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1.  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.
PMCID: PMC3307119  PMID: 22332236
2.  Speeding up all-against-all protein comparisons while maintaining sensitivity by considering subsequence-level homology 
PeerJ  2014;2:e607.
Orthology inference and other sequence analyses across multiple genomes typically start by performing exhaustive pairwise sequence comparisons, a process referred to as “all-against-all”. As this process scales quadratically in terms of the number of sequences analysed, this step can become a bottleneck, thus limiting the number of genomes that can be simultaneously analysed. Here, we explored ways of speeding-up the all-against-all step while maintaining its sensitivity. By exploiting the transitivity of homology and, crucially, ensuring that homology is defined in terms of consistent protein subsequences, our proof-of-concept resulted in a 4× speedup while recovering >99.6% of all homologs identified by the full all-against-all procedure on empirical sequences sets. In comparison, state-of-the-art k-mer approaches are orders of magnitude faster but only recover 3–14% of all homologous pairs. We also outline ideas to further improve the speed and recall of the new approach. An open source implementation is provided as part of the OMA standalone software at
PMCID: PMC4193403  PMID: 25320677
All-against-all; Sequence alignment; Homology; Orthology; Smith–Waterman
3.  Big data and other challenges in the quest for orthologs 
Bioinformatics  2014;30(21):2993-2998.
Given the rapid increase of species with a sequenced genome, the need to identify orthologous genes between them has emerged as a central bioinformatics task. Many different methods exist for orthology detection, which makes it difficult to decide which one to choose for a particular application.
Here, we review the latest developments and issues in the orthology field, and summarize the most recent results reported at the third ‘Quest for Orthologs’ meeting. We focus on community efforts such as the adoption of reference proteomes, standard file formats and benchmarking. Progress in these areas is good, and they are already beneficial to both orthology consumers and providers. However, a major current issue is that the massive increase in complete proteomes poses computational challenges to many of the ortholog database providers, as most orthology inference algorithms scale at least quadratically with the number of proteomes.
The Quest for Orthologs consortium is an open community with a number of working groups that join efforts to enhance various aspects of orthology analysis, such as defining standard formats and datasets, documenting community resources and benchmarking.
Availability and implementation: All such materials are available at
Contact: or
PMCID: PMC4201156  PMID: 25064571
4.  Global regulatory architecture of human, mouse and rat tissue transcriptomes 
BMC Genomics  2013;14:716.
Predicting molecular responses in human by extrapolating results from model organisms requires a precise understanding of the architecture and regulation of biological mechanisms across species.
Here, we present a large-scale comparative analysis of organ and tissue transcriptomes involving the three mammalian species human, mouse and rat. To this end, we created a unique, highly standardized compendium of tissue expression. Representative tissue specific datasets were aggregated from more than 33,900 Affymetrix expression microarrays. For each organism, we created two expression datasets covering over 55 distinct tissue types with curated data from two independent microarray platforms. Principal component analysis (PCA) revealed that the tissue-specific architecture of transcriptomes is highly conserved between human, mouse and rat. Moreover, tissues with related biological function clustered tightly together, even if the underlying data originated from different labs and experimental settings. Overall, the expression variance caused by tissue type was approximately 10 times higher than the variance caused by perturbations or diseases, except for a subset of cancers and chemicals. Pairs of gene orthologs exhibited higher expression correlation between mouse and rat than with human. Finally, we show evidence that tissue expression profiles, if combined with sequence similarity, can improve the correct assignment of functionally related homologs across species.
The results demonstrate that tissue-specific regulation is the main determinant of transcriptome composition and is highly conserved across mammalian species.
PMCID: PMC4008137  PMID: 24138449
5.  Bidirectional Best Hits Miss Many Orthologs in Duplication-Rich Clades such as Plants and Animals 
Genome Biology and Evolution  2013;5(10):1800-1806.
