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1.  Short and long-term genome stability analysis of prokaryotic genomes 
BMC Genomics  2013;14:309.
Background
Gene organization dynamics is actively studied because it provides useful evolutionary information, makes functional annotation easier and often enables to characterize pathogens. There is therefore a strong interest in understanding the variability of this trait and the possible correlations with life-style. Two kinds of events affect genome organization: on one hand translocations and recombinations change the relative position of genes shared by two genomes (i.e. the backbone gene order); on the other, insertions and deletions leave the backbone gene order unchanged but they alter the gene neighborhoods by breaking the syntenic regions. A complete picture about genome organization evolution therefore requires to account for both kinds of events.
Results
We developed an approach where we model chromosomes as graphs on which we compute different stability estimators; we consider genome rearrangements as well as the effect of gene insertions and deletions. In a first part of the paper, we fit a measure of backbone gene order conservation (hereinafter called backbone stability) against phylogenetic distance for over 3000 genome comparisons, improving existing models for the divergence in time of backbone stability. Intra- and inter-specific comparisons were treated separately to focus on different time-scales. The use of multiple genomes of a same species allowed to identify genomes with diverging gene order with respect to their conspecific. The inter-species analysis indicates that pathogens are more often unstable with respect to non-pathogens. In a second part of the text, we show that in pathogens, gene content dynamics (insertions and deletions) have a much more dramatic effect on genome organization stability than backbone rearrangements.
Conclusion
In this work, we studied genome organization divergence taking into account the contribution of both genome order rearrangements and genome content dynamics. By studying species with multiple sequenced genomes available, we were able to explore genome organization stability at different time-scales and to find significant differences for pathogen and non-pathogen species. The output of our framework also allows to identify the conserved gene clusters and/or partial occurrences thereof, making possible to explore how gene clusters assembled during evolution.
doi:10.1186/1471-2164-14-309
PMCID: PMC3683328  PMID: 23651581
2.  Sampling solution traces for the problem of sorting permutations by signed reversals 
Background
Traditional algorithms to solve the problem of sorting by signed reversals output just one optimal solution while the space of all optimal solutions can be huge. A so-called trace represents a group of solutions which share the same set of reversals that must be applied to sort the original permutation following a partial ordering. By using traces, we therefore can represent the set of optimal solutions in a more compact way. Algorithms for enumerating the complete set of traces of solutions were developed. However, due to their exponential complexity, their practical use is limited to small permutations. A partial enumeration of traces is a sampling of the complete set of traces and can be an alternative for the study of distinct evolutionary scenarios of big permutations. Ideally, the sampling should be done uniformly from the space of all optimal solutions. This is however conjectured to be ♯P-complete.
Results
We propose and evaluate three algorithms for producing a sampling of the complete set of traces that instead can be shown in practice to preserve some of the characteristics of the space of all solutions. The first algorithm (RA) performs the construction of traces through a random selection of reversals on the list of optimal 1-sequences. The second algorithm (DFALT) consists in a slight modification of an algorithm that performs the complete enumeration of traces. Finally, the third algorithm (SWA) is based on a sliding window strategy to improve the enumeration of traces. All proposed algorithms were able to enumerate traces for permutations with up to 200 elements.
Conclusions
We analysed the distribution of the enumerated traces with respect to their height and average reversal length. Various works indicate that the reversal length can be an important aspect in genome rearrangements. The algorithms RA and SWA show a tendency to lose traces with high average reversal length. Such traces are however rare, and qualitatively our results show that, for testable-sized permutations, the algorithms DFALT and SWA produce distributions which approximate the reversal length distributions observed with a complete enumeration of the set of traces.
doi:10.1186/1748-7188-7-18
PMCID: PMC3537553  PMID: 22704580
Reversals; Traces; Sampling; Genome rearrangement
3.  KISSPLICE: de-novo calling alternative splicing events from RNA-seq data 
BMC Bioinformatics  2012;13(Suppl 6):S5.
Background
In this paper, we address the problem of identifying and quantifying polymorphisms in RNA-seq data when no reference genome is available, without assembling the full transcripts. Based on the fundamental idea that each polymorphism corresponds to a recognisable pattern in a De Bruijn graph constructed from the RNA-seq reads, we propose a general model for all polymorphisms in such graphs. We then introduce an exact algorithm, called KISSPLICE, to extract alternative splicing events.
Results
We show that KISSPLICE enables to identify more correct events than general purpose transcriptome assemblers. Additionally, on a 71 M reads dataset from human brain and liver tissues, KISSPLICE identified 3497 alternative splicing events, out of which 56% are not present in the annotations, which confirms recent estimates showing that the complexity of alternative splicing has been largely underestimated so far.
Conclusions
We propose new models and algorithms for the detection of polymorphism in RNA-seq data. This opens the way to a new kind of studies on large HTS RNA-seq datasets, where the focus is not the global reconstruction of full-length transcripts, but local assembly of polymorphic regions. KISSPLICE is available for download at http://alcovna.genouest.org/kissplice/.
doi:10.1186/1471-2105-13-S6-S5
PMCID: PMC3358658  PMID: 22537044
4.  Biosynthesis of Vitamins and Cofactors in Bacterium-Harbouring Trypanosomatids Depends on the Symbiotic Association as Revealed by Genomic Analyses 
PLoS ONE  2013;8(11):e79786.
