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Accueil > Départements > Biologie des Génomes > Olivier LESPINET : Bio-Informatique Moléculaire

Publications de l’équipe


  • T. Denecker, W. Durand, J. Maupetit, C. Hébert, J. - M. Camadro, P. Poulain, et G. Lelandais, « Pixel: a content management platform for quantitative omics data », PeerJ, vol. 7, p. e6623, 2019.
    Résumé : Background: In biology, high-throughput experimental technologies, also referred as "omics" technologies, are increasingly used in research laboratories. Several thousands of gene expression measurements can be obtained in a single experiment. Researchers are routinely facing the challenge to annotate, store, explore and mine all the biological information they have at their disposal. We present here the Pixel web application (Pixel Web App), an original content management platform to help people involved in a multi-omics biological project. Methods: The Pixel Web App is built with open source technologies and hosted on the collaborative development platform GitHub ( It is written in Python using the Django framework and stores all the data in a PostgreSQL database. It is developed in the open and licensed under the BSD 3-clause license. The Pixel Web App is also heavily tested with both unit and functional tests, a strong code coverage and continuous integration provided by CircleCI. To ease the development and the deployment of the Pixel Web App, Docker and Docker Compose are used to bundle the application as well as its dependencies. Results: The Pixel Web App offers researchers an intuitive way to annotate, store, explore and mine their multi-omics results. It can be installed on a personal computer or on a server to fit the needs of many users. In addition, anyone can enhance the application to better suit their needs, either by contributing directly on GitHub (encouraged) or by extending Pixel on their own. The Pixel Web App does not provide any computational programs to analyze the data. Still, it helps to rapidly explore and mine existing results and holds a strategic position in the management of research data.
    Mots-clés : BIM, candida-glabrata, Data cycle analyses, DBG, Omics, Open source, Pixel Web App.

  • E. Godat, J. - C. Preiser, J. - C. Aude, et P. Kalfon, « Dynamic properties of glucose complexity during the course of critical illness: a pilot study », Journal of Clinical Monitoring and Computing, mars 2019.
    Résumé : Methods to control the blood glucose (BG) levels of patients in intensive care units (ICU) improve the outcomes. The development of continuous BG levels monitoring devices has also permitted to optimize these processes. Recently it was shown that a complexity loss of the BG signal is linked to poor clinical outcomes. Thus, it becomes essential to decipher this relation to design efficient BG level control methods. In previous studies the BG signal complexity was calculated as a single index for the whole ICU stay. Although, these approaches did not grasp the potential variability of the BG signal complexity. Therefore, we setup this pilot study using a continuous monitoring of central venous BG levels in ten critically ill patients (EIRUS platform, Maquet Critical CARE AB, Solna, Sweden). Data were processed and the complexity was assessed by the detrended fluctuation analysis and multiscale entropy (MSE) methods. Finally, recordings were split into 24 h overlapping intervals and a MSE analysis was applied to each of them. The MSE analysis on time intervals revealed an entropy variation and allowed periodic BG signal complexity assessments. To highlight differences of MSE between each time interval we calculated the MSE complexity index defined as the area under the curve. This new approach could pave the way to future studies exploring new strategies aimed at restoring blood glucose complexity during the ICU stay.
    Mots-clés : BIM, Continuous glucose monitoring, Critically ill patients, DBG, Glucose control, Multiscale entropy, Signal complexity.