Bidirectional best hits (BBH), which entails identifying the pairs of genes in two different genomes that are more similar to each other than either is to any other gene in the other genome, is a simple and widely used method to infer orthology. A recent study has analyzed the link between BBH and orthology in bacteria and archaea and concluded that, given the very high consistency in BBH they observed among triplets of neighboring genes, a high proportion of BBH are likely to be bona fide orthologs. However, limited by their analysis setup, the previous study could not easily test the reverse question: which proportion of orthologs are BBH? In this follow-up study, we consider this question in theory and answer it based on conceptual arguments, simulated data, and real biological data from all three domains of life. Our analyses corroborate the findings of the previous study, but also show that because of the high rate of gene duplication in plants and animals, as much as 60% of orthologous relations are missed by the BBH criterion.
PMCID: PMC3814191  PMID: 24013106
orthology; bidirectional best hit; reciprocal best hit; comparative genomics; evolutionary relationships; in-paralogy
6.  Toward practical high-capacity low-maintenance storage of digital information in synthesised DNA 
Nature  2013;494(7435):77-80.
The shift to digital systems for the creation, transmission and storage of information has led to increasing complexity in archiving, requiring active, ongoing maintenance of the digital media. DNA is an attractive target for information storage1 because of its capacity for high density information encoding, longevity under easily-achieved conditions2–4 and proven track record as an information bearer. Previous DNA-based information storage approaches have encoded only trivial amounts of information5–7 or were not amenable to scaling-up8, and used no robust error-correction and lacked examination of their cost-efficiency for large-scale information archival9. Here we describe a scalable method that can reliably store more information than has been handled before. We encoded computer files totalling 739 kB of hard disk storage and with an estimated Shannon information10 of 5.2 × 106 bits into a DNA code, synthesised this DNA, sequenced it and reconstructed the original files with 100% accuracy. Theoretical analysis indicates that our DNA-storage scheme scales far beyond current global information volumes. These results demonstrate DNA-storage to be a realistic technology for large-scale digital archiving that may already be cost-effective for low access, multi-century-long archiving tasks. Within a decade, as costs fall rapidly under realistic scenarios for technological advances, it may be cost-effective for sub-50-year archival.
PMCID: PMC3672958  PMID: 23354052
7.  The Impact of Gene Duplication, Insertion, Deletion, Lateral Gene Transfer and Sequencing Error on Orthology Inference: A Simulation Study 
PLoS ONE  2013;8(2):e56925.
The identification of orthologous genes, a prerequisite for numerous analyses in comparative and functional genomics, is commonly performed computationally from protein sequences. Several previous studies have compared the accuracy of orthology inference methods, but simulated data has not typically been considered in cross-method assessment studies. Yet, while dependent on model assumptions, simulation-based benchmarking offers unique advantages: contrary to empirical data, all aspects of simulated data are known with certainty. Furthermore, the flexibility of simulation makes it possible to investigate performance factors in isolation of one another.
Here, we use simulated data to dissect the performance of six methods for orthology inference available as standalone software packages (Inparanoid, OMA, OrthoInspector, OrthoMCL, QuartetS, SPIMAP) as well as two generic approaches (bidirectional best hit and reciprocal smallest distance). We investigate the impact of various evolutionary forces (gene duplication, insertion, deletion, and lateral gene transfer) and technological artefacts (ambiguous sequences) on orthology inference. We show that while gene duplication/loss and insertion/deletion are well handled by most methods (albeit for different trade-offs of precision and recall), lateral gene transfer disrupts all methods. As for ambiguous sequences, which might result from poor sequencing, assembly, or genome annotation, we show that they affect alignment score-based orthology methods more strongly than their distance-based counterparts.
PMCID: PMC3581572  PMID: 23451112
8.  Inferring Hierarchical Orthologous Groups from Orthologous Gene Pairs 
PLoS ONE  2013;8(1):e53786.
