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1.  Thousands of Rab GTPases for the Cell Biologist 
PLoS Computational Biology  2011;7(10):e1002217.
Rab proteins are small GTPases that act as essential regulators of vesicular trafficking. 44 subfamilies are known in humans, performing specific sets of functions at distinct subcellular localisations and tissues. Rab function is conserved even amongst distant orthologs. Hence, the annotation of Rabs yields functional predictions about the cell biology of trafficking. So far, annotating Rabs has been a laborious manual task not feasible for current and future genomic output of deep sequencing technologies. We developed, validated and benchmarked the Rabifier, an automated bioinformatic pipeline for the identification and classification of Rabs, which achieves up to 90% classification accuracy. We cataloged roughly 8.000 Rabs from 247 genomes covering the entire eukaryotic tree. The full Rab database and a web tool implementing the pipeline are publicly available at www.RabDB.org. For the first time, we describe and analyse the evolution of Rabs in a dataset covering the whole eukaryotic phylogeny. We found a highly dynamic family undergoing frequent taxon-specific expansions and losses. We dated the origin of human subfamilies using phylogenetic profiling, which enlarged the Rab repertoire of the Last Eukaryotic Common Ancestor with Rab14, 32 and RabL4. Furthermore, a detailed analysis of the Choanoflagellate Monosiga brevicollis Rab family pinpointed the changes that accompanied the emergence of Metazoan multicellularity, mainly an important expansion and specialisation of the secretory pathway. Lastly, we experimentally establish tissue specificity in expression of mouse Rabs and show that neo-functionalisation best explains the emergence of new human Rab subfamilies. With the Rabifier and RabDB, we provide tools that easily allows non-bioinformaticians to integrate thousands of Rabs in their analyses. RabDB is designed to enable the cell biology community to keep pace with the increasing number of fully-sequenced genomes and change the scale at which we perform comparative analysis in cell biology.
Author Summary
Intracellular compartmentalisation via membrane-delimited organelles is a fundamental feature of the eukaryotic cell. Understanding its origins and specialisation into functionally distinct compartments is a major challenge in evolutionary cell biology. We focus on the Rab enzymes, critical organisers of the trafficking pathways that link the endomembrane system. Rabs form a large family of evolutionarily related proteins, regulating distinct steps in vesicle transport. They mark pathways and organelles due to their specific subcellular and tissue localisation. We propose a solution to the problem of identifying and annotating Rabs in hundreds of sequenced genomes. We developed an accurate bioinformatics pipeline that is able to take into account pre-existing and often inconsistent, manual annotations. We made it available to the community in form of a web tool, as well as a database containing thousands of Rabs assigned to sub-families, which yields clear functional predictions. Thousands of Rabs allow for a new level of analysis. We illustrate this by characterising for the first time the global evolutionary dynamics of the Rab family. We dated the emergence of subfamilies and suggest that the Rab family expands by duplicates acquiring new functions.
doi:10.1371/journal.pcbi.1002217
PMCID: PMC3192815  PMID: 22022256
2.  Untangling the evolution of Rab G proteins: implications of a comprehensive genomic analysis 
BMC Biology  2012;10:71.
Background
Membrane-bound organelles are a defining feature of eukaryotic cells, and play a central role in most of their fundamental processes. The Rab G proteins are the single largest family of proteins that participate in the traffic between organelles, with 66 Rabs encoded in the human genome. Rabs direct the organelle-specific recruitment of vesicle tethering factors, motor proteins, and regulators of membrane traffic. Each organelle or vesicle class is typically associated with one or more Rab, with the Rabs present in a particular cell reflecting that cell's complement of organelles and trafficking routes.
Results
Through iterative use of hidden Markov models and tree building, we classified Rabs across the eukaryotic kingdom to provide the most comprehensive view of Rab evolution obtained to date. A strikingly large repertoire of at least 20 Rabs appears to have been present in the last eukaryotic common ancestor (LECA), consistent with the 'complexity early' view of eukaryotic evolution. We were able to place these Rabs into six supergroups, giving a deep view into eukaryotic prehistory.