Some non-pathogenic trypanosomatids maintain a mutualistic relationship with a betaproteobacterium of the Alcaligenaceae family. Intensive nutritional exchanges have been reported between the two partners, indicating that these protozoa are excellent biological models to study metabolic co-evolution. We previously sequenced and herein investigate the entire genomes of five trypanosomatids which harbor a symbiotic bacterium (SHTs for Symbiont-Haboring Trypanosomatids) and the respective bacteria (TPEs for Trypanosomatid Proteobacterial Endosymbiont), as well as two trypanosomatids without symbionts (RTs for Regular Trypanosomatids), for the presence of genes of the classical pathways for vitamin biosynthesis. Our data show that genes for the biosynthetic pathways of thiamine, biotin, and nicotinic acid are absent from all trypanosomatid genomes. This is in agreement with the absolute growth requirement for these vitamins in all protozoa of the family. Also absent from the genomes of RTs are the genes for the synthesis of pantothenic acid, folic acid, riboflavin, and vitamin B6. This is also in agreement with the available data showing that RTs are auxotrophic for these essential vitamins. On the other hand, SHTs are autotrophic for such vitamins. Indeed, all the genes of the corresponding biosynthetic pathways were identified, most of them in the symbiont genomes, while a few genes, mostly of eukaryotic origin, were found in the host genomes. The only exceptions to the latter are: the gene coding for the enzyme ketopantoate reductase (EC:1.1.1.169) which is related instead to the Firmicutes bacteria; and two other genes, one involved in the salvage pathway of pantothenic acid and the other in the synthesis of ubiquinone, that are related to Gammaproteobacteria. Their presence in trypanosomatids may result from lateral gene transfer. Taken together, our results reinforce the idea that the low nutritional requirement of SHTs is associated with the presence of the symbiotic bacterium, which contains most genes for vitamin production.
doi:10.1371/journal.pone.0079786
PMCID: PMC3833962  PMID: 24260300
5.  Telling metabolic stories to explore metabolomics data: a case study on the yeast response to cadmium exposure 
Bioinformatics  2013;30(1):61-70.
Motivation: The increasing availability of metabolomics data enables to better understand the metabolic processes involved in the immediate response of an organism to environmental changes and stress. The data usually come in the form of a list of metabolites whose concentrations significantly changed under some conditions, and are thus not easy to interpret without being able to precisely visualize how such metabolites are interconnected.
Results: We present a method that enables to organize the data from any metabolomics experiment into metabolic stories. Each story corresponds to a possible scenario explaining the flow of matter between the metabolites of interest. These scenarios may then be ranked in different ways depending on which interpretation one wishes to emphasize for the causal link between two affected metabolites: enzyme activation, enzyme inhibition or domino effect on the concentration changes of substrates and products. Equally probable stories under any selected ranking scheme can be further grouped into a single anthology that summarizes, in a unique subnetwork, all equivalently plausible alternative stories. An anthology is simply a union of such stories. We detail an application of the method to the response of yeast to cadmium exposure. We use this system as a proof of concept for our method, and we show that we are able to find a story that reproduces very well the current knowledge about the yeast response to cadmium. We further show that this response is mostly based on enzyme activation. We also provide a framework for exploring the alternative pathways or side effects this local response is expected to have in the rest of the network. We discuss several interpretations for the changes we see, and we suggest hypotheses that could in principle be experimentally tested. Noticeably, our method requires simple input data and could be used in a wide variety of applications.
Availability and implementation: The code for the method presented in this article is available at http://gobbolino.gforge.inria.fr.
Contact: pvmilreu@gmail.com; vincent.lacroix@univ-lyon1.fr; marie-france.sagot@inria.fr
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt597
PMCID: PMC3866556  PMID: 24167155
6.  Close 3D proximity of evolutionary breakpoints argues for the notion of spatial synteny 
BMC Genomics  2011;12:303.
Background
Folding and intermingling of chromosomes has the potential of bringing close to each other loci that are very distant genomically or even on different chromosomes. On the other hand, genomic rearrangements also play a major role in the reorganisation of loci proximities. Whether the same loci are involved in both mechanisms has been studied in the case of somatic rearrangements, but never from an evolutionary standpoint.
Results
In this paper, we analysed the correlation between two datasets: (i) whole-genome chromatin contact data obtained in human cells using the Hi-C protocol; and (ii) a set of breakpoint regions resulting from evolutionary rearrangements which occurred since the split of the human and mouse lineages. Surprisingly, we found that two loci distant in the human genome but adjacent in the mouse genome are significantly more often observed in close proximity in the human nucleus than expected. Importantly, we show that this result holds for loci located on the same chromosome regardless of the genomic distance separating them, and the signal is stronger in gene-rich and open-chromatin regions.