  • L. Marichal, G. Giraudon--Colas, F. Cousin, A. Thill, J. Labarre, Y. Boulard, J. - C. Aude, S. Pin, et J. P. Renault, « Protein–Nanoparticle Interactions: What Are the Protein–Corona Thickness and Organization? », Langmuir, vol. 35, nᵒ 33, p. 10831-10837, août 2019.
    Résumé : Protein adsorption on a surface is generally evaluated in terms of the evolution of the proteins’ structures and functions. However, when the surface is that of a nanoparticle, the protein corona formed around it possesses a particular supramolecular structure that gives a “biological identity” to the new object. Little is known about the actual shape of the protein corona. Here, the protein corona formed by the adsorption of model proteins (myoglobin and hemoglobin) on silica nanoparticles was studied. Small-angle neutron scattering and oxygenation studies were combined to assess both the structural and functional impacts of the adsorption on proteins. Large differences in the oxygenation properties could be found while no significant global shape changes were seen after adsorption. Moreover, the structural study showed that the adsorbed proteins form an organized yet discontinuous monolayer around the nanoparticles.
    Mots-clés : B3S, BIM, DBG, IMAPP, PEPS.
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  • A. Petitalot, E. Dardillac, E. Jacquet, N. Nhiri, J. Guirouilh-Barbat, P. Julien, I. Bouazzaoui, D. Bonte, J. Feunteun, J. A. Schnell, P. Lafitte, J. - C. Aude, C. Nogues, E. Rouleau, R. Lidereau, B. S. Lopez, S. Zinn-Justin, S. M. Caputo, F. Bonnet, N. Jones, V. Bubien, M. Longy, N. Sevenet, S. Krieger, L. Casters, D. Vaur, N. Uhrhammer, Y. J. Bignon, S. Lizard, A. Dumont, F. Revillion, M. Leone, N. Boutry-Kryza, O. Sinilnikova, A. Remenieras, V. Bourdon, T. Noguchi, H. Sobol, P. - O. Harmand, P. Vilquin, P. Pujol, P. Jonveaux, M. Bronner, J. Sokolowska, C. Delnatte, V. Guibert, C. Garrec, S. Bezieau, F. Soubrier, E. Guillerm, F. Coulet, C. Lefol, V. Caux-Moncoutier, L. Golmard, C. Houdayer, D. Stoppa-Lyonnet, C. Delvincoun, O. Beaudoux, D. Muller, C. Toulas, M. Guillaud-Bataille, et B. Bressac-De Paillerets, « Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk », Molecular Cancer Research, vol. 17, nᵒ 1, p. 54-69, janv. 2019.
    Résumé : BRCA1 mutations have been identified that increase the risk of developing hereditary breast and ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected. To better understand the significance of these variants, a high-throughput structural and functional analysis was performed on a large set of BRCA1 VUS. Information on both cellular localization and homology-directed DNA repair (HR) capacity was obtained for 78 BRCT missense variants in the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT domains. This extensive and systematic analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects. A classification is presented on the basis of mutated BRCT domain solubility, phosphopeptide-binding properties, and VUS HR capacity. These data suggest that HR-defective variants, which present, in addition, BRCT domains either insoluble in bacteria or defective for phosphopeptide binding, lead to an increased cancer risk. Furthermore, the data suggest that variants with a WT HR activity and whose BRCT domains bind with a WT affinity to the 5 phosphopeptides are neutral. The case of variants with WT HR activity and defective phosphopeptide binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis. Implications: The analysis of the current study on BRCA1 structural and functional defects on cancer risk and classification presented may improve clinical interpretation and therapeutic selection.
    Mots-clés : B3S, bach1 phosphopeptide, BIM, classification, DBG, dna-damage, domain, functional-analysis, hereditary breast, INTGEN, missense variants, ovarian, repair, structural basis.