Conclusions
Tracing the fate of the LECA Rabs revealed extensive losses with many extant eukaryotes having fewer Rabs, and none having the full complement. We found that other Rabs have expanded and diversified, including a large expansion at the dawn of metazoans, which could be followed to provide an account of the evolutionary history of all human Rabs. Some Rab changes could be correlated with differences in cellular organization, and the relative lack of variation in other families of membrane-traffic proteins suggests that it is the changes in Rabs that primarily underlies the variation in organelles between species and cell types.
doi:10.1186/1741-7007-10-71
PMCID: PMC3425129  PMID: 22873208
Organelles; G proteins; humans; last eukaryotic common ancestor
3.  Prospects for automated diagnosis of verbal autopsies 
BMC Medicine  2014;12:18.
Verbal autopsy is a method for assessing probable causes of death from lay reporting of signs, symptoms and circumstances by family members or caregivers of a deceased person. Several methods of automated diagnoses of causes of death from standardized verbal autopsy questionnaires have been developed recently (Inter-VA, Tariff, Random Forest and King-Lu). Their performances have been assessed in a series of papers in BMC Medicine. Overall, and despite high specificity, the current strategies of automated computer diagnoses lead to relatively low sensitivity and positive predictive values, even for causes which are expected to be easily assessed by interview. Some methods have even abnormally low sensitivity for selected diseases of public health importance and could probably be improved. Ways to improve the current strategies are proposed: more detailed questionnaires; using more information on disease duration; stratifying for large groups of causes of death by age, sex and main category; using clusters of signs and symptoms rather than quantitative scores or ranking; separating indeterminate causes; imputing unknown cause with appropriate methods.
Please see related articles: http://www.biomedcentral.com/1741-7015/12/5; http://www.biomedcentral.com/1741-7015/12/19; http://www.biomedcentral.com/1741-7015/12/20; http://www.biomedcentral.com/1741-7015/12/21; http://www.biomedcentral.com/1741-7015/12/22; http://www.biomedcentral.com/1741-7015/12/23.
doi:10.1186/1741-7015-12-18
PMCID: PMC3912493  PMID: 24495788
Cause of death; Verbal autopsy; Automated diagnosis; Health information system; Evaluation of health programs; Public health
4.  Comprehensive Analysis Reveals Dynamic and Evolutionary Plasticity of Rab GTPases and Membrane Traffic in Tetrahymena thermophila 
PLoS Genetics  2010;6(10):e1001155.
Cellular sophistication is not exclusive to multicellular organisms, and unicellular eukaryotes can resemble differentiated animal cells in their complex network of membrane-bound structures. These comparisons can be illuminated by genome-wide surveys of key gene families. We report a systematic analysis of Rabs in a complex unicellular Ciliate, including gene prediction and phylogenetic clustering, expression profiling based on public data, and Green Fluorescent Protein (GFP) tagging. Rabs are monomeric GTPases that regulate membrane traffic. Because Rabs act as compartment-specific determinants, the number of Rabs in an organism reflects intracellular complexity. The Tetrahymena Rab family is similar in size to that in humans and includes both expansions in conserved Rab clades as well as many divergent Rabs. Importantly, more than 90% of Rabs are expressed concurrently in growing cells, while only a small subset appears specialized for other conditions. By localizing most Rabs in living cells, we could assign the majority to specific compartments. These results validated most phylogenetic assignments, but also indicated that some sequence-conserved Rabs were co-opted for novel functions. Our survey uncovered a rare example of a nuclear Rab and substantiated the existence of a previously unrecognized core Rab clade in eukaryotes. Strikingly, several functionally conserved pathways or structures were found to be associated entirely with divergent Rabs. These pathways may have permitted rapid evolution of the associated Rabs or may have arisen independently in diverse lineages and then converged. Thus, characterizing entire gene families can provide insight into the evolutionary flexibility of fundamental cellular pathways.