Conclusions
These findings strongly suggest that part of the 3D organisation of chromosomes may be conserved across very large evolutionary distances. To characterise this phenomenon, we propose to use the notion of spatial synteny which generalises the notion of genomic synteny to the 3D case.
doi:10.1186/1471-2164-12-303
PMCID: PMC3132170  PMID: 21663614
7.  Bacterial syntenies: an exact approach with gene quorum 
BMC Bioinformatics  2011;12:193.
Background
The automatic identification of syntenies across multiple species is a key step in comparative genomics that helps biologists shed light both on evolutionary and functional problems.
Results
In this paper, we present a versatile tool to extract all syntenies from multiple bacterial species based on a clear-cut and very flexible definition of the synteny blocks that allows for gene quorum, partial gene correspondence, gaps, and a partial or total conservation of the gene order.
Conclusions
We apply this tool to two different kinds of studies. The first one is a search for functional gene associations. In this context, we compare our tool to a widely used heuristic - I-ADHORE - and show that at least up to ten genomes, the problem remains tractable with our exact definition and algorithm. The second application is linked to evolutionary studies: we verify in a multiple alignment setting that pairs of orthologs in synteny are more conserved than pairs outside, thus extending a previous pairwise study. We then show that this observation is in fact a function of the size of the synteny: the larger the block of synteny is, the more conserved the genes are.
doi:10.1186/1471-2105-12-193
PMCID: PMC3121647  PMID: 21605461
8.  Combination of measures distinguishes pre-miRNAs from other stem-loops in the genome of the newly sequenced Anopheles darlingi 
BMC Genomics  2010;11:529.
Background
Efforts using computational algorithms towards the enumeration of the full set of miRNAs of an organism have been limited by strong reliance on arguments of precursor conservation and feature similarity. However, miRNA precursors may arise anew or be lost across the evolutionary history of a species and a newly sequenced genome may be evolutionarily too distant from other genomes for an adequate comparative analysis. In addition, the learning of intricate classification rules based purely on features shared by miRNA precursors that are currently known may reflect a perpetuating identification bias rather than a sound means to tell true miRNAs from other genomic stem-loops.
Results
We show that there is a strong bias amongst annotated pre-miRNAs towards robust stem-loops in the genomes of Drosophila melanogaster and Anopheles gambiae and we propose a scoring scheme for precursor candidates which combines four robustness measures. Additionally, we identify several known pre-miRNA homologs in the newly sequenced Anopheles darlingi and show that most are found amongst the top-scoring precursor candidates. Furthermore, a comparison of the performance of our approach is made against two single-genome pre-miRNA classification methods.
Conclusions
In this paper we present a strategy to sieve through the vast amount of stem-loops found in metazoan genomes in search of pre-miRNAs, significantly reducing the set of candidates while retaining most known miRNA precursors. This approach makes no use of conservation data and relies solely on properties derived from our knowledge of miRNA biogenesis.
doi:10.1186/1471-2164-11-529
PMCID: PMC2997018  PMID: 20920257
9.  An asymmetric approach to preserve common intervals while sorting by reversals 
Background
The reversal distance and optimal sequences of reversals to transform a genome into another are useful tools to analyse evolutionary scenarios. However, the number of sequences is huge and some additional criteria should be used to obtain a more accurate analysis. One strategy is searching for sequences that respect constraints, such as the common intervals (clusters of co-localised genes). Another approach is to explore the whole space of sorting sequences, eventually grouping them into classes of equivalence. Recently both strategies started to be put together, to restrain the space to the sequences that respect constraints. In particular an algorithm has been proposed to list classes whose sorting sequences do not break the common intervals detected between the two inital genomes A and B. This approach may reduce the space of sequences and is symmetric (the result of the analysis sorting A into B can be obtained from the analysis sorting B into A).
Results
We propose an alternative approach to restrain the space of sorting sequences, using progressive instead of initial detection of common intervals (the list of common intervals is updated after applying each reversal). This may reduce the space of sequences even more, but is shown to be asymmetric.
Conclusions
We suggest that our method may be more realistic when the relation ancestor-descendant between the analysed genomes is clear and we apply it to do a better characterisation of the evolutionary scenario of the bacterium Rickettsia felis with respect to one of its ancestors.
doi:10.1186/1748-7188-4-16
PMCID: PMC2813847  PMID: 20042101
10.  Analysis of fine-scale mammalian evolutionary breakpoints provides new insight into their relation to genome organisation 
BMC Genomics  2009;10:335.
Background
The Intergenic Breakage Model, which is the current model of structural genome evolution, considers that evolutionary rearrangement breakages happen with a uniform propensity along the genome but are selected against in genes, their regulatory regions and in-between. However, a growing body of evidence shows that there exists regions along mammalian genomes that present a high susceptibility to breakage. We reconsidered this question taking advantage of a recently published methodology for the precise detection of rearrangement breakpoints based on pairwise genome comparisons.