  • A. - R. Tidjani, J. - N. Lorenzi, M. Toussaint, E. van Dijk, D. Naquin, O. Lespinet, C. Bontemps, et P. Leblond, « Genome Sequences of 11 Conspecific Streptomyces sp. Strains », Microbiology Resource Announcements, vol. 8, nᵒ 38, p. e00863-19, sept. 2019.
    Résumé : The genomes of 11 conspecific Streptomyces strains, i.e., from the same species and inhabiting the same ecological niche, were sequenced and assembled. This data set offers an ideal framework to assess the genome evolution of Streptomyces species in their ecological context.
    Mots-clés : BIM, DBG, NGS, PF.
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  • A. - R. Tidjani, J. - N. Lorenzi, M. Toussaint, E. van Dijk, D. Naquin, O. Lespinet, C. Bontemps, et P. Leblond, « Massive Gene Flux Drives Genome Diversity between Sympatric Streptomyces Conspecifics », mBio, vol. 10, nᵒ 5, sept. 2019.
    Résumé : In this work, by comparing genomes of closely related individuals of Streptomyces isolated at a spatial microscale (millimeters or centimeters), we investigated the extent and impact of horizontal gene transfer in the diversification of a natural Streptomyces population. We show that despite these conspecific strains sharing a recent common ancestor, all harbored significantly different gene contents, implying massive and rapid gene flux. The accessory genome of the strains was distributed across insertion/deletion events (indels) ranging from one to several hundreds of genes. Indels were preferentially located in the arms of the linear chromosomes (ca. 12 Mb) and appeared to form recombination hot spots. Some of them harbored biosynthetic gene clusters (BGCs) whose products confer an inhibitory capacity and may constitute public goods that can favor the cohesiveness of the bacterial population. Moreover, a significant proportion of these variable genes were either plasmid borne or harbored signatures of actinomycete integrative and conjugative elements (AICEs). We propose that conjugation is the main driver for the indel flux and diversity in Streptomyces populations.IMPORTANCE Horizontal gene transfer is a rapid and efficient way to diversify bacterial gene pools. Currently, little is known about this gene flux within natural soil populations. Using comparative genomics of Streptomyces strains belonging to the same species and isolated at microscale, we reveal frequent transfer of a significant fraction of the pangenome. We show that it occurs at a time scale enabling the population to diversify and to cope with its changing environment, notably, through the production of public goods.
    Mots-clés : BIM, conjugation, DBG, gene transfer, NGS, PF, plasticity, population, Streptomyces.
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  • A. Zaharia, B. Labedan, C. Froidevaux, et A. Denise, « CoMetGeNe: mining conserved neighborhood patterns in metabolic and genomic contexts », BMC bioinformatics, vol. 20, nᵒ 1, p. 19, janv. 2019.
    Résumé : BACKGROUND: In systems biology, there is an acute need for integrative approaches in heterogeneous network mining in order to exploit the continuous flux of genomic data. Simultaneous analysis of the metabolic pathways and genomic context of a given species leads to the identification of patterns consisting in reaction chains catalyzed by products of neighboring genes. Similar such patterns across several species can reveal their mode of conservation throughout the tree of life. RESULTS: We present CoMetGeNe (COnserved METabolic and GEnomic NEighborhoods), a novel method that identifies metabolic and genomic patterns consisting in maximal trails of reactions being catalyzed by products of neighboring genes. Patterns determined by CoMetGeNe in one species are subsequently employed in order to reflect their degree of conservation across multiple prokaryotic species. These interspecies comparisons help to improve genome annotation and can reveal putative alternative metabolic routes as well as unexpected gene ordering occurrences. CONCLUSIONS: CoMetGeNe is an exploratory tool at both the genomic and the metabolic levels, leading to insights into the conservation of functionally related clusters of neighboring enzyme-coding genes. The open-source CoMetGeNe pipeline is freely available at .
    Mots-clés : BIM, complexes, Conserved interspecies patterns, DBG, evolution, gene, Gene neighborhood, geobacter-sulfurreducens, global alignment, Graph mining, Heterogeneous networks, Heterogeneous networks, identification, Metabolic pathway, operons, organization, pathways, protein-interaction networks, Trail finding.


  • N. Abdollahi, A. Albani, E. Anthony, A. Baud, M. Cardon, R. Clerc, D. Czernecki, R. Conte, L. David, A. Delaune, S. Djerroud, P. Fourgoux, N. Guiglielmoni, J. Laurentie, N. Lehmann, C. Lochard, R. Montagne, V. Myrodia, V. Opuu, E. Parey, L. Polit, S. Privé, C. Quignot, M. Ruiz-Cuevas, M. Sissoko, N. Sompairac, A. Vallerix, V. Verrecchia, M. Delarue, R. Guérois, Y. Ponty, S. Sacquin-Mora, A. Carbone, C. Froidevaux, S. Le Crom, O. Lespinet, M. Weigt, S. Abboud, J. Bernardes, G. Bouvier, C. Dequeker, A. Ferré, P. Fuchs, G. Lelandais, P. Poulain, H. Richard, H. Schweke, E. Laine, et A. Lopes, « Meet-U: Educating through research immersion », PLoS computational biology, vol. 14, nᵒ 3, p. e1005992, mars 2018.
    Résumé : We present a new educational initiative called Meet-U that aims to train students for collaborative work in computational biology and to bridge the gap between education and research. Meet-U mimics the setup of collaborative research projects and takes advantage of the most popular tools for collaborative work and of cloud computing. Students are grouped in teams of 4-5 people and have to realize a project from A to Z that answers a challenging question in biology. Meet-U promotes "coopetition," as the students collaborate within and across the teams and are also in competition with each other to develop the best final product. Meet-U fosters interactions between different actors of education and research through the organization of a meeting day, open to everyone, where the students present their work to a jury of researchers and jury members give research seminars. This very unique combination of education and research is strongly motivating for the students and provides a formidable opportunity for a scientific community to unite and increase its visibility. We report on our experience with Meet-U in two French universities with master's students in bioinformatics and modeling, with protein-protein docking as the subject of the course. Meet-U is easy to implement and can be straightforwardly transferred to other fields and/or universities. All the information and data are available at
    Mots-clés : AMIG, B3S, BIM, DBG.