Author Summary
Single-celled organisms appear simple compared to multicellular organisms, but this may not be true at the level of the individual cell. In fact, microscopic observations suggest that protists can possess networks of organelles just as elaborate as those in animal cells. Consistent with this idea, recent analysis has identified large families of genes in protists that are predicted to act as determinants for complex membrane networks. To test these predictions and to probe relationships between cellular structures across a wide swath of evolution, we focused on one gene family in the single-celled organism Tetrahymena. These genes control the traffic between organelles, with each gene controlling a single step in this traffic. We asked three questions about each of 56 genes in the family. First, what is the gene related to in humans? Second, under what conditions is the gene being used in Tetrahymena? Third, what is the role of each gene? The results provide insights into both the dynamics and evolution of membrane traffic, including the finding that some pathways appearing both structurally and functionally similar in protists and animals are likely to have arisen independently in the two lineages.
doi:10.1371/journal.pgen.1001155
PMCID: PMC2954822  PMID: 20976245
5.  The water flea Daphnia - a 'new' model system for ecology and evolution? 
Journal of Biology  2010;9(2):21.
Daphnia pulex is the first crustacean to have its genome sequenced. Availability of the genome sequence will have implications for research in aquatic ecology and evolution in particular, as addressed by a series of papers published recently in BMC Evolutionary Biology and BMC Genomics.
See research articles http://www.biomedcentral.com/1471-2148/9/78, http://www.biomedcentral.com/1471-2164/10/527, http://www.biomedcentral.com/1471-2148/9/79, http://www.biomedcentral.com/1471-2164/10/175, http://www.biomedcentral.com/1471-2164/10/172, http://www.biomedcentral.com/1471-2164/10/169, http://www.biomedcentral.com/1471-2164/10/170 and http://www.biomedcentral.com/1471-2148/9/243.
doi:10.1186/jbiol212
PMCID: PMC2871515  PMID: 20478012
6.  Phylogeny and evolution of Rab7 and Rab9 proteins 
Background
An important role in the evolution of intracellular trafficking machinery in eukaryotes played small GTPases belonging to the Rab family known as pivotal regulators of vesicle docking, fusion and transport. The Rab family is very diversified and divided into several specialized subfamilies. We focused on the VII functional group comprising Rab7 and Rab9, two related subfamilies, and analysed 210 sequences of these proteins. Rab7 regulates traffic from early to late endosomes and from late endosome to vacuole/lysosome, whereas Rab9 participates in transport from late endosomes to the trans-Golgi network.
Results
Although Rab7 and Rab9 proteins are quite small and show heterogeneous rates of substitution in different lineages, we found a phylogenetic signal and inferred evolutionary relationships between them. Rab7 proteins evolved before radiation of main eukaryotic supergroups while Rab9 GTPases diverged from Rab7 before split of choanoflagellates and metazoans. Additional duplication of Rab9 and Rab7 proteins resulting in several isoforms occurred in the early evolution of vertebrates and next in teleost fishes and tetrapods. Three Rab7 lineages emerged before divergence of monocots and eudicots and subsequent duplications of Rab7 genes occurred in particular angiosperm clades. Interestingly, several Rab7 copies were identified in some representatives of excavates, ciliates and amoebozoans. The presence of many Rab copies is correlated with significant differences in their expression level. The diversification of analysed Rab subfamilies is also manifested by non-conserved sequences and structural features, many of which are involved in the interaction with regulators and effectors. Individual sites discriminating different subgroups of Rab7 and Rab9 GTPases have been identified.
Conclusion
Phylogenetic reconstructions of Rab7 and Rab9 proteins were performed by a variety of methods. These Rab GTPases show diversification both at the phylogenetic, expression and structural levels. The presence of many Rab7 and Rab9 isoforms suggests their functional specialization and complexity of subcellular trafficking even in unicellular eukaryotes. The identified less conserved regions in analysed Rab sequences may directly contribute to such a differentiation.
doi:10.1186/1471-2148-9-101
PMCID: PMC2693434  PMID: 19442299
7.  Regeneration review reprise 
Journal of Biology  2010;9(2):15.
There have been notable advances in the scientific understanding of regeneration within the past year alone, including two recently published in BMC Biology. Increasingly, progress in the regeneration field is being inspired by comparisons with stem cell biology and enabled by newly developed techniques that allow simultaneous examination of thousands of genes and proteins.