Hierarchical orthologous groups are defined as sets of genes that have descended from a single common ancestor within a taxonomic range of interest. Identifying such groups is useful in a wide range of contexts, including inference of gene function, study of gene evolution dynamics and comparative genomics. Hierarchical orthologous groups can be derived from reconciled gene/species trees but, this being a computationally costly procedure, many phylogenomic databases work on the basis of pairwise gene comparisons instead (“graph-based” approach). To our knowledge, there is only one published algorithm for graph-based hierarchical group inference, but both its theoretical justification and performance in practice are as of yet largely uncharacterised. We establish a formal correspondence between the orthology graph and hierarchical orthologous groups. Based on that, we devise GETHOGs (“Graph-based Efficient Technique for Hierarchical Orthologous Groups”), a novel algorithm to infer hierarchical groups directly from the orthology graph, thus without needing gene tree inference nor gene/species tree reconciliation. GETHOGs is shown to correctly reconstruct hierarchical orthologous groups when applied to perfect input, and several extensions with stringency parameters are provided to deal with imperfect input data. We demonstrate its competitiveness using both simulated and empirical data. GETHOGs is implemented as a part of the freely-available OMA standalone package ( Furthermore, hierarchical groups inferred by GETHOGs (“OMA HOGs”) on >1,000 genomes can be interactively queried via the OMA browser (
PMCID: PMC3544860  PMID: 23342000
9.  Approximate Bayesian Computation 
PLoS Computational Biology  2013;9(1):e1002803.
Approximate Bayesian computation (ABC) constitutes a class of computational methods rooted in Bayesian statistics. In all model-based statistical inference, the likelihood function is of central importance, since it expresses the probability of the observed data under a particular statistical model, and thus quantifies the support data lend to particular values of parameters and to choices among different models. For simple models, an analytical formula for the likelihood function can typically be derived. However, for more complex models, an analytical formula might be elusive or the likelihood function might be computationally very costly to evaluate. ABC methods bypass the evaluation of the likelihood function. In this way, ABC methods widen the realm of models for which statistical inference can be considered. ABC methods are mathematically well-founded, but they inevitably make assumptions and approximations whose impact needs to be carefully assessed. Furthermore, the wider application domain of ABC exacerbates the challenges of parameter estimation and model selection. ABC has rapidly gained popularity over the last years and in particular for the analysis of complex problems arising in biological sciences (e.g., in population genetics, ecology, epidemiology, and systems biology).
PMCID: PMC3547661  PMID: 23341757
10.  Quality of Computationally Inferred Gene Ontology Annotations 
PLoS Computational Biology  2012;8(5):e1002533.
Gene Ontology (GO) has established itself as the undisputed standard for protein function annotation. Most annotations are inferred electronically, i.e. without individual curator supervision, but they are widely considered unreliable. At the same time, we crucially depend on those automated annotations, as most newly sequenced genomes are non-model organisms. Here, we introduce a methodology to systematically and quantitatively evaluate electronic annotations. By exploiting changes in successive releases of the UniProt Gene Ontology Annotation database, we assessed the quality of electronic annotations in terms of specificity, reliability, and coverage. Overall, we not only found that electronic annotations have significantly improved in recent years, but also that their reliability now rivals that of annotations inferred by curators when they use evidence other than experiments from primary literature. This work provides the means to identify the subset of electronic annotations that can be relied upon—an important outcome given that >98% of all annotations are inferred without direct curation.
Author Summary
In the UniProt Gene Ontology Annotation database, the largest repository of functional annotations, over 98% of all function annotations are inferred in silico, without curator oversight. Yet these “electronic GO annotations” are generally perceived as unreliable; they are disregarded in many studies. In this article, we introduce novel methodology to systematically evaluate the quality of electronic annotations. We then provide the first comprehensive assessment of the reliability of electronic GO annotations. Overall, we found that electronic annotations are more reliable than generally believed, to an extent that they are competitive with annotations inferred by curators when they use evidence other than experiments from primary literature. But we also report significant variations among inference methods, types of annotations, and organisms. This work provides guidance for Gene Ontology users and lays the foundations for improving computational approaches to GO function inference.
PMCID: PMC3364937  PMID: 22693439
11.  Resolving the Ortholog Conjecture: Orthologs Tend to Be Weakly, but Significantly, More Similar in Function than Paralogs 
PLoS Computational Biology  2012;8(5):e1002514.
The function of most proteins is not determined experimentally, but is extrapolated from homologs. According to the “ortholog conjecture”, or standard model of phylogenomics, protein function changes rapidly after duplication, leading to paralogs with different functions, while orthologs retain the ancestral function. We report here that a comparison of experimentally supported functional annotations among homologs from 13 genomes mostly supports this model. We show that to analyze GO annotation effectively, several confounding factors need to be controlled: authorship bias, variation of GO term frequency among species, variation of background similarity among species pairs, and propagated annotation bias. After controlling for these biases, we observe that orthologs have generally more similar functional annotations than paralogs. This is especially strong for sub-cellular localization. We observe only a weak decrease in functional similarity with increasing sequence divergence. These findings hold over a large diversity of species; notably orthologs from model organisms such as E. coli, yeast or mouse have conserved function with human proteins.