Results
We applied this methodology between the genome of human and those of five sequenced eutherian mammals which allowed us to delineate evolutionary breakpoint regions along the human genome with a finer resolution (median size 26.6 kb) than obtained before. We investigated the distribution of these breakpoints with respect to genome organisation into domains of different activity. In agreement with the Intergenic Breakage Model, we observed that breakpoints are under-represented in genes. Surprisingly however, the density of breakpoints in small intergenes (1 per Mb) appears significantly higher than in gene deserts (0.1 per Mb).
More generally, we found a heterogeneous distribution of breakpoints that follows the organisation of the genome into isochores (breakpoints are more frequent in GC-rich regions). We then discuss the hypothesis that regions with an enhanced susceptibility to breakage correspond to regions of high transcriptional activity and replication initiation.
Conclusion
We propose a model to describe the heterogeneous distribution of evolutionary breakpoints along human chromosomes that combines natural selection and a mutational bias linked to local open chromatin state.
doi:10.1186/1471-2164-10-335
PMCID: PMC2722678  PMID: 19630943
11.  Lossless filter for multiple repeats with bounded edit distance 
Background
Identifying local similarity between two or more sequences, or identifying repeats occurring at least twice in a sequence, is an essential part in the analysis of biological sequences and of their phylogenetic relationship. Finding such fragments while allowing for a certain number of insertions, deletions, and substitutions, is however known to be a computationally expensive task, and consequently exact methods can usually not be applied in practice.
Results
The filter TUIUIU that we introduce in this paper provides a possible solution to this problem. It can be used as a preprocessing step to any multiple alignment or repeats inference method, eliminating a possibly large fraction of the input that is guaranteed not to contain any approximate repeat. It consists in the verification of several strong necessary conditions that can be checked in a fast way. We implemented three versions of the filter. The first is simply a straightforward extension to the case of multiple sequences of an application of conditions already existing in the literature. The second uses a stronger condition which, as our results show, enable to filter sensibly more with negligible (if any) additional time. The third version uses an additional condition and pushes the sensibility of the filter even further with a non negligible additional time in many circumstances; our experiments show that it is particularly useful with large error rates. The latter version was applied as a preprocessing of a multiple alignment tool, obtaining an overall time (filter plus alignment) on average 63 and at best 530 times smaller than before (direct alignment), with in most cases a better quality alignment.
Conclusion
To the best of our knowledge, TUIUIU is the first filter designed for multiple repeats and for dealing with error rates greater than 10% of the repeats length.
doi:10.1186/1748-7188-4-3
PMCID: PMC2661881  PMID: 19183438
12.  Precise detection of rearrangement breakpoints in mammalian chromosomes 
BMC Bioinformatics  2008;9:286.
Background
Genomes undergo large structural changes that alter their organisation. The chromosomal regions affected by these rearrangements are called breakpoints, while those which have not been rearranged are called synteny blocks. We developed a method to precisely delimit rearrangement breakpoints on a genome by comparison with the genome of a related species. Contrary to current methods which search for synteny blocks and simply return what remains in the genome as breakpoints, we propose to go further and to investigate the breakpoints themselves in order to refine them.
Results
Given some reliable and non overlapping synteny blocks, the core of the method consists in refining the regions that are not contained in them. By aligning each breakpoint sequence against its specific orthologous sequences in the other species, we can look for weak similarities inside the breakpoint, thus extending the synteny blocks and narrowing the breakpoints. The identification of the narrowed breakpoints relies on a segmentation algorithm and is statistically assessed. Since this method requires as input synteny blocks with some properties which, though they appear natural, are not verified by current methods for detecting such blocks, we further give a formal definition and provide an algorithm to compute them.
The whole method is applied to delimit breakpoints on the human genome when compared to the mouse and dog genomes. Among the 355 human-mouse and 240 human-dog breakpoints, 168 and 146 respectively span less than 50 Kb. We compared the resulting breakpoints with some publicly available ones and show that we achieve a better resolution. Furthermore, we suggest that breakpoints are rarely reduced to a point, and instead consist in often large regions that can be distinguished from the sequences around in terms of segmental duplications, similarity with related species, and transposable elements.
Conclusion
Our method leads to smaller breakpoints than already published ones and allows for a better description of their internal structure. In the majority of cases, our refined regions of breakpoint exhibit specific biological properties (no similarity, presence of segmental duplications and of transposable elements). We hope that this new result may provide some insight into the mechanism and evolutionary properties of chromosomal rearrangements.
doi:10.1186/1471-2105-9-286
PMCID: PMC2443379  PMID: 18564416
13.  Navigating the unexplored seascape of pre-miRNA candidates in single-genome approaches 
Bioinformatics  2012;28(23):3034-3041.
Motivation: The computational search for novel microRNA (miRNA) precursors often involves some sort of structural analysis with the aim of identifying which type of structures are prone to being recognized and processed by the cellular miRNA-maturation machinery. A natural way to tackle this problem is to perform clustering over the candidate structures along with known miRNA precursor structures. Mixed clusters allow then the identification of candidates that are similar to known precursors. Given the large number of pre-miRNA candidates that can be identified in single-genome approaches, even after applying several filters for precursor robustness and stability, a conventional structural clustering approach is unfeasible.