See research articles http://www.biomedcentral.com/1741-7007/7/83 and http://www.biomedcentral.com/1741-7007/8/5.
doi:10.1186/jbiol224
PMCID: PMC2871519  PMID: 20236485
8.  No severe and global X chromosome inactivation in meiotic male germline of Drosophila 
BMC Biology  2012;10:50.
This article is a response to Vibranovski et al.
See correspondence article http://www.biomedcentral.com/1741-7007/10/49 and the original research article http://www.biomedcentral.com/1741-7007/9/29
We have previously reported a high propensity of testis-expressed X-linked genes to activation in meiotic cells, a similarity in global gene expression between the X chromosome and autosomes in meiotic germline, and under-representation of various types of tissue-specific genes on the X chromosome. Based on our findings and a critical review of the current literature, we believe that there is no global and severe silencing of the X chromosome in the meiotic male germline of Drosophila. The term 'meiotic sex chromosome inactivation' (MSCI) therefore seems misleading when used to describe the minor underexpression of the X chromosome in the testis of Drosophila, because this term erroneously implies a profound and widespread silencing of the X-linked genes, by analogy to the well-studied MSCI system in mammals, and therefore distracts from identification and analysis of the real mechanisms that orchestrate gene expression and evolution in this species.
doi:10.1186/1741-7007-10-50
PMCID: PMC3391177
9.  Inferring the Tree of Life: chopping a phylogenomic problem down to size? 
BMC Biology  2011;9:59.
The combination of molecular sequence data and bioinformatics has revolutionized phylogenetic inference over the past decade, vastly increasing the scope of the evolutionary trees that we are able to infer. A recent paper in BMC Biology describing a new phylogenomic pipeline to help automate the inference of evolutionary trees from public sequence databases provides another important tool in our efforts to derive the Tree of Life.
See research article: http://www.biomedcentral.com/1741-7007/9/55
doi:10.1186/1741-7007-9-59
PMCID: PMC3176480  PMID: 21933452
10.  Following autophagy step by step 
BMC Biology  2011;9:39.
Autophagy is an evolutionarily conserved lysosomal degradation route for soluble components of the cytosol and organelles. There is great interest in identifying compounds that modulate autophagy because they may have applications in the treatment of major diseases including cancer and neurodegenerative disease. Hundeshagen and colleagues describe this month in BMC Biology a screening assay based on flow cytometry that makes it possible to track distinct steps in the autophagic process and thereby identify novel modulators of autophagy.
See research article: http://www.biomedcentral.com/1741-7007/9/38
doi:10.1186/1741-7007-9-39
PMCID: PMC3107173  PMID: 21635796
11.  DNA replication: archaeal oriGINS 
BMC Biology  2011;9:36.
GINS is an essential eukaryotic DNA replication factor that is found in a simplified form in Archaea. A new study in this issue of BMC Biology reveals the first structure of the archaeal GINS complex. The structure reveals the anticipated similarity to the previously determined eukaryotic complex but also has some intriguing differences in the relative disposition of subunit domains.
See research article: http://www.biomedcentral.com/1741-7007/9/28
doi:10.1186/1741-7007-9-36
PMCID: PMC3104950  PMID: 21627856
12.  Genome of a songbird unveiled 
Journal of Biology  2010;9(3):19.
An international collaborative effort has recently uncovered the genome of the zebra finch, a songbird model that has provided unique insights into an array of biological phenomena.
See research articles http://www.biomedcentral.com/1471-2164/9/131, http://www.biomedcentral.com/1471-2164/11/220/, http://www.biomedcentral.com/1471-2202/11/46/ and http://www.biomedcentral.com/1741-7007/8/28/
doi:10.1186/jbiol222
PMCID: PMC2871510  PMID: 20359317
13.  The (r)evolution of cancer genetics 
BMC Biology  2010;8:74.
The identification of an increasing number of cancer genes is opening up unexpected scenarios in cancer genetics. When analyzed for their systemic properties, these genes show a general fragility towards perturbation. A recent paper published in BMC Biology shows how the founder domains of known cancer genes emerged at two macroevolutionary transitions - the advent of the first cell and the transition to metazoan multicellularity.
See research article http://www.biomedcentral.com/1741-7007/8/66
doi:10.1186/1741-7007-8-74
PMCID: PMC2883958  PMID: 20594288
14.  History and phylogeny of intermediate filaments: Now in insects 
BMC Biology  2011;9:16.
Intermediate filaments include the nuclear lamins, which are universal in metazoans, and the cytoplasmic intermediate filaments, which are much more varied and form cell type-specific networks in animal cells. Until now, it has been thought that insects harbor lamins only. This view is fundamentally challenged by the discovery, reported in BMC Biology, of an intermediate filament-like cytoplasmic protein, isomin, in the hexapod Isotomurus maculatus. Here we briefly review the history of research on intermediate filaments, and discuss the implications of this latest finding in the context of what is known of their structure and functions.
See research article: http://www.biomedcentral.com/1741-7007/9/17
doi:10.1186/1741-7007-9-16
PMCID: PMC3046923  PMID: 21356127
15.  How the vertebrates were made: selective pruning of a double-duplicated genome 
BMC Biology  2010;8:144.
Vertebrates are the result of an ancient double duplication of the genome. A new study published in BMC Biology explores the selective retention of genes after this event, finding an extensive enrichment of signaling proteins and transcription factors. Analysis of their expression patterns, interactions and subsequent history reflect the forces that drove their evolution, and with it the evolution of vertebrate complexity.
See research article: http://www.biomedcentral.com/1741-7007/8/146/abstract
doi:10.1186/1741-7007-8-144
PMCID: PMC3001425  PMID: 21144066
16.  Difficult phylogenetic questions: more data, maybe; better methods, certainly 
BMC Biology  2011;9:91.
Contradicting the prejudice that endosymbiosis is a rare phenomenon, Husník and co-workers show in BMC Biology that bacterial endosymbiosis has occured several times independently during insect evolution. Rigorous phylogenetic analyses, in particular using complex models of sequence evolution and an original site removal procedure, allow this conclusion to be established after eschewing inference artefacts that usually plague the positioning of highly divergent endosymbiont genomic sequences.
See research article http://www.biomedcentral.com/1741-7007/9/87
doi:10.1186/1741-7007-9-91
PMCID: PMC3248379  PMID: 22206462
17.  p97 complexes as signal integration hubs 
BMC Biology  2012;10:48.
In the ubiquitin-proteasome system, a subset of ubiquitylated proteins requires the AAA+ ATPase p97 (also known as VCP or Cdc48) for extraction from membranes or protein complexes before delivery to the proteasome for degradation. Diverse ubiquitin adapters are known to link p97 to its client proteins, but two recent papers on the adapter protein UBXD7, including one by Bandau et al. in BMC Biology, suggest that rather than simply linking p97 to ubiquitylated proteins, this adapter may be essential to coordinate ubiquitylation and p97-mediated extraction of the proteasome substrate. These findings add to growing indications of richly diverse roles of adapters in p97-mediated signaling functions.
See research article: http://www.biomedcentral.com/1741-7007/10/36
doi:10.1186/1741-7007-10-48
PMCID: PMC3374291  PMID: 22694940
18.  Mapping the protistan 'rare biosphere' 
Journal of Biology  2009;8(12):105.
The use of cultivation-independent approaches to map microbial diversity, including recent work published in BMC Biology, has now shown that protists, like bacteria/archaea, are much more diverse than had been realized. Uncovering eukaryotic diversity may now be limited not by access to samples or cost but rather by the availability of full-length reference sequence data.
See research article http://www.biomedcentral.com/1741-7007/7/72
doi:10.1186/jbiol201
PMCID: PMC2804278  PMID: 20067591
19.  Vertebrate Hedgehog signaling: cilia rule 
BMC Biology  2010;8:102.
The Hedgehog (Hh) signaling pathway differentially utilizes the primary cilium in mammals and fruit flies. Recent work, including a study in BMC Biology, demonstrates that Hh signals through the cilium in zebrafish, clarifying the evolution of Hh signal transduction.
See research article: http://www.biomedcentral.com/1741-7007/8/65
doi:10.1186/1741-7007-8-102
PMCID: PMC2912248  PMID: 20687907
20.  Scale-eating cichlids: from hand(ed) to mouth 
Journal of Biology  2010;9(2):11.