Author Summary
To infer the function of an unknown gene, possibly the most effective way is to identify a well-characterized evolutionarily related gene, and assume that they have both kept their ancestral function. If several such homologs are available, all else being equal, it has long been assumed that those that diverged by speciation (“ortholog”) are functionally closer than those that diverged by duplication (“paralogs”); thus function is more reliably inferred from the former. But despite its prevalence, this model mostly rests on first principles, as for the longest time we have not had sufficient data to test it empirically. Recently, some studies began investigating this question and have cast doubt on the validity of this model. Here, we show that by considering a wide range of organisms and data, and, crucially, by correcting for several easily overlooked biases affecting functional annotations, the standard model is corroborated by the presently available experimental data.
PMCID: PMC3355068  PMID: 22615551
12.  ALF—A Simulation Framework for Genome Evolution 
Molecular Biology and Evolution  2011;29(4):1115-1123.
In computational evolutionary biology, verification and benchmarking is a challenging task because the evolutionary history of studied biological entities is usually not known. Computer programs for simulating sequence evolution in silico have shown to be viable test beds for the verification of newly developed methods and to compare different algorithms. However, current simulation packages tend to focus either on gene-level aspects of genome evolution such as character substitutions and insertions and deletions (indels) or on genome-level aspects such as genome rearrangement and speciation events. Here, we introduce Artificial Life Framework (ALF), which aims at simulating the entire range of evolutionary forces that act on genomes: nucleotide, codon, or amino acid substitution (under simple or mixture models), indels, GC-content amelioration, gene duplication, gene loss, gene fusion, gene fission, genome rearrangement, lateral gene transfer (LGT), or speciation. The other distinctive feature of ALF is its user-friendly yet powerful web interface. We illustrate the utility of ALF with two possible applications: 1) we reanalyze data from a study of selection after globin gene duplication and test the statistical significance of the original conclusions and 2) we demonstrate that LGT can dramatically decrease the accuracy of two well-established orthology inference methods. ALF is available as a stand-alone application or via a web interface at
PMCID: PMC3341827  PMID: 22160766
simulation; genome evolution; codon models; indel; lateral gene transfer; GC-content amelioration
13.  Conceptual framework and pilot study to benchmark phylogenomic databases based on reference gene trees 
Briefings in Bioinformatics  2011;12(5):423-435.
Phylogenomic databases provide orthology predictions for species with fully sequenced genomes. Although the goal seems well-defined, the content of these databases differs greatly. Seven ortholog databases (Ensembl Compara, eggNOG, HOGENOM, InParanoid, OMA, OrthoDB, Panther) were compared on the basis of reference trees. For three well-conserved protein families, we observed a generally high specificity of orthology assignments for these databases. We show that differences in the completeness of predicted gene relationships and in the phylogenetic information are, for the great majority, not due to the methods used, but to differences in the underlying database concepts. According to our metrics, none of the databases provides a fully correct and comprehensive protein classification. Our results provide a framework for meaningful and systematic comparisons of phylogenomic databases. In the future, a sustainable set of ‘Gold standard’ phylogenetic trees could provide a robust method for phylogenomic databases to assess their current quality status, measure changes following new database releases and diagnose improvements subsequent to an upgrade of the analysis procedure.
PMCID: PMC3178055  PMID: 21737420
conceptual comparison; phylogenomic databases; quality assessment; reference gene trees
14.  Comparative genomics approach to detecting split-coding regions in a low-coverage genome: lessons from the chimaera Callorhinchus milii (Holocephali, Chondrichthyes) 
Briefings in Bioinformatics  2011;12(5):474-484.
