23127152
22.  Revealing Mammalian Evolutionary Relationships by Comparative Analysis of Gene Clusters 
Genome Biology and Evolution  2012;4(4):586-601.
Many software tools for comparative analysis of genomic sequence data have been released in recent decades. Despite this, it remains challenging to determine evolutionary relationships in gene clusters due to their complex histories involving duplications, deletions, inversions, and conversions. One concept describing these relationships is orthology. Orthologs derive from a common ancestor by speciation, in contrast to paralogs, which derive from duplication. Discriminating orthologs from paralogs is a necessary step in most multispecies sequence analyses, but doing so accurately is impeded by the occurrence of gene conversion events. We propose a refined method of orthology assignment based on two paradigms for interpreting its definition: by genomic context or by sequence content. X-orthology (based on context) traces orthology resulting from speciation and duplication only, while N-orthology (based on content) includes the influence of conversion events. We developed a computational method for automatically mapping both types of orthology on a per-nucleotide basis in gene cluster regions studied by comparative sequencing, and we make this mapping accessible by visualizing the output. All of these steps are incorporated into our newly extended CHAP 2 package. We evaluate our method using both simulated data and real gene clusters (including the well-characterized α-globin and β-globin clusters). We also illustrate use of CHAP 2 by analyzing four more loci: CCL (chemokine ligand), IFN (interferon), CYP2abf (part of cytochrome P450 family 2), and KIR (killer cell immunoglobulin-like receptors). These new methods facilitate and extend our understanding of evolution at these and other loci by adding automated accurate evolutionary inference to the biologist's toolkit. The CHAP 2 package is freely available from http://www.bx.psu.edu/miller_lab.
doi:10.1093/gbe/evs032
PMCID: PMC3342878  PMID: 22454131
gene clusters; orthology; conversion; evolutionary inference; KIR
23.  Construction of a Phylogenetic Tree of Photosynthetic Prokaryotes Based on Average Similarities of Whole Genome Sequences 
PLoS ONE  2013;8(7):e70290.
Phylogenetic trees have been constructed for a wide range of organisms using gene sequence information, especially through the identification of orthologous genes that have been vertically inherited. The number of available complete genome sequences is rapidly increasing, and many tools for construction of genome trees based on whole genome sequences have been proposed. However, development of a reasonable method of using complete genome sequences for construction of phylogenetic trees has not been established. We have developed a method for construction of phylogenetic trees based on the average sequence similarities of whole genome sequences. We used this method to examine the phylogeny of 115 photosynthetic prokaryotes, i.e., cyanobacteria, Chlorobi, proteobacteria, Chloroflexi, Firmicutes and nonphotosynthetic organisms including Archaea. Although the bootstrap values for the branching order of phyla were low, probably due to lateral gene transfer and saturated mutation, the obtained tree was largely consistent with the previously reported phylogenetic trees, indicating that this method is a robust alternative to traditional phylogenetic methods.
doi:10.1371/journal.pone.0070290
PMCID: PMC3724816  PMID: 23922968
24.  From event-labeled gene trees to species trees 
BMC Bioinformatics  2012;13(Suppl 19):S6.
Background
Tree reconciliation problems have long been studied in phylogenetics. A particular variant of the reconciliation problem for a gene tree T and a species tree S assumes that for each interior vertex x of T it is known whether x represents a speciation or a duplication. This problem appears in the context of analyzing orthology data.
Results
We show that S is a species tree for T if and only if S displays all rooted triples of T that have three distinct species as their leaves and are rooted in a speciation vertex. A valid reconciliation map can then be found in polynomial time. Simulated data shows that the event-labeled gene trees convey a large amount of information on underlying species trees, even for a large percentage of losses.
Conclusions
The knowledge of event labels in a gene tree strongly constrains the possible species tree and, for a given species tree, also the possible reconciliation maps. Nevertheless, many degrees of freedom remain in the space of feasible solutions. In order to disambiguate the alternative solutions additional external constraints as well as optimization criteria could be employed.
doi:10.1186/1471-2105-13-S19-S6
PMCID: PMC3526900
25.  Phylogenomic Analysis of Marine Roseobacters 
PLoS ONE  2010;5(7):e11604.
Background
Members of the Roseobacter clade which play a key role in the biogeochemical cycles of the ocean are diverse and abundant, comprising 10–25% of the bacterioplankton in most marine surface waters. The rapid accumulation of whole-genome sequence data for the Roseobacter clade allows us to obtain a clearer picture of its evolution.
Methodology/Principal Findings
In this study about 1,200 likely orthologous protein families were identified from 17 Roseobacter bacteria genomes. Functional annotations for these genes are provided by iProClass. Phylogenetic trees were constructed for each gene using maximum likelihood (ML) and neighbor joining (NJ). Putative organismal phylogenetic trees were built with phylogenomic methods. These trees were compared and analyzed using principal coordinates analysis (PCoA), approximately unbiased (AU) and Shimodaira–Hasegawa (SH) tests. A core set of 694 genes with vertical descent signal that are resistant to horizontal gene transfer (HGT) is used to reconstruct a robust organismal phylogeny. In addition, we also discovered the most likely 109 HGT genes. The core set contains genes that encode ribosomal apparatus, ABC transporters and chaperones often found in the environmental metagenomic and metatranscriptomic data. These genes in the core set are spread out uniformly among the various functional classes and biological processes.
Conclusions/Significance
Here we report a new multigene-derived phylogenetic tree of the Roseobacter clade. Of particular interest is the HGT of eleven genes involved in vitamin B12 synthesis as well as key enzynmes for dimethylsulfoniopropionate (DMSP) degradation. These aquired genes are essential for the growth of Roseobacters and their eukaryotic partners.
doi:10.1371/journal.pone.0011604
PMCID: PMC2904699  PMID: 20657646

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