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1.  Evolution of the Animal Apoptosis Network 
The number of available eukaryotic genomes has expanded to the point where we can evaluate the complete evolutionary history of many cellular processes. Such analyses for the apoptosis regulatory networks suggest that this network already existed in the ancestor of the entire animal kingdom (Metazoa) in a form more complex than in some popular animal model organisms. This supports the growing realization that regulatory networks do not necessarily evolve from simple to complex and that the relative simplicity of these networks in nematodes and insects does not represent an ancestral state, but is the result of secondary simplifications. Network evolution is not a process of monotonous increase in complexity, but a dynamic process that includes lineage-specific gene losses and expansions, protein domain reshuffling, and emergence/reemergence of similar protein architectures by parallel evolution. Studying the evolution of such networks is a challenging yet interesting subject for research and investigation, and such studies on the apoptosis networks provide us with interesting hints of how these networks, critical in so many human diseases, have developed.
Regulatory networks do not necessarily evolve from simple to complex. The apoptosis machinery may have been more complex in ancestral organisms than it is in modern model organisms (e.g., C. elegans).
PMCID: PMC3578353  PMID: 23457257
2.  Phylogenomic analysis of glycogen branching and debranching enzymatic duo 
Branched polymers of glucose are universally used for energy storage in cells, taking the form of glycogen in animals, fungi, Bacteria, and Archaea, and of amylopectin in plants. Some enzymes involved in glycogen and amylopectin metabolism are similarly conserved in all forms of life, but some, interestingly, are not. In this paper we focus on the phylogeny of glycogen branching and debranching enzymes, respectively involved in introducing and removing of the α(1–6) bonds in glucose polymers, bonds that provide the unique branching structure to glucose polymers.
We performed a large-scale phylogenomic analysis of branching and debranching enzymes in over 400 completely sequenced genomes, including more than 200 from eukaryotes. We show that branching and debranching enzymes can be found in all kingdoms of life, including all major groups of eukaryotes, and thus were likely to have been present in the last universal common ancestor (LUCA) but have been lost in seemingly random fashion in numerous single-celled eukaryotes. We also show how animal branching and debranching enzymes evolved from their LUCA ancestors by acquiring additional domains. Furthermore, we show that enzymes commonly perceived as orthologous, such as human branching enzyme GBE1 and E. coli branching enzyme GlgB, are in fact related by a gene duplication and consequently paralogous.
Despite being usually associated with animal liver glycogen and plant starch, energy storage in the form of branched glucose polymers is clearly an ancient process and has probably been present in the last universal common ancestor of all present life. The evolution of the enzymes enabling this form of energy storage is more complex than previously thought and illustrates the need for explicit phylogenomic analysis in the study of even seemingly “simple” metabolic enzymes. Patterns of conservation in the evolution of the glycogen/starch branching and debranching enzymes hint at some as yet unknown mechanisms, as mutations disrupting these patterns lead to a variety of genetic diseases in humans and other mammals.
PMCID: PMC4236520  PMID: 25148856
Glycogen; Starch; Branching; Debranching; Glycogen storage disease; AGL; GBE1; GlgB; GlgX; TreX
3.  Divergent evolution of protein conformational dynamics in dihydrofolate reductase 
Nature structural & molecular biology  2013;20(11):10.1038/nsmb.2676.
Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, E. coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics, following a pattern of divergent evolution that is tuned by the cellular environment.
PMCID: PMC3823643  PMID: 24077226
4.  Structural genomics analysis of uncharacterized protein families overrepresented in human gut bacteria identifies a novel glycoside hydrolase 
BMC Bioinformatics  2014;15:112.
Bacteroides spp. form a significant part of our gut microbiome and are well known for optimized metabolism of diverse polysaccharides. Initial analysis of the archetypal Bacteroides thetaiotaomicron genome identified 172 glycosyl hydrolases and a large number of uncharacterized proteins associated with polysaccharide metabolism.
BT_1012 from Bacteroides thetaiotaomicron VPI-5482 is a protein of unknown function and a member of a large protein family consisting entirely of uncharacterized proteins. Initial sequence analysis predicted that this protein has two domains, one on the N- and one on the C-terminal. A PSI-BLAST search found over 150 full length and over 90 half size homologs consisting only of the N-terminal domain. The experimentally determined three-dimensional structure of the BT_1012 protein confirms its two-domain architecture and structural analysis of both domains suggests their specific functions. The N-terminal domain is a putative catalytic domain with significant similarity to known glycoside hydrolases, the C-terminal domain has a beta-sandwich fold typically found in C-terminal domains of other glycosyl hydrolases, however these domains are typically involved in substrate binding. We describe the structure of the BT_1012 protein and discuss its sequence-structure relationship and their possible functional implications.