  • M. Benchouaia, H. Ripoche, M. Sissoko, A. Thiébaut, J. Merhej, T. Delaveau, L. Fasseu, S. Benaissa, G. Lorieux, L. Jourdren, S. Le Crom, G. Lelandais, E. Corel, et F. Devaux, « Comparative Transcriptomics Highlights New Features of the Iron Starvation Response in the Human Pathogen Candida glabrata », Frontiers in Microbiology, vol. 9, p. 2689, 2018.
    Résumé : In this work, we used comparative transcriptomics to identify regulatory outliers (ROs) in the human pathogen Candida glabrata. ROs are genes that have very different expression patterns compared to their orthologs in other species. From comparative transcriptome analyses of the response of eight yeast species to toxic doses of selenite, a pleiotropic stress inducer, we identified 38 ROs in C. glabrata. Using transcriptome analyses of C. glabrata response to five different stresses, we pointed out five ROs which were more particularly responsive to iron starvation, a process which is very important for C. glabrata virulence. Global chromatin Immunoprecipitation and gene profiling analyses showed that four of these genes are actually new targets of the iron starvation responsive Aft2 transcription factor in C. glabrata. Two of them (HBS1 and DOM34b) are required for C. glabrata optimal growth in iron limited conditions. In S. cerevisiae, the orthologs of these two genes are involved in ribosome rescue by the NO GO decay (NGD) pathway. Hence, our results suggest a specific contribution of NGD co-factors to the C. glabrata adaptation to iron starvation.
    Mots-clés : Aft, ascomycete fungi, BIM, ChIP-seq, comparative genomics, DBG, evolution, gene regulatory networks, glutathione transferase, messenger-rna, monothiol glutaredoxins, NO GO decay, oxidative stress-response, schistosoma-mansoni, selenite toxicity, yeast, yeast saccharomyces-cerevisiae.

  • T. Denecker et G. Lelandais, « Empowering the detection of ChIP-seq "basic peaks" (bPeaks) in small eukaryotic genomes with a web user-interactive interface », BMC research notes, vol. 11, nᵒ 1, p. 698, oct. 2018.
    Résumé : OBJECTIVE: bPeaks is a peak calling program to detect protein DNA-binding sites from ChIPseq data in small eukaryotic genomes. The simplicity of the bPeaks method is well appreciated by users, but its use via an R package is challenging and time-consuming for people without programming skills. In addition, user feedback has highlighted the lack of a convenient way to carefully explore bPeaks result files. In this context, the development of a web user interface represents an important added value for expanding the bPeaks user community. RESULTS: We developed a new bPeaks application (bPeaks App). The application allows the user to perform all the peak-calling analysis steps with bPeaks in a few mouse clicks via a web browser. We added new features relative to the original R package, particularly the possibility to import personal annotation files to compare the location of the detected peaks with specific genomic elements of interest of the user, in any organism, and a new organization of the result files which are directly manageable via a user-interactive genome browser. This significantly improves the ability of the user to explore all detected basic peaks in detail.
    Mots-clés : BIM, bPeaks, ChIP-seq, DBG, Peak calling, Protein DNA-binding sites, Small eukaryotic genomes.