Results: We propose a method to represent candidate structures in a feature space, which summarizes key sequence/structure characteristics of each candidate. We demonstrate that proximity in this feature space is related to sequence/structure similarity, and we select candidates that have a high similarity to known precursors. Additional filtering steps are then applied to further reduce the number of candidates to those with greater transcriptional potential. Our method is compared with another single-genome method (TripletSVM) in two datasets, showing better performance in one and comparable performance in the other, for larger training sets. Additionally, we show that our approach allows for a better interpretation of the results.
Availability and Implementation: The MinDist method is implemented using Perl scripts and is freely available at http://www.cravela.org/?mindist=1.
Contact: backofen@informatik.uni-freiburg.de
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts574
PMCID: PMC3516144  PMID: 23052038
14.  BRASERO: A Resource for Benchmarking RNA Secondary Structure Comparison Algorithms 
Advances in Bioinformatics  2012;2012:893048.
The pairwise comparison of RNA secondary structures is a fundamental problem, with direct application in mining databases for annotating putative noncoding RNA candidates in newly sequenced genomes. An increasing number of software tools are available for comparing RNA secondary structures, based on different models (such as ordered trees or forests, arc annotated sequences, and multilevel trees) and computational principles (edit distance, alignment). We describe here the website BRASERO that offers tools for evaluating such software tools on real and synthetic datasets.
doi:10.1155/2012/893048
PMCID: PMC3366197  PMID: 22675348
15.  CycADS: an annotation database system to ease the development and update of BioCyc databases 
In recent years, genomes from an increasing number of organisms have been sequenced, but their annotation remains a time-consuming process. The BioCyc databases offer a framework for the integrated analysis of metabolic networks. The Pathway tool software suite allows the automated construction of a database starting from an annotated genome, but it requires prior integration of all annotations into a specific summary file or into a GenBank file. To allow the easy creation and update of a BioCyc database starting from the multiple genome annotation resources available over time, we have developed an ad hoc data management system that we called Cyc Annotation Database System (CycADS). CycADS is centred on a specific database model and on a set of Java programs to import, filter and export relevant information. Data from GenBank and other annotation sources (including for example: KAAS, PRIAM, Blast2GO and PhylomeDB) are collected into a database to be subsequently filtered and extracted to generate a complete annotation file. This file is then used to build an enriched BioCyc database using the PathoLogic program of Pathway Tools. The CycADS pipeline for annotation management was used to build the AcypiCyc database for the pea aphid (Acyrthosiphon pisum) whose genome was recently sequenced. The AcypiCyc database webpage includes also, for comparative analyses, two other metabolic reconstruction BioCyc databases generated using CycADS: TricaCyc for Tribolium castaneum and DromeCyc for Drosophila melanogaster. Linked to its flexible design, CycADS offers a powerful software tool for the generation and regular updating of enriched BioCyc databases. The CycADS system is particularly suited for metabolic gene annotation and network reconstruction in newly sequenced genomes. Because of the uniform annotation used for metabolic network reconstruction, CycADS is particularly useful for comparative analysis of the metabolism of different organisms.
Database URL: http://www.cycadsys.org
doi:10.1093/database/bar008
PMCID: PMC3072769  PMID: 21474551
16.  Graph-Based Analysis of the Metabolic Exchanges between Two Co-Resident Intracellular Symbionts, Baumannia cicadellinicola and Sulcia muelleri, with Their Insect Host, Homalodisca coagulata 
PLoS Computational Biology  2010;6(9):e1000904.
Endosymbiotic bacteria from different species can live inside cells of the same eukaryotic organism. Metabolic exchanges occur between host and bacteria but also between different endocytobionts. Since a complete genome annotation is available for both, we built the metabolic network of two endosymbiotic bacteria, Sulcia muelleri and Baumannia cicadellinicola, that live inside specific cells of the sharpshooter Homalodisca coagulata and studied the metabolic exchanges involving transfers of carbon atoms between the three. We automatically determined the set of metabolites potentially exogenously acquired (seeds) for both metabolic networks. We show that the number of seeds needed by both bacteria in the carbon metabolism is extremely reduced. Moreover, only three seeds are common to both metabolic networks, indicating that the complementarity of the two metabolisms is not only manifested in the metabolic capabilities of each bacterium, but also by their different use of the same environment. Furthermore, our results show that the carbon metabolism of S. muelleri may be completely independent of the metabolic network of B. cicadellinicola. On the contrary, the carbon metabolism of the latter appears dependent on the metabolism of S. muelleri, at least for two essential amino acids, threonine and lysine. Next, in order to define which subsets of seeds (precursor sets) are sufficient to produce the metabolites involved in a symbiotic function, we used a graph-based method, PITUFO, that we recently developed. Our results highly refine our knowledge about the complementarity between the metabolisms of the two bacteria and their host. We thus indicate seeds that appear obligatory in the synthesis of metabolites are involved in the symbiotic function. Our results suggest both B. cicadellinicola and S. muelleri may be completely independent of the metabolites provided by the co-resident endocytobiont to produce the carbon backbone of the metabolites provided to the symbiotic system (., thr and lys are only exploited by B. cicadellinicola to produce its proteins).
Author Summary
Some bacteria, called endocytobionts, permanently live inside the cells of a pluricellular organism and often bring an adaptative advantage to their host by providing compounds that the latter cannot produce or find in its diet. The association may involve several species of bacteria within the same host. The sap-feeding insect called glassy-winged sharpshooter thus maintains a permanent metabolic association with two different species of bacteria that it hosts within specialised cells. Complete genome annotations of the two endocytobionts allowed to reconstruction of their metabolism. By manually inspecting those annotations and comparing them to reference metabolic functions, earlier studies revealed a great complementarity between the metabolisms of the two endocytobionts and indicated potential metabolic exchanges between them. However, the metabolism of an organism is complex enough that such an approach could only give a partial description of the metabolic exchanges in the symbiotic system. We therefore determined all the metabolic exchanges in the symbiotic system by a systematic and automatic exploration of the full metabolism of the two endocytobionts in order to detail those leading to the biosynthesis of compounds involved in the symbiotic function of each bacterium. Our results highly refine our knowledge about the complementarity and the connections between the metabolisms of the two bacteria and their host.
doi:10.1371/journal.pcbi.1000904
PMCID: PMC2936742  PMID: 20838465
17.  Cassis: detection of genomic rearrangement breakpoints 
Bioinformatics  2010;26(15):1897-1898.
Summary: Genomes undergo large structural changes that alter their organization. The chromosomal regions affected by these rearrangements are called breakpoints, while those which have not been rearranged are called synteny blocks. Lemaitre et al. presented a new method to precisely delimit rearrangement breakpoints in a genome by comparison with the genome of a related species. Receiving as input a list of one2one orthologous genes found in the genomes of two species, the method builds a set of reliable and non-overlapping synteny blocks and refines the regions that are not contained into them. Through the alignment of each breakpoint sequence against its specific orthologous sequences in the other species, we can look for weak similarities inside the breakpoint, thus extending the synteny blocks and narrowing the breakpoints. The identification of the narrowed breakpoints relies on a segmentation algorithm and is statistically assessed. Here, we present the package Cassis that implements this method of precise detection of genomic rearrangement breakpoints.
Availability: Perl and R scripts are freely available for download at http://pbil.univ-lyon1.fr/software/Cassis/. Documentation with methodological background, technical aspects, download and setup instructions, as well as examples of applications are available together with the package. The package was tested on Linux and Mac OS environments and is distributed under the GNU GPL License.
Contact: Marie-France.Sagot@inria.fr
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btq301
PMCID: PMC2905553  PMID: 20576622
18.  MetExplore: a web server to link metabolomic experiments and genome-scale metabolic networks 
Nucleic Acids Research  2010;38(Web Server issue):W132-W137.
High-throughput metabolomic experiments aim at identifying and ultimately quantifying all metabolites present in biological systems. The metabolites are interconnected through metabolic reactions, generally grouped into metabolic pathways. Classical metabolic maps provide a relational context to help interpret metabolomics experiments and a wide range of tools have been developed to help place metabolites within metabolic pathways. However, the representation of metabolites within separate disconnected pathways overlooks most of the connectivity of the metabolome. By definition, reference pathways cannot integrate novel pathways nor show relationships between metabolites that may be linked by common neighbours without being considered as joint members of a classical biochemical pathway. MetExplore is a web server that offers the possibility to link metabolites identified in untargeted metabolomics experiments within the context of genome-scale reconstructed metabolic networks. The analysis pipeline comprises mapping metabolomics data onto the specific metabolic network of an organism, then applying graph-based methods and advanced visualization tools to enhance data analysis. The MetExplore web server is freely accessible at http://metexplore.toulouse.inra.fr.
doi:10.1093/nar/gkq312
PMCID: PMC2896158  PMID: 20444866
19.  ISMB/ECCB 2009 Stockholm 
Bioinformatics  2009;25(12):1570-1573.
The International Society for Computational Biology (ISCB; http://www.iscb.org) presents the Seventeenth Annual International Conference on Intelligent Systems for Molecular Biology (ISMB), organized jointly with the Eighth Annual European Conference on Computational Biology (ECCB; http://bioinf.mpi-inf.mpg.de/conferences/eccb/eccb.htm), in Stockholm, Sweden, 27 June to 2 July 2009. The organizers are putting the finishing touches on the year's premier computational biology conference, with an expected attendance of 1400 computer scientists, mathematicians, statisticians, biologists and scientists from other disciplines related to and reliant on this multi-disciplinary science. ISMB/ECCB 2009 (http://www.iscb.org/ismbeccb2009/) follows the framework introduced at the ISMB/ECCB 2007 (http://www.iscb.org/ismbeccb2007/) in Vienna, and further refined at the ISMB 2008 (http://www.iscb.org/ismb2008/) in Toronto; a framework developed to specifically encourage increased participation from often under-represented disciplines at conferences on computational biology. During the main ISMB conference dates of 29 June to 2 July, keynote talks from highly regarded scientists, including ISCB Award winners, are the featured presentations that bring all attendees together twice a day. The remainder of each day offers a carefully balanced selection of parallel sessions to choose from: proceedings papers, special sessions on emerging topics, highlights of the past year's published research, special interest group meetings, technology demonstrations, workshops and several unique sessions of value to the broad audience of students, faculty and industry researchers. Several hundred posters displayed for the duration of the conference has become a standard of the ISMB and ECCB conference series, and an extensive commercial exhibition showcases the latest bioinformatics publications, software, hardware and services available on the market today. The main conference is preceded by 2 days of Special Interest Group (SIG) and Satellite meetings running in parallel to the fifth Student Council Symposium on 27 June, and in parallel to Tutorials on 28 June. All scientific sessions take place at the Stockholmsmässan/Stockholm International Fairs conference and exposition facility.