Recent development of deep sequencing technologies has facilitated de novo genome sequencing projects, now conducted even by individual laboratories. However, this will yield more and more genome sequences that are not well assembled, and will hinder thorough annotation when no closely related reference genome is available. One of the challenging issues is the identification of protein-coding sequences split into multiple unassembled genomic segments, which can confound orthology assignment and various laboratory experiments requiring the identification of individual genes. In this study, using the genome of a cartilaginous fish, Callorhinchus milii, as test case, we performed gene prediction using a model specifically trained for this genome. We implemented an algorithm, designated ESPRIT, to identify possible linkages between multiple protein-coding portions derived from a single genomic locus split into multiple unassembled genomic segments. We developed a validation framework based on an artificially fragmented human genome, improvements between early and recent mouse genome assemblies, comparison with experimentally validated sequences from GenBank, and phylogenetic analyses. Our strategy provided insights into practical solutions for efficient annotation of only partially sequenced (low-coverage) genomes. To our knowledge, our study is the first formulation of a method to link unassembled genomic segments based on proteomes of relatively distantly related species as references.
PMCID: PMC3178057  PMID: 21712341
Chondrichthyes; trained gene prediction; next generation sequencing; genome assembly; orthology
15.  Survey of Branch Support Methods Demonstrates Accuracy, Power, and Robustness of Fast Likelihood-based Approximation Schemes 
Systematic Biology  2011;60(5):685-699.
Phylogenetic inference and evaluating support for inferred relationships is at the core of many studies testing evolutionary hypotheses. Despite the popularity of nonparametric bootstrap frequencies and Bayesian posterior probabilities, the interpretation of these measures of tree branch support remains a source of discussion. Furthermore, both methods are computationally expensive and become prohibitive for large data sets. Recent fast approximate likelihood-based measures of branch supports (approximate likelihood ratio test [aLRT] and Shimodaira–Hasegawa [SH]-aLRT) provide a compelling alternative to these slower conventional methods, offering not only speed advantages but also excellent levels of accuracy and power. Here we propose an additional method: a Bayesian-like transformation of aLRT (aBayes). Considering both probabilistic and frequentist frameworks, we compare the performance of the three fast likelihood-based methods with the standard bootstrap (SBS), the Bayesian approach, and the recently introduced rapid bootstrap. Our simulations and real data analyses show that with moderate model violations, all tests are sufficiently accurate, but aLRT and aBayes offer the highest statistical power and are very fast. With severe model violations aLRT, aBayes and Bayesian posteriors can produce elevated false-positive rates. With data sets for which such violation can be detected, we recommend using SH-aLRT, the nonparametric version of aLRT based on a procedure similar to the Shimodaira–Hasegawa tree selection. In general, the SBS seems to be excessively conservative and is much slower than our approximate likelihood-based methods.
PMCID: PMC3158332  PMID: 21540409
Accuracy; aLRT; branch support methods; evolution; model violation; phylogenetic inference; power; SH-aLRT
16.  The what, where, how and why of gene ontology—a primer for bioinformaticians 
Briefings in Bioinformatics  2011;12(6):723-735.
With high-throughput technologies providing vast amounts of data, it has become more important to provide systematic, quality annotations. The Gene Ontology (GO) project is the largest resource for cataloguing gene function. Nonetheless, its use is not yet ubiquitous and is still fraught with pitfalls. In this review, we provide a short primer to the GO for bioinformaticians. We summarize important aspects of the structure of the ontology, describe sources and types of functional annotations, survey measures of GO annotation similarity, review typical uses of GO and discuss other important considerations pertaining to the use of GO in bioinformatics applications.
PMCID: PMC3220872  PMID: 21330331
gene ontology; gene annotation; semantic similarity; gene function; function prediction
17.  Base-calling for next-generation sequencing platforms 
Briefings in Bioinformatics  2011;12(5):489-497.
Next-generation sequencing platforms are dramatically reducing the cost of DNA sequencing. With these technologies, bases are inferred from light intensity signals, a process commonly referred to as base-calling. Thus, understanding and improving the quality of sequence data generated using these approaches are of high interest. Recently, a number of papers have characterized the biases associated with base-calling and proposed methodological improvements. In this review, we summarize recent development of base-calling approaches for the Illumina and Roche 454 sequencing platforms.
PMCID: PMC3178052  PMID: 21245079
Base-calling; next generation sequencing; deep sequencing; illumina/solexa; roche/454; bustard
18.  OMA 2011: orthology inference among 1000 complete genomes 
Nucleic Acids Research  2010;39(Database issue):D289-D294.