  • L. M. Godinho, M. E. S. Fadel, C. Monniot, L. Jakutyte, I. Auzat, A. Labarde, K. Djacem, L. Oliveira, R. Carballido-Lopez, S. Ayora, et P. Tavares, « The Revisited Genome of Bacillus subtilis Bacteriophage SPP1 », Viruses-Basel, vol. 10, nᵒ 12, p. 705, déc. 2018.
    Résumé : Bacillus subtilis bacteriophage SPP1 is a lytic siphovirus first described 50 years ago. Its complete DNA sequence was reported in 1997. Here we present an updated annotation of the 44,016 bp SPP1 genome and its correlation to different steps of the viral multiplication process. Five early polycistronic transcriptional units encode phage DNA replication proteins and lysis functions together with less characterized, mostly non-essential, functions. Late transcription drives synthesis of proteins necessary for SPP1 viral particles assembly and for cell lysis, together with a short set of proteins of unknown function. The extensive genetic, biochemical and structural biology studies on the molecular mechanisms of SPP1 DNA replication and phage particle assembly rendered it a model system for tailed phages research. We propose SPP1 as the reference species for a new SPP1-like viruses genus of the Siphoviridae family.
    Mots-clés : Bacillus subtilis, Bacteriophage, BIM, complete nucleotide-sequence, crystal-structure, DBG, DNA replication, dna-replication, functional-analysis, genome organization, nucleoprotein complex, PHAG+, phage spp1, portal protein, Siphoviridae, small-subunit, spp1, structural rearrangements, to-tail interface, VIRO, virus assembly, virus DNA packaging, virus evolution.

  • C. Henríquez-Castillo, H. Botebol, A. Mouton, S. Ramírez-Flandes, J. - C. Lozano, G. Lelandais, S. Andrade, N. Trefault, R. De la Iglesia, et F. - Y. Bouget, « Ostreococcus tauri Luminescent Reporter Lines as Biosensors for Detecting Pollution From Copper-Mine Tailing Effluents in Coastal Environments », Frontiers in Environmental Science, vol. 6, 2018.
    Résumé : Phytoplankton cells are excellent biosensors for environmental monitoring and toxicity assessments in different natural systems. Green algae, in particular, appear to be more responsive to copper (Cu) disturbances. This is interesting considering that Cu pollution in coastal environments has increased over the last century, with enormous repercussions to marine ecosystems. Unfortunately, no high-throughput method exists for the environmental monitoring of Cu toxicity in seawater. To assess potential uses as biosensors of Cu pollution, high-throughput screening was performed on five luminescence reporter lines constructed in the green algae Ostreococcus tauri RCC745. The reporter line expressing the iron storage ferritin protein fused to luciferase (Fer-Luc) was the most sensitive, responding to Cu concentrations in the µM range. Fer-Luc was also the most sensitive reporter line for detecting toxicity in mining-derived polluted seawater predominantly contaminated by soluble Cu. Nevertheless, the Cyclin-Dependent-Kinase A (CDKA) reporter was most suitable for detecting the toxicity of copper-mine tailing effluents containing other metals (e.g., iron). These results highlight that Ostreococcus biosensors can serve as a reliable, inexpensive, and automated, high-throughput laboratory approach for performing seawater analyses of coastal areas subjected to metal disturbances. When challenged with Cu, Ostreococcus tauri not only evidenced a rapid, transcriptional response for the tested genes, but also showed changes in a broad range of genes, especially as related to the stress response. Overall, the obtained results reinforce that a single biosensor is insufficient when dealing with complex mixtures of toxic compounds in natural environments.
    Mots-clés : BIM, Biosensors, CDKA reporter, CDKAL1, Copper pollution, DBG, ferritin, luciferase reporter, Mine tailings, Ostreococcus.
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  • L. Marichal, J. - P. Renault, S. Chédin, G. Lagniel, G. Klein, J. - C. Aude, C. Tellier-Lebegue, J. Armengaud, S. Pin, J. Labarre, et Y. Boulard, « Importance of Post-translational Modifications in the Interaction of Proteins with Mineral Surfaces: The Case of Arginine Methylation and Silica surfaces », Langmuir: the ACS journal of surfaces and colloids, vol. 34, nᵒ 18, p. 5312-5322, mai 2018.
    Résumé : Understanding the mechanisms involved in the interaction of proteins with inorganic surfaces is of major interest for both basic research and practical applications involving nanotechnology. From the list of cellular proteins with the highest affinity for silica nanoparticles, we highlighted the group of proteins containing arginine-glycine-glycine (RGG) motifs. Biochemical experiments confirmed that RGG motifs interact strongly with the silica surfaces. The affinity of these motifs is further increased when the R residue is asymmetrically, but not symmetrically, dimethylated. Molecular dynamics simulations show that the asymmetrical dimethylation generates an electrostatic asymmetry in the guanidinium group of the R residue, orientating and stabilizing it on the silica surface. The RGG motifs (methylated or not) systematically target the siloxide groups on the silica surface through an ionic interaction, immediately strengthened by hydrogen bonds with proximal silanol and siloxane groups. Given that, in vivo, RGG motifs are often asymmetrically dimethylated by specific cellular methylases, our data add support to the idea that this type of methylation is a key mechanism for cells to regulate the interaction of the RGG proteins with their cellular partners.
    Mots-clés : B3S, BIM, DBG, IMAPP, PEPS.