Contact: bj@iscb.org
doi:10.1093/bioinformatics/btp280
PMCID: PMC2687994  PMID: 19447790
20.  Footprints of Inversions at Present and Past Pseudoautosomal Boundaries in Human Sex Chromosomes 
The human sex chromosomes have stopped recombining gradually, which has left five evolutionary strata on the X chromosome. Y inversions are thought to have suppressed X–Y recombination but clear evidence is missing. Here, we looked for such evidence by focusing on a region—the X-added region (XAR)—that includes the pseudoautosomal region and the most recent strata 3 to 5. We estimated and analyzed the whole set of parsimonious scenarios of Y inversions given the gene order in XAR and its Y homolog. Comparing these to scenarios for simulated sequences suggests that the strata 4 and 5 were formed by Y inversions. By comparing the X and Y DNA sequences, we found clear evidence of two Y inversions associated with duplications that coincide with the boundaries of strata 4 and 5. Divergence between duplicates is in agreement with the timing of strata 4 and 5 formation. These duplicates show a complex pattern of gene conversion that resembles the pattern previously found for AMELXY, a stratum 3 locus. This suggests that this locus—despite AMELY being unbroken—was possibly involved in a Y inversion that formed stratum 3. However, no clear evidence supporting the formation of stratum 3 by a Y inversion was found, probably because this stratum is too old for such an inversion to be detectable. Our results strongly support the view that the most recent human strata have arisen by Y inversions and suggest that inversions have played a major role in the differentiation of our sex chromosomes.
doi:10.1093/gbe/evp006
PMCID: PMC2817401  PMID: 20333177
inversion; duplication; recombination; sex chromosomes; evolutionary strata
21.  Assessing the Exceptionality of Coloured Motifs in Networks 
Various methods have been recently employed to characterise the structure of biological networks. In particular, the concept of network motif and the related one of coloured motif have proven useful to model the notion of a functional/evolutionary building block. However, algorithms that enumerate all the motifs of a network may produce a very large output, and methods to decide which motifs should be selected for downstream analysis are needed. A widely used method is to assess if the motif is exceptional, that is, over- or under-represented with respect to a null hypothesis. Much effort has been put in the last thirty years to derive -values for the frequencies of topological motifs, that is, fixed subgraphs. They rely either on (compound) Poisson and Gaussian approximations for the motif count distribution in Erdös-Rényi random graphs or on simulations in other models. We focus on a different definition of graph motifs that corresponds to coloured motifs. A coloured motif is a connected subgraph with fixed vertex colours but unspecified topology. Our work is the first analytical attempt to assess the exceptionality of coloured motifs in networks without any simulation. We first establish analytical formulae for the mean and the variance of the count of a coloured motif in an Erdös-Rényi random graph model. Using simulations under this model, we further show that a Pólya-Aeppli distribution better approximates the distribution of the motif count compared to Gaussian or Poisson distributions. The Pólya-Aeppli distribution, and more generally the compound Poisson distributions, are indeed well designed to model counts of clumping events. Altogether, these results enable to derive a -value for a coloured motif, without spending time on simulations.
doi:10.1186/1687-4153-2009-616234
PMCID: PMC3171434  PMID: 21910927
22.  Metabolic network visualization eliminating node redundance and preserving metabolic pathways 
BMC Systems Biology  2007;1:29.
Background
The tools that are available to draw and to manipulate the representations of metabolism are usually restricted to metabolic pathways. This limitation becomes problematic when studying processes that span several pathways. The various attempts that have been made to draw genome-scale metabolic networks are confronted with two shortcomings: 1- they do not use contextual information which leads to dense, hard to interpret drawings, 2- they impose to fit to very constrained standards, which implies, in particular, duplicating nodes making topological analysis considerably more difficult.
Results
We propose a method, called MetaViz, which enables to draw a genome-scale metabolic network and that also takes into account its structuration into pathways. This method consists in two steps: a clustering step which addresses the pathway overlapping problem and a drawing step which consists in drawing the clustered graph and each cluster.
Conclusion
The method we propose is original and addresses new drawing issues arising from the no-duplication constraint. We do not propose a single drawing but rather several alternative ways of presenting metabolism depending on the pathway on which one wishes to focus. We believe that this provides a valuable tool to explore the pathway structure of metabolism.
doi:10.1186/1752-0509-1-29
PMCID: PMC1934383  PMID: 17608928
23.  SURVEY AND SUMMARY: Current methods of gene prediction, their strengths and weaknesses 
Nucleic Acids Research  2002;30(19):4103-4117.