Structural and sequence analyses of the BT_1012 protein identifies it as a glycosyl hydrolase, expanding an already impressive catalog of enzymes involved in polysaccharide metabolism in Bacteroides spp. Based on this we have renamed the Pfam families representing the two domains found in the BT_1012 protein, PF13204 and PF12904, as putative glycoside hydrolase and glycoside hydrolase-associated C-terminal domain respectively.
PMCID: PMC4032388  PMID: 24742328
Glycoside hydrolase; Carbohydrate metabolism; 3D structure; Protein family; Protein function prediction; Domain of unknown function; DUF
5.  BioHackathon series in 2011 and 2012: penetration of ontology and linked data in life science domains 
Katayama, Toshiaki | Wilkinson, Mark D | Aoki-Kinoshita, Kiyoko F | Kawashima, Shuichi | Yamamoto, Yasunori | Yamaguchi, Atsuko | Okamoto, Shinobu | Kawano, Shin | Kim, Jin-Dong | Wang, Yue | Wu, Hongyan | Kano, Yoshinobu | Ono, Hiromasa | Bono, Hidemasa | Kocbek, Simon | Aerts, Jan | Akune, Yukie | Antezana, Erick | Arakawa, Kazuharu | Aranda, Bruno | Baran, Joachim | Bolleman, Jerven | Bonnal, Raoul JP | Buttigieg, Pier Luigi | Campbell, Matthew P | Chen, Yi-an | Chiba, Hirokazu | Cock, Peter JA | Cohen, K Bretonnel | Constantin, Alexandru | Duck, Geraint | Dumontier, Michel | Fujisawa, Takatomo | Fujiwara, Toyofumi | Goto, Naohisa | Hoehndorf, Robert | Igarashi, Yoshinobu | Itaya, Hidetoshi | Ito, Maori | Iwasaki, Wataru | Kalaš, Matúš | Katoda, Takeo | Kim, Taehong | Kokubu, Anna | Komiyama, Yusuke | Kotera, Masaaki | Laibe, Camille | Lapp, Hilmar | Lütteke, Thomas | Marshall, M Scott | Mori, Takaaki | Mori, Hiroshi | Morita, Mizuki | Murakami, Katsuhiko | Nakao, Mitsuteru | Narimatsu, Hisashi | Nishide, Hiroyo | Nishimura, Yosuke | Nystrom-Persson, Johan | Ogishima, Soichi | Okamura, Yasunobu | Okuda, Shujiro | Oshita, Kazuki | Packer, Nicki H | Prins, Pjotr | Ranzinger, Rene | Rocca-Serra, Philippe | Sansone, Susanna | Sawaki, Hiromichi | Shin, Sung-Ho | Splendiani, Andrea | Strozzi, Francesco | Tadaka, Shu | Toukach, Philip | Uchiyama, Ikuo | Umezaki, Masahito | Vos, Rutger | Whetzel, Patricia L | Yamada, Issaku | Yamasaki, Chisato | Yamashita, Riu | York, William S | Zmasek, Christian M | Kawamoto, Shoko | Takagi, Toshihisa
The application of semantic technologies to the integration of biological data and the interoperability of bioinformatics analysis and visualization tools has been the common theme of a series of annual BioHackathons hosted in Japan for the past five years. Here we provide a review of the activities and outcomes from the BioHackathons held in 2011 in Kyoto and 2012 in Toyama. In order to efficiently implement semantic technologies in the life sciences, participants formed various sub-groups and worked on the following topics: Resource Description Framework (RDF) models for specific domains, text mining of the literature, ontology development, essential metadata for biological databases, platforms to enable efficient Semantic Web technology development and interoperability, and the development of applications for Semantic Web data. In this review, we briefly introduce the themes covered by these sub-groups. The observations made, conclusions drawn, and software development projects that emerged from these activities are discussed.