  • V. Reinharz, A. Soule, E. Westhof, J. Waldispuhl, et A. Denise, « Mining for recurrent long-range interactions in RNA structures reveals embedded hierarchies in network families », Nucleic Acids Research, vol. 46, nᵒ 8, p. 3841-3851, mai 2018.
    Résumé : The wealth of the combinatorics of nucleotide base pairs enables RNA molecules to assemble into so-phisticated interaction networks, which are used to create complex 3D substructures. These interaction networks are essential to shape the 3D architecture of the molecule, and also to provide the key elements to carry molecular functions such as protein or ligand binding. They are made of organised sets of long-range tertiary interactions which connect distinct secondary structure elements in 3D structures. Here, we present a de novo data-driven approach to extract automatically from large data sets of full RNA 3D structures the recurrent interaction networks (RINs). Our methodology enables us for the first time to detect the interaction networks connecting distinct components of the RNA structure, highlighting their diversity and conservation through non-related functional RNAs. We use a graphical model to perform pairwise comparisons of all RNA structures available and to extract RINs and modules. Our analysis yields a complete catalog of RNA 3D structures available in the Protein Data Bank and reveals the intricate hierarchical organization of the RNA interaction networks and modules. We assembled our results in an online database ( which will be regularly updated. Within the site, a tool allows users with a novel RNA structure to detect automatically whether the novel structure contains previously observed RINs.
    Mots-clés : 3d motifs, base-pairs, BIM, classification, DBG, discovery, identification, isomorphisms, isostericity matrices, prediction, representation, tertiary interactions.

  • C. M. Vicente, A. Thibessard, J. - N. Lorenzi, M. Benhadj, L. Hotel, D. Gacemi-Kirane, O. Lespinet, P. Leblond, et B. Aigle, « Comparative Genomics among Closely Related Streptomyces Strains Revealed Specialized Metabolite Biosynthetic Gene Cluster Diversity », Antibiotics-Basel, vol. 7, nᵒ 4, p. 86, déc. 2018.
    Résumé : Specialized metabolites are of great interest due to their possible industrial and clinical applications. The increasing number of antimicrobial resistant infectious agents is a major health threat and therefore, the discovery of chemical diversity and new antimicrobials is crucial. Extensive genomic data from Streptomyces spp. confirm their production potential and great importance. Genome sequencing of the same species strains indicates that specialized metabolite biosynthetic gene cluster (SMBGC) diversity is not exhausted, and instead, a pool of novel specialized metabolites still exists. Here, we analyze the genome sequence data from six phylogenetically close Streptomyces strains. The results reveal that the closer strains are phylogenetically, the number of shared gene clusters is higher. Eight specialized metabolites comprise the core metabolome, although some strains have only six core gene clusters. The number of conserved gene clusters common between the isolated strains and their closest phylogenetic counterparts varies from nine to 23 SMBGCs. However, the analysis of these phylogenetic relationships is not affected by the acquisition of gene clusters, probably by horizontal gene transfer events, as each strain also harbors strain-specific SMBGCs. Between one and 15 strain-specific gene clusters were identified, of which up to six gene clusters in a single strain are unknown and have no identifiable orthologs in other species, attesting to the existing SMBGC novelty at the strain level.
    Mots-clés : BIM, biosynthetic gene cluster, clade, coelicolor, DBG, dna, expression, family, lividans, multilocus sequence-analysis, natural-product, specialized metabolites, strain, Streptomyces.