While the genomes of many organisms have been sequenced over the last few years, transforming such raw sequence data into knowledge remains a hard task. A great number of prediction programs have been developed that try to address one part of this problem, which consists of locating the genes along a genome. This paper reviews the existing approaches to predicting genes in eukaryotic genomes and underlines their intrinsic advantages and limitations. The main mathematical models and computational algorithms adopted are also briefly described and the resulting software classified according to both the method and the type of evidence used. Finally, the several difficulties and pitfalls encountered by the programs are detailed, showing that improvements are needed and that new directions must be considered.
PMCID: PMC140543  PMID: 12364589
24.  Endosymbiosis in trypanosomatids: the genomic cooperation between bacterium and host in the synthesis of essential amino acids is heavily influenced by multiple horizontal gene transfers 
Background
Trypanosomatids of the genera Angomonas and Strigomonas live in a mutualistic association characterized by extensive metabolic cooperation with obligate endosymbiotic Betaproteobacteria. However, the role played by the symbiont has been more guessed by indirect means than evidenced. Symbiont-harboring trypanosomatids, in contrast to their counterparts lacking symbionts, exhibit lower nutritional requirements and are autotrophic for essential amino acids. To evidence the symbiont’s contributions to this autotrophy, entire genomes of symbionts and trypanosomatids with and without symbionts were sequenced here.
Results
Analyses of the essential amino acid pathways revealed that most biosynthetic routes are in the symbiont genome. By contrast, the host trypanosomatid genome contains fewer genes, about half of which originated from different bacterial groups, perhaps only one of which (ornithine cyclodeaminase, EC:4.3.1.12) derived from the symbiont. Nutritional, enzymatic, and genomic data were jointly analyzed to construct an integrated view of essential amino acid metabolism in symbiont-harboring trypanosomatids. This comprehensive analysis showed perfect concordance among all these data, and revealed that the symbiont contains genes for enzymes that complete essential biosynthetic routes for the host amino acid production, thus explaining the low requirement for these elements in symbiont-harboring trypanosomatids. Phylogenetic analyses show that the cooperation between symbionts and their hosts is complemented by multiple horizontal gene transfers, from bacterial lineages to trypanosomatids, that occurred several times in the course of their evolution. Transfers occur preferentially in parts of the pathways that are missing from other eukaryotes.
Conclusion
We have herein uncovered the genetic and evolutionary bases of essential amino acid biosynthesis in several trypanosomatids with and without endosymbionts, explaining and complementing decades of experimental results. We uncovered the remarkable plasticity in essential amino acid biosynthesis pathway evolution in these protozoans, demonstrating heavy influence of horizontal gene transfer events, from Bacteria to trypanosomatid nuclei, in the evolution of these pathways.
doi:10.1186/1471-2148-13-190
PMCID: PMC3846528  PMID: 24015778
Endosymbiosis; Trypanosomatids; Amino acid biosynthesis; Phylogeny; Genomic analyses; Metabolic pathway evolution; Proteobacteria
25.  Exploration of the core metabolism of symbiotic bacteria 
BMC Genomics  2012;13:438.
Background
A large number of genome-scale metabolic networks is now available for many organisms, mostly bacteria. Previous works on minimal gene sets, when analysing host-dependent bacteria, found small common sets of metabolic genes. When such analyses are restricted to bacteria with similar lifestyles, larger portions of metabolism are expected to be shared and their composition is worth investigating. Here we report a comparative analysis of the small molecule metabolism of symbiotic bacteria, exploring common and variable portions as well as the contribution of different lifestyle groups to the reduction of a common set of metabolic capabilities.
Results
We found no reaction shared by all the bacteria analysed. Disregarding those with the smallest genomes, we still do not find a reaction core, however we did find a core of biochemical capabilities. While obligate intracellular symbionts have no core of reactions within their group, extracellular and cell-associated symbionts do have a small core composed of disconnected fragments. In agreement with previous findings in Escherichia coli, their cores are enriched in biosynthetic processes whereas the variable metabolisms have similar ratios of biosynthetic and degradation reactions. Conversely, the variable metabolism of obligate intracellular symbionts is enriched in anabolism.
Conclusion
Even when removing the symbionts with the most reduced genomes, there is no core of reactions common to the analysed symbiotic bacteria. The main reason is the very high specialisation of obligate intracellular symbionts, however, host-dependence alone is not an explanation for such absence. The composition of the metabolism of cell-associated and extracellular bacteria shows that while they have similar needs in terms of the building blocks of their cells, they have to adapt to very distinct environments. On the other hand, in obligate intracellular bacteria, catabolism has largely disappeared, whereas synthetic routes appear to have been selected for depending on the nature of the symbiosis. As more genomes are added, we expect, based on our simulations, that the core of cell-associated and extracellular bacteria continues to diminish, converging to approximately 60 reactions.
doi:10.1186/1471-2164-13-438
PMCID: PMC3543179  PMID: 22938206

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