OMA (Orthologous MAtrix) is a database that identifies orthologs among publicly available, complete genomes. Initiated in 2004, the project is at its 11th release. It now includes 1000 genomes, making it one of the largest resources of its kind. Here, we describe recent developments in terms of species covered; the algorithmic pipeline—in particular regarding the treatment of alternative splicing, and new features of the web (OMA Browser) and programming interface (SOAP API). In the second part, we review the various representations provided by OMA and their typical applications. The database is publicly accessible at
PMCID: PMC3013747  PMID: 21113020
19.  Phylogenetic assessment of alignments reveals neglected tree signal in gaps 
Genome Biology  2010;11(4):R37.
Tree-based tests of alignment methods enable the evaluation of the effect of gap placement on the inference of phylogenetic relationships.
The alignment of biological sequences is of chief importance to most evolutionary and comparative genomics studies, yet the two main approaches used to assess alignment accuracy have flaws: reference alignments are derived from the biased sample of proteins with known structure, and simulated data lack realism.
Here, we introduce tree-based tests of alignment accuracy, which not only use large and representative samples of real biological data, but also enable the evaluation of the effect of gap placement on phylogenetic inference. We show that (i) the current belief that consistency-based alignments outperform scoring matrix-based alignments is misguided; (ii) gaps carry substantial phylogenetic signal, but are poorly exploited by most alignment and tree building programs; (iii) even so, excluding gaps and variable regions is detrimental; (iv) disagreement among alignment programs says little about the accuracy of resulting trees.
This study provides the broad community relying on sequence alignment with important practical recommendations, sets superior standards for assessing alignment accuracy, and paves the way for the development of phylogenetic inference methods of significantly higher resolution.
PMCID: PMC2884540  PMID: 20370897
20.  Evaluating the robustness of phylogenetic methods to among-site variability in substitution processes 
Computer simulations provide a flexible method for assessing the power and robustness of phylogenetic inference methods. Unfortunately, simulated data are often obviously atypical of data encountered in studies of molecular evolution. Unrealistic simulations can lead to conclusions that are irrelevant to real-data analyses or can provide a biased view of which methods perform well. Here, we present a software tool designed to generate data under a complex codon model that allows each residue in the protein sequence to have a different set of equilibrium amino acid frequencies. The software can obtain maximum-likelihood estimates of the parameters of the Halpern and Bruno model from empirical data and a fixed tree; given an arbitrary tree and a fixed set of parameters, the software can then simulate artificial datasets. We present the results of a simulation experiment using randomly generated tree shapes and substitution parameters estimated from 1610 mammalian cytochrome b sequences. We tested tree inference at the amino acid, nucleotide and codon levels and under parsimony, maximum-likelihood, Bayesian and distance criteria (for a total of more than 650 analyses on each dataset). Based on these simulations, nucleotide-level analyses seem to be more accurate than amino acid and codon analyses. The performance of distance-based phylogenetic methods appears to be quite sensitive to the choice of model and the form of rate heterogeneity used. Further studies are needed to assess the generality of these conclusions. For example, fitting parameters of the Halpern Bruno model to sequences from other genes will reveal the extent to which our conclusions were influenced by the choice of cytochrome b. Incorporating codon bias and more sources heterogeneity into the simulator will be crucial to determining whether the current results are caused by a bias in the current simulation study in favour of nucleotide analyses.
PMCID: PMC2607409  PMID: 18852108
simulation; phylogenetic inference; codon model; mixture model; partitioned model; RY coding
21.  Joining forces in the quest for orthologs 
Genome Biology  2009;10(9):403.
Building momentum to coordinate and leverage community orthology prediction resources.
Better orthology-prediction resources would be beneficial for the whole biological community. A recent meeting discussed how to coordinate and leverage current efforts.
PMCID: PMC2768974  PMID: 19785718
22.  Algorithm of OMA for large-scale orthology inference 
BMC Bioinformatics  2009;10:220.
Since the publication of our article (Roth, Gonnet, and Dessimoz: BMC Bioinformatics 2008 9: 518), we have noticed several errors, which we correct in the following.
PMCID: PMC2729779
23.  The Microbe browser for comparative genomics 
Nucleic Acids Research  2009;37(Web Server issue):W296-W299.
The Microbe browser is a web server providing comparative microbial genomics data. It offers comprehensive, integrated data from GenBank, RefSeq, UniProt, InterPro, Gene Ontology and the Orthologs Matrix Project (OMA) database, displayed along with gene predictions from five software packages. The Microbe browser is daily updated from the source databases and includes all completely sequenced bacterial and archaeal genomes. The data are displayed in an easy-to-use, interactive website based on Ensembl software. The Microbe browser is available at Programmatic access is available through the OMA application programming interface (API) at
PMCID: PMC2703916  PMID: 19406928
24.  Phylogenetic and Functional Assessment of Orthologs Inference Projects and Methods 
PLoS Computational Biology  2009;5(1):e1000262.
Accurate genome-wide identification of orthologs is a central problem in comparative genomics, a fact reflected by the numerous orthology identification projects developed in recent years. However, only a few reports have compared their accuracy, and indeed, several recent efforts have not yet been systematically evaluated. Furthermore, orthology is typically only assessed in terms of function conservation, despite the phylogeny-based original definition of Fitch. We collected and mapped the results of nine leading orthology projects and methods (COG, KOG, Inparanoid, OrthoMCL, Ensembl Compara, Homologene, RoundUp, EggNOG, and OMA) and two standard methods (bidirectional best-hit and reciprocal smallest distance). We systematically compared their predictions with respect to both phylogeny and function, using six different tests. This required the mapping of millions of sequences, the handling of hundreds of millions of predicted pairs of orthologs, and the computation of tens of thousands of trees. In phylogenetic analysis or in functional analysis where high specificity is required, we find that OMA and Homologene perform best. At lower functional specificity but higher coverage level, OrthoMCL outperforms Ensembl Compara, and to a lesser extent Inparanoid. Lastly, the large coverage of the recent EggNOG can be of interest to build broad functional grouping, but the method is not specific enough for phylogenetic or detailed function analyses. In terms of general methodology, we observe that the more sophisticated tree reconstruction/reconciliation approach of Ensembl Compara was at times outperformed by pairwise comparison approaches, even in phylogenetic tests. Furthermore, we show that standard bidirectional best-hit often outperforms projects with more complex algorithms. First, the present study provides guidance for the broad community of orthology data users as to which database best suits their needs. Second, it introduces new methodology to verify orthology. And third, it sets performance standards for current and future approaches.
Author Summary
The identification of orthologs, pairs of homologous genes in different species that started diverging through speciation events, is a central problem in genomics with applications in many research areas, including comparative genomics, phylogenetics, protein function annotation, and genome rearrangement. An increasing number of projects aim at inferring orthologs from complete genomes, but little is known about their relative accuracy or coverage. Because the exact evolutionary history of entire genomes remains largely unknown, predictions can only be validated indirectly, that is, in the context of the different applications of orthology. The few comparison studies published so far have asssessed orthology exclusively from the expectation that orthologs have conserved protein function. In the present work, we introduce methodology to verify orthology in terms of phylogeny and perform a comprehensive comparison of nine leading ortholog inference projects and two methods using both phylogenetic and functional tests. The results show large variations among the different projects in terms of performances, which indicates that the choice of orthology database can have a strong impact on any downstream analysis.
PMCID: PMC2612752  PMID: 19148271
25.  Algorithm of OMA for large-scale orthology inference 
BMC Bioinformatics  2008;9:518.
OMA is a project that aims to identify orthologs within publicly available, complete genomes. With 657 genomes analyzed to date, OMA is one of the largest projects of its kind.
The algorithm of OMA improves upon standard bidirectional best-hit approach in several respects: it uses evolutionary distances instead of scores, considers distance inference uncertainty, includes many-to-many orthologous relations, and accounts for differential gene losses. Herein, we describe in detail the algorithm for inference of orthology and provide the rationale for parameter selection through multiple tests.
OMA contains several novel improvement ideas for orthology inference and provides a unique dataset of large-scale orthology assignments.
PMCID: PMC2639434  PMID: 19055798

Results 1-25 (29)