  • J. Audoux, N. Philippe, R. Chikhi, M. Salson, M. Gallopin, M. Gabriel, J. Le Coz, E. Drouineau, T. Commes, et D. Gautheret, « DE-kupl: exhaustive capture of biological variation in RNA-seq data through k-mer decomposition », Genome Biology, vol. 18, nᵒ 1, p. 243, déc. 2017.
    Résumé : We introduce a k-mer-based computational protocol, DE-kupl, for capturing local RNA variation in a set of RNA-seq libraries, independently of a reference genome or transcriptome. DE-kupl extracts all k-mers with differential abundance directly from the raw data files. This enables the retrieval of virtually all variation present in an RNA-seq data set. This variation is subsequently assigned to biological events or entities such as differential long non-coding RNAs, splice and polyadenylation variants, introns, repeats, editing or mutation events, and exogenous RNA. Applying DE-kupl to human RNA-seq data sets identified multiple types of novel events, reproducibly across independent RNA-seq experiments.
    Mots-clés : BIM, DBG, SSFA.

  • M. Boudard, D. Barth, J. Bernauer, A. Denise, et J. Cohen, « GARN2: coarse-grained prediction of 3D structure of large RNA molecules by regret minimization », Bioinformatics (Oxford, England), avr. 2017.
    Résumé : Motivation: Predicting the 3D structure of RNA molecules is a key feature towards predicting their functions. Methods which work at atomic or nucleotide level are not suitable for large molecules. In these cases, coarse-grained prediction methods aim to predict a shape which could be refined later by using more precise methods on smaller parts of the molecule. Results: We developed a complete method for sampling 3D RNA structure at a coarse-grained model, taking a secondary structure as input. One of the novelties of our method is that a second step extracts two best possible structures close to the native, from a set of possible structures. Although our method benefits from the first version of GARN, some of the main features on GARN2 are very different. GARN2 is much faster than the previous version and than the well-known methods of the state-of-art. Our experiments show that GARN2 can also provide better structures than the other state-of-the-art methods. Availability and implementations: GARN2 is written in Java. It is freely distributed and available at: . Contacts: , Supplementary information: Supplementary data are available at Bioinformatics online.
    Mots-clés : BIM, DBG.

  • J. - F. Dallery, N. Lapalu, A. Zampounis, S. Pigné, I. Luyten, J. Amselem, A. H. J. Wittenberg, S. Zhou, M. V. de Queiroz, G. P. Robin, A. Auger, M. Hainaut, B. Henrissat, K. - T. Kim, Y. - H. Lee, O. Lespinet, D. C. Schwartz, M. R. Thon, et R. J. O'Connell, « Gapless genome assembly of Colletotrichum higginsianum reveals chromosome structure and association of transposable elements with secondary metabolite gene clusters », BMC genomics, vol. 18, nᵒ 1, p. 667, août 2017.
    Résumé : BACKGROUND: The ascomycete fungus Colletotrichum higginsianum causes anthracnose disease of brassica crops and the model plant Arabidopsis thaliana. Previous versions of the genome sequence were highly fragmented, causing errors in the prediction of protein-coding genes and preventing the analysis of repetitive sequences and genome architecture. RESULTS: Here, we re-sequenced the genome using single-molecule real-time (SMRT) sequencing technology and, in combination with optical map data, this provided a gapless assembly of all twelve chromosomes except for the ribosomal DNA repeat cluster on chromosome 7. The more accurate gene annotation made possible by this new assembly revealed a large repertoire of secondary metabolism (SM) key genes (89) and putative biosynthetic pathways (77 SM gene clusters). The two mini-chromosomes differed from the ten core chromosomes in being repeat- and AT-rich and gene-poor but were significantly enriched with genes encoding putative secreted effector proteins. Transposable elements (TEs) were found to occupy 7% of the genome by length. Certain TE families showed a statistically significant association with effector genes and SM cluster genes and were transcriptionally active at particular stages of fungal development. All 24 subtelomeres were found to contain one of three highly-conserved repeat elements which, by providing sites for homologous recombination, were probably instrumental in four segmental duplications. CONCLUSION: The gapless genome of C. higginsianum provides access to repeat-rich regions that were previously poorly assembled, notably the mini-chromosomes and subtelomeres, and allowed prediction of the complete SM gene repertoire. It also provides insights into the potential role of TEs in gene and genome evolution and host adaptation in this asexual pathogen.
    Mots-clés : accessory chromosomes, BIM, Colletotrichum higginsianum, DBG, Fungal genome, optical map, secondary metabolism genes, segmental duplication, SMRT sequencing, subtelomeres, transposable elements.