PMCID: PMC3978116  PMID: 24495517
BioHackathon; Bioinformatics; Semantic Web; Web services; Ontology; Visualization; Knowledge representation; Databases; Semantic interoperability; Data models; Data sharing; Data integration
6.  aLeaves facilitates on-demand exploration of metazoan gene family trees on MAFFT sequence alignment server with enhanced interactivity 
Nucleic Acids Research  2013;41(Web Server issue):W22-W28.
We report a new web server, aLeaves (, for homologue collection from diverse animal genomes. In molecular comparative studies involving multiple species, orthology identification is the basis on which most subsequent biological analyses rely. It can be achieved most accurately by explicit phylogenetic inference. More and more species are subjected to large-scale sequencing, but the resultant resources are scattered in independent project-based, and multi-species, but separate, web sites. This complicates data access and is becoming a serious barrier to the comprehensiveness of molecular phylogenetic analysis. aLeaves, launched to overcome this difficulty, collects sequences similar to an input query sequence from various data sources. The collected sequences can be passed on to the MAFFT sequence alignment server (, which has been significantly improved in interactivity. This update enables to switch between (i) sequence selection using the Archaeopteryx tree viewer, (ii) multiple sequence alignment and (iii) tree inference. This can be performed as a loop until one reaches a sensible data set, which minimizes redundancy for better visibility and handling in phylogenetic inference while covering relevant taxa. The work flow achieved by the seamless link between aLeaves and MAFFT provides a convenient online platform to address various questions in zoology and evolutionary biology.
PMCID: PMC3692103  PMID: 23677614
7.  Phylotastic! Making tree-of-life knowledge accessible, reusable and convenient 
BMC Bioinformatics  2013;14:158.
Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great “Tree of Life” (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user’s needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces.
With the aim of building such a “phylotastic” system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service,, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (, a website (, and a server image.
Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.
PMCID: PMC3669619  PMID: 23668630
Phylogeny; Taxonomy; Hackathon; Web services; Data reuse; Tree of life
8.  The 3rd DBCLS BioHackathon: improving life science data integration with Semantic Web technologies 
BioHackathon 2010 was the third in a series of meetings hosted by the Database Center for Life Sciences (DBCLS) in Tokyo, Japan. The overall goal of the BioHackathon series is to improve the quality and accessibility of life science research data on the Web by bringing together representatives from public databases, analytical tool providers, and cyber-infrastructure researchers to jointly tackle important challenges in the area of in silico biological research.
The theme of BioHackathon 2010 was the 'Semantic Web', and all attendees gathered with the shared goal of producing Semantic Web data from their respective resources, and/or consuming or interacting those data using their tools and interfaces. We discussed on topics including guidelines for designing semantic data and interoperability of resources. We consequently developed tools and clients for analysis and visualization.
We provide a meeting report from BioHackathon 2010, in which we describe the discussions, decisions, and breakthroughs made as we moved towards compliance with Semantic Web technologies - from source provider, through middleware, to the end-consumer.
PMCID: PMC3598643  PMID: 23398680
BioHackathon; Open source; Software; Semantic Web; Databases; Data integration; Data visualization; Web services; Interfaces
9.  This Déjà Vu Feeling—Analysis of Multidomain Protein Evolution in Eukaryotic Genomes 
PLoS Computational Biology  2012;8(11):e1002701.
Evolutionary innovation in eukaryotes and especially animals is at least partially driven by genome rearrangements and the resulting emergence of proteins with new domain combinations, and thus potentially novel functionality. Given the random nature of such rearrangements, one could expect that proteins with particularly useful multidomain combinations may have been rediscovered multiple times by parallel evolution. However, existing reports suggest a minimal role of this phenomenon in the overall evolution of eukaryotic proteomes. We assembled a collection of 172 complete eukaryotic genomes that is not only the largest, but also the most phylogenetically complete set of genomes analyzed so far. By employing a maximum parsimony approach to compare repertoires of Pfam domains and their combinations, we show that independent evolution of domain combinations is significantly more prevalent than previously thought. Our results indicate that about 25% of all currently observed domain combinations have evolved multiple times. Interestingly, this percentage is even higher for sets of domain combinations in individual species, with, for instance, 70% of the domain combinations found in the human genome having evolved independently at least once in other species. We also show that previous, much lower estimates of this rate are most likely due to the small number and biased phylogenetic distribution of the genomes analyzed. The process of independent emergence of identical domain combination is widespread, not limited to domains with specific functional categories. Besides data from large-scale analyses, we also present individual examples of independent domain combination evolution. The surprisingly large contribution of parallel evolution to the development of the domain combination repertoire in extant genomes has profound consequences for our understanding of the evolution of pathways and cellular processes in eukaryotes and for comparative functional genomics.
Author Summary
Most proteins in eukaryotes are composed of two or more domains, evolutionary independent units with (often) their own individual functions. The specific repertoire of multidomain proteins in a given species defines the topology of pathways and networks that carry out its metabolic and regulatory processes. When proteins with new domain combinations emerge by gene fusion and fission, it directly affects topology of cellular networks in this organism. To better understand the evolution of such networks we analyzed a large set of eukaryotic genomes for the evolutionary history of known domain combinations. Our analysis shows that 70% of all domain combinations present in the human genome independently appeared in at least one other eukaryotic genome. Overall, over 25% of all known multidomain architectures emerged independently several times in the history of life. The difference between a global and species specific picture can be explained by the existence of a core set of domain combinations that keeps reemerging in different species, which are accompanied by a smaller number of unique domain combinations that do not appear anywhere else.
PMCID: PMC3499355  PMID: 23166479
10.  TIR domain-containing adaptor SARM is a late addition to the ongoing microbe–host dialog 
Toll/interleukin-1 receptor (TIR) domain-containing proteins play important roles in defense against pathogens in both animals and plants, connecting the immunity signaling pathways via a chain of specific protein–protein interactions. Among them is SARM, the only TIR domain-containing adaptor that can negatively regulate TLR signaling. By extensive phylogenetic analysis, we show here that SARM is closely related to bacterial proteins with TIR domains, suggesting that this family has a different evolutionary history from other animal TIR-containing adaptors, possibly emerging via a lateral gene transfer from bacteria to animals. We also show evidence of several similar, independent transfer events, none of which, however, survived in vertebrates. An evolutionary relationship between the animal SARM adaptor and bacterial proteins with TIR domains illustrates the possible role that bacterial TIR-containing proteins play in regulating eukaryotic immune responses and how this mechanism was possibly adapted by the eukaryotes themselves.
PMCID: PMC3085110  PMID: 21110998
Toll-like receptor; host–commensal interaction; host–pathogen interaction; lateral gene transfer; commensal microflora; innate immunity
11.  Activation and Specificity of human Caspase-10 
Biochemistry  2010;49(38):8307-8315.
Two apical caspases, caspase-8 and-10, are involved in the extrinsic death receptor pathway in humans but it is mainly caspase-8 in its apoptotic and non-apoptotic functions that has been an intense research focus. In this study we concentrate on caspase-10, its mechanism of activation and the role of the inter-subunit cleavage. Our data obtained through in vitro dimerization assays strongly suggest that caspase-10 follows the proximity–induced dimerization model for apical caspases. Furthermore, we compare the specificity and activity of the wildtype protease with a mutant incapable of autoprocessing, by using positional scanning substrate analysis and cleavage of natural protein substrates. These experiments reveal a striking difference between the wildtype and the mutant, leading us to hypothesize that the single chain enzyme has restricted activity on most proteins, but high activity on the pro-apoptotic protein Bid, potentially supporting a pro-death role for both cleaved and uncleaved caspase-10.
PMCID: PMC2943529  PMID: 20795673
12.  Taking the First Steps towards a Standard for Reporting on Phylogenies: Minimal Information about a Phylogenetic Analysis (MIAPA) 
In the eight years since phylogenomics was introduced as the intersection of genomics and phylogenetics, the field has provided fundamental insights into gene function, genome history and organismal relationships. The utility of phylogenomics is growing with the increase in the number and diversity of taxa for which whole genome and large transcriptome sequence sets are being generated. We assert that the synergy between genomic and phylogenetic perspectives in comparative biology would be enhanced by the development and refinement of minimal reporting standards for phylogenetic analyses. Encouraged by the development of the Minimum Information About a Microarray Experiment (MIAME) standard, we propose a similar roadmap for the development of a Minimal Information About a Phylogenetic Analysis (MIAPA) standard. Key in the successful development and implementation of such a standard will be broad participation by developers of phylogenetic analysis software, phylogenetic database developers, practitioners of phylogenomics, and journal editors.
PMCID: PMC3167193  PMID: 16901231
13.  A Mighty Small Heart: The Cardiac Proteome of Adult Drosophila melanogaster 
PLoS ONE  2011;6(4):e18497.
Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca2+-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease.
PMCID: PMC3081823  PMID: 21541028
14.  Strong functional patterns in the evolution of eukaryotic genomes revealed by the reconstruction of ancestral protein domain repertoires 
Genome Biology  2011;12(1):R4.
Genome size and complexity, as measured by the number of genes or protein domains, is remarkably similar in most extant eukaryotes and generally exhibits no correlation with their morphological complexity. Underlying trends in the evolution of the functional content and capabilities of different eukaryotic genomes might be hidden by simultaneous gains and losses of genes.
We reconstructed the domain repertoires of putative ancestral species at major divergence points, including the last eukaryotic common ancestor (LECA). We show that, surprisingly, during eukaryotic evolution domain losses in general outnumber domain gains. Only at the base of the animal and the vertebrate sub-trees do domain gains outnumber domain losses. The observed gain/loss balance has a distinct functional bias, most strikingly seen during animal evolution, where most of the gains represent domains involved in regulation and most of the losses represent domains with metabolic functions. This trend is so consistent that clustering of genomes according to their functional profiles results in an organization similar to the tree of life. Furthermore, our results indicate that metabolic functions lost during animal evolution are likely being replaced by the metabolic capabilities of symbiotic organisms such as gut microbes.
While protein domain gains and losses are common throughout eukaryote evolution, losses oftentimes outweigh gains and lead to significant differences in functional profiles. Results presented here provide additional arguments for a complex last eukaryotic common ancestor, but also show a general trend of losses in metabolic capabilities and gain in regulatory complexity during the rise of animals.
PMCID: PMC3091302  PMID: 21241503
15.  TOPSAN: a dynamic web database for structural genomics 
Nucleic Acids Research  2010;39(Database issue):D494-D496.
The Open Protein Structure Annotation Network (TOPSAN) is a web-based collaboration platform for exploring and annotating structures determined by structural genomics efforts. Characterization of those structures presents a challenge since the majority of the proteins themselves have not yet been characterized. Responding to this challenge, the TOPSAN platform facilitates collaborative annotation and investigation via a user-friendly web-based interface pre-populated with automatically generated information. Semantic web technologies expand and enrich TOPSAN’s content through links to larger sets of related databases, and thus, enable data integration from disparate sources and data mining via conventional query languages. TOPSAN can be found at
PMCID: PMC3013775  PMID: 20961957
17.  GreenPhylDB v2.0: comparative and functional genomics in plants 
Nucleic Acids Research  2010;39(Database issue):D1095-D1102.
GreenPhylDB is a database designed for comparative and functional genomics based on complete genomes. Version 2 now contains sixteen full genomes of members of the plantae kingdom, ranging from algae to angiosperms, automatically clustered into gene families. Gene families are manually annotated and then analyzed phylogenetically in order to elucidate orthologous and paralogous relationships. The database offers various lists of gene families including plant, phylum and species specific gene families. For each gene cluster or gene family, easy access to gene composition, protein domains, publications, external links and orthologous gene predictions is provided. Web interfaces have been further developed to improve the navigation through information related to gene families. New analysis tools are also available, such as a gene family ontology browser that facilitates exploration. GreenPhylDB is a component of the South Green Bioinformatics Platform ( and is accessible at It enables comparative genomics in a broad taxonomy context to enhance the understanding of evolutionary processes and thus tends to speed up gene discovery.
PMCID: PMC3013755  PMID: 20864446
18.  The DBCLS BioHackathon: standardization and interoperability for bioinformatics web services and workflows. The DBCLS BioHackathon Consortium* 
Web services have become a key technology for bioinformatics, since life science databases are globally decentralized and the exponential increase in the amount of available data demands for efficient systems without the need to transfer entire databases for every step of an analysis. However, various incompatibilities among database resources and analysis services make it difficult to connect and integrate these into interoperable workflows. To resolve this situation, we invited domain specialists from web service providers, client software developers, Open Bio* projects, the BioMoby project and researchers of emerging areas where a standard exchange data format is not well established, for an intensive collaboration entitled the BioHackathon 2008. The meeting was hosted by the Database Center for Life Science (DBCLS) and Computational Biology Research Center (CBRC) and was held in Tokyo from February 11th to 15th, 2008. In this report we highlight the work accomplished and the common issues arisen from this event, including the standardization of data exchange formats and services in the emerging fields of glycoinformatics, biological interaction networks, text mining, and phyloinformatics. In addition, common shared object development based on BioSQL, as well as technical challenges in large data management, asynchronous services, and security are discussed. Consequently, we improved interoperability of web services in several fields, however, further cooperation among major database centers and continued collaborative efforts between service providers and software developers are still necessary for an effective advance in bioinformatics web service technologies.
PMCID: PMC2939597  PMID: 20727200
19.  Domain architecture evolution of pattern-recognition receptors 
Immunogenetics  2010;62(5):263-272.
In animals, the innate immune system is the first line of defense against invading microorganisms, and the pattern-recognition receptors (PRRs) are the key components of this system, detecting microbial invasion and initiating innate immune defenses. Two families of PRRs, the intracellular NOD-like receptors (NLRs) and the transmembrane Toll-like receptors (TLRs), are of particular interest because of their roles in a number of diseases. Understanding the evolutionary history of these families and their pattern of evolutionary changes may lead to new insights into the functioning of this critical system. We found that the evolution of both NLR and TLR families included massive species-specific expansions and domain shuffling in various lineages, which resulted in the same domain architectures evolving independently within different lineages in a process that fits the definition of parallel evolution. This observation illustrates both the dynamics of the innate immune system and the effects of “combinatorially constrained” evolution, where existence of the limited numbers of functionally relevant domains constrains the choices of domain architectures for new members in the family, resulting in the emergence of independently evolved proteins with identical domain architectures, often mistaken for orthologs.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-010-0428-1) contains supplementary material, which is available to authorized users.
PMCID: PMC2858798  PMID: 20195594
Parallel evolution; Lineage-specific expansion; Domain shuffling; NOD-like receptor; Toll-like receptor; Innate immunity
20.  phyloXML: XML for evolutionary biology and comparative genomics 
BMC Bioinformatics  2009;10:356.
Evolutionary trees are central to a wide range of biological studies. In many of these studies, tree nodes and branches need to be associated (or annotated) with various attributes. For example, in studies concerned with organismal relationships, tree nodes are associated with taxonomic names, whereas tree branches have lengths and oftentimes support values. Gene trees used in comparative genomics or phylogenomics are usually annotated with taxonomic information, genome-related data, such as gene names and functional annotations, as well as events such as gene duplications, speciations, or exon shufflings, combined with information related to the evolutionary tree itself. The data standards currently used for evolutionary trees have limited capacities to incorporate such annotations of different data types.
We developed a XML language, named phyloXML, for describing evolutionary trees, as well as various associated data items. PhyloXML provides elements for commonly used items, such as branch lengths, support values, taxonomic names, and gene names and identifiers. By using "property" elements, phyloXML can be adapted to novel and unforeseen use cases. We also developed various software tools for reading, writing, conversion, and visualization of phyloXML formatted data.
PhyloXML is an XML language defined by a complete schema in XSD that allows storing and exchanging the structures of evolutionary trees as well as associated data. More information about phyloXML itself, the XSD schema, as well as tools implementing and supporting phyloXML, is available at .
PMCID: PMC2774328  PMID: 19860910
21.  Novel genes dramatically alter regulatory network topology in amphioxus 
Genome Biology  2008;9(8):R123.
Domain rearrangements in the innate immune network of amphioxus suggests that domain shuffling has shaped the evolution of immune systems.
Regulation in protein networks often utilizes specialized domains that 'join' (or 'connect') the network through specific protein-protein interactions. The innate immune system, which provides a first and, in many species, the only line of defense against microbial and viral pathogens, is regulated in this way. Amphioxus (Branchiostoma floridae), whose genome was recently sequenced, occupies a unique position in the evolution of innate immunity, having diverged within the chordate lineage prior to the emergence of the adaptive immune system in vertebrates.
The repertoire of several families of innate immunity proteins is expanded in amphioxus compared to both vertebrates and protostome invertebrates. Part of this expansion consists of genes encoding proteins with unusual domain architectures, which often contain both upstream receptor and downstream activator domains, suggesting a potential role for direct connections (shortcuts) that bypass usual signal transduction pathways.
Domain rearrangements can potentially alter the topology of protein-protein interaction (and regulatory) networks. The extent of such arrangements in the innate immune network of amphioxus suggests that domain shuffling, which is an important mechanism in the evolution of multidomain proteins, has also shaped the development of immune systems.
PMCID: PMC2575513  PMID: 18680598
22.  The 2006 NESCent Phyloinformatics Hackathon: A Field Report 
In December, 2006, a group of 26 software developers from some of the most widely used life science programming toolkits and phylogenetic software projects converged on Durham, North Carolina, for a Phyloinformatics Hackathon, an intense five-day collaborative software coding event sponsored by the National Evolutionary Synthesis Center (NESCent). The goal was to help researchers to integrate multiple phylogenetic software tools into automated workflows. Participants addressed deficiencies in interoperability between programs by implementing “glue code” and improving support for phylogenetic data exchange standards (particularly NEXUS) across the toolkits. The work was guided by use-cases compiled in advance by both developers and users, and the code was documented as it was developed. The resulting software is freely available for both users and developers through incorporation into the distributions of several widely-used open-source toolkits. We explain the motivation for the hackathon, how it was organized, and discuss some of the outcomes and lessons learned. We conclude that hackathons are an effective mode of solving problems in software interoperability and usability, and are underutilized in scientific software development.
PMCID: PMC2684128
phylogenetics; phyloinformatics; open source software; analysis workflow
23.  Surprising complexity of the ancestral apoptosis network 
Genome Biology  2007;8(10):R226.
A comparative genomics approach revealed that the genes for several components of the apoptosis network with single copies in vertebrates have multiple paralogs in cnidarian-bilaterian ancestors, suggesting a complex evolutionary history for this network.
Apoptosis, one of the main types of programmed cell death, is regulated and performed by a complex protein network. Studies in model organisms, mostly in the nematode Caenorhabditis elegans, identified a relatively simple apoptotic network consisting of only a few proteins. However, analysis of several recently sequenced invertebrate genomes, ranging from the cnidarian sea anemone Nematostella vectensis, representing one of the morphologically simplest metazoans, to the deuterostomes sea urchin and amphioxus, contradicts the current paradigm of a simple ancestral network that expanded in vertebrates.
Here we show that the apoptosome-forming CED-4/Apaf-1 protein, present in single copy in vertebrate, nematode, and insect genomes, had multiple paralogs in the cnidarian-bilaterian ancestor. Different members of this ancestral Apaf-1 family led to the extant proteins in nematodes/insects and in deuterostomes, explaining significant functional differences between proteins that until now were believed to be orthologous. Similarly, the evolution of the Bcl-2 and caspase protein families appears surprisingly complex and apparently included significant gene loss in nematodes and insects and expansions in deuterostomes.
The emerging picture of the evolution of the apoptosis network is one of a succession of lineage-specific expansions and losses, which combined with the limited number of 'apoptotic' protein families, resulted in apparent similarities between networks in different organisms that mask an underlying complex evolutionary history. Similar results are beginning to surface for other regulatory networks, contradicting the intuitive notion that regulatory networks evolved in a linear way, from simple to complex.
PMCID: PMC2246300  PMID: 17958905
24.  RIO: Analyzing proteomes by automated phylogenomics using resampled inference of orthologs 
BMC Bioinformatics  2002;3:14.
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.
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 A web server is at RIO was tested on the Arabidopsis thaliana and Caenorhabditis elegans proteomes.
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.
PMCID: PMC116988  PMID: 12028595
25.  Immune System Dysfunction and Autoimmune Disease in Mice Lacking Emk (Par-1) Protein Kinase 
Molecular and Cellular Biology  2001;21(9):3206-3219.
Emk is a serine/threonine protein kinase implicated in regulating polarity, cell cycle progression, and microtubule dynamics. To delineate the role of Emk in development and adult tissues, mice lacking Emk were generated by targeted gene disruption. Emk−/− mice displayed growth retardation and immune cell dysfunction. Although B- and T-cell development were normal, CD4+T cells lacking Emk exhibited a marked upregulation of the memory marker CD44/pgp-1 and produced more gamma interferon and interleukin-4 on stimulation through the T-cell receptor in vitro. In addition, B-cell responses to T-cell-dependent and -independent antigen challenge were altered in vivo. As Emk−/− animals aged, they developed splenomegaly, lymphadenopathy, membranoproliferative glomerulonephritis, and lymphocytic infiltrates in the lungs, parotid glands and kidneys. Taken together, these results demonstrate that the Emk protein kinase is essential for maintaining immune system homeostasis and that loss of Emk may contribute to autoimmune disease in mammals.
PMCID: PMC86958  PMID: 11287624

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