Two recent studies in BMC Biology and Evolution raise important questions about a textbook case of frequency-dependent selection in scale-eating cichlid fishes. They also suggest a fascinating new line of research testing the effects of handed behavior on morphological asymmetry.
See research article http://www.biomedcentral.com/1741-7007/8/8.
doi:10.1186/jbiol218
PMCID: PMC2871516  PMID: 20236497
21.  Modularity of gene-regulatory networks revealed in sea-star development 
BMC Biology  2011;9:6.
Evidence that conserved developmental gene-regulatory networks can change as a unit during deutersostome evolution emerges from a study published in BMC Biology. This shows that genes consistently expressed in anterior brain patterning in hemichordates and chordates are expressed in a similar spatial pattern in another deuterostome, an asteroid echinoderm (sea star), but in a completely different developmental context (the animal-vegetal axis). This observation has implications for hypotheses on the type of development present in the deuterostome common ancestor.
See research article: http://www.biomedcentral.com/1741-7007/8/143/abstract
doi:10.1186/1741-7007-9-6
PMCID: PMC3032766  PMID: 21281525
22.  A view to kill 
BMC Biology  2012;10:18.
Genome and proteome data from Hydra magnipapillata have opened the way for the molecular analysis of an ancient nervous system, which includes stinging cells, an unusual neurosensory and neurosecretory cell type. They hold some surprises for the mechanisms and evolution of sensory transduction that could not have been anticipated from what has been learned from flies and vertebrates. Research in BMC Biology now implicates the ancient opsin-mediated transduction pathway in the neuronal control of stinging cell discharge.
See research article http://www.biomedcentral.com/1741-7007/10/17
doi:10.1186/1741-7007-10-18
PMCID: PMC3293708  PMID: 22390773
23.  Constrained evolution drives limited influenza diversity 
BMC Biology  2012;10:43.
H3N2 influenza A viruses have been widely circulating in human populations since the pandemic of 1968. A striking feature of the evolutionary development of this strain has been its 'canalized' nature, with narrow evolutionary trees dominated by long trunks with few branching, or bifurcation events and a consequent lack of standing diversity at any single point. This is puzzling, as one might expect that the strong human immune response against the virus would create an environment encouraging more diversity, not less. Previous models have used various assumptions in order to account for this finding. A new analysis published in BMC Biology suggests that this processive evolution down a single path can be recapitulated by a relatively simple model incorporating only two primary parameters - the mutation rate of the virus, and the immunological distance created by each mutation - so long as these parameters are within a particular narrow but biologically plausible range.
See research article: http://www.biomedcentral.com/1741-7007/10/38
doi:10.1186/1741-7007-10-43
PMCID: PMC3357320  PMID: 22613866
24.  Cambrian problematica and the diversification of deuterostomes 
BMC Biology  2012;10:79.
Vetulicolians are an enigmatic group of Cambrian organisms that have been affiliated at various times with arthropods, lobopodians, kinorhynchs and deuterostomes. New evidence on the structure of the lateral pores of vetulicolians published in BMC Biology strengthens the view that they may be total group deuterostomes, but unfortunately sheds no new light on early deuterostome evolution.
See research article http://www.biomedcentral.com/1741-7007/10/81
doi:10.1186/1741-7007-10-79
PMCID: PMC3462677  PMID: 23031503
25.  Revisiting the relationship between regenerative ability and aging 
BMC Biology  2013;11:2.
Contrary to the longstanding view that newts (Notophthalamus viridescens), but not axolotls (Ambystoma mexicanum), can regenerate a lens, a recent report in BMC Biology by Panagiotis Tsonis and colleagues shows axolotls indeed possess this ability during early larval stages. In contrast, they show that zebrafish never posses this ability, even as embryos. This underscores the importance of comparing regenerative ability across species and reinforces the need to consider organ regeneration in the context of evolution, development, and aging.
See research article: http://www.biomedcentral.com/1741-7007/10/103
doi:10.1186/1741-7007-11-2
PMCID: PMC3549786  PMID: 23336699

Results 1-25 (272930)