  • K. Forslund, C. Pereira, S. Capella-Gutierrez, A. Sousa da Silva, A. Altenhoff, J. Huerta-Cepas, M. Muffato, M. Patricio, K. Vandepoele, I. Ebersberger, J. Blake, J. T. Fernández Breis, Quest for Orthologs Consortium, B. Boeckmann, T. Gabaldón, E. Sonnhammer, C. Dessimoz, et S. Lewis, « Gearing up to handle the mosaic nature of life in the quest for orthologs », Bioinformatics (Oxford, England), août 2017.
    Résumé : The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been improved, evaluated, and adapted to handle large datasets. All this would not have occurred without the long-term collaboration of Consortium members. Meeting regularly to review and coordinate complementary activities from a broad spectrum of innovative researchers clearly benefits the community. Highlights of the meeting include addressing sources of and legitimacy of disagreements between orthology calls, the context dependency of orthology definitions, special challenges encountered when analyzing very anciently rooted orthologies, orthology in the light of whole-genome duplications, and the concept of orthologous versus paralogous relationships at different levels, including domain-level orthology. Furthermore, particular needs for different applications (e.g. plant genomics, ancient gene families, and others) and the infrastructure for making orthology inferences available (e.g. interfaces with model organism databases) were discussed, with several ongoing efforts that are expected to be reported on during the upcoming 2017 QfO meeting.
    Mots-clés : BIM, DBG.

  • A. Glatigny, P. Gambette, A. Bourand-Plantefol, G. Dujardin, et M. - H. Mucchielli-Giorgi, « Development of an in silico method for the identification of subcomplexes involved in the biogenesis of multiprotein complexes in Saccharomyces cerevisiae », BMC systems biology, vol. 11, nᵒ 1, p. 67, juill. 2017.
    Résumé : BACKGROUND: Large sets of protein-protein interaction data coming either from biological experiments or predictive methods are available and can be combined to construct networks from which information about various cell processes can be extracted. We have developed an in silico approach based on these information to model the biogenesis of multiprotein complexes in the yeast Saccharomyces cerevisiae. RESULTS: Firstly, we have built three protein interaction networks by collecting the protein-protein interactions, which involved the subunits of three complexes, from different databases. The protein-protein interactions come from different kinds of biological experiments or are predicted. We have chosen the elongator and the mediator head complexes that are soluble and exhibit an architecture with subcomplexes that could be functional modules, and the mitochondrial bc 1 complex, which is an integral membrane complex and for which a late assembly subcomplex has been described. Secondly, by applying a clustering strategy to these networks, we were able to identify subcomplexes involved in the biogenesis of the complexes as well as the proteins interacting with each subcomplex. Thirdly, in order to validate our in silico results for the cytochrome bc1 complex we have analysed the physical interactions existing between three subunits by performing immunoprecipitation experiments in several genetic context. CONCLUSIONS: For the two soluble complexes (the elongator and mediator head), our model shows a strong clustering of subunits that belong to a known subcomplex or module. For the membrane bc 1 complex, our approach has suggested new interactions between subunits in the early steps of the assembly pathway that were experimentally confirmed. Scripts can be downloaded from the site: .
    Mots-clés : BIM, BIOCELL, BIOMIT, Complex assembly, DBG, Graph clustering, PPI network, Protein complex, Protein-protein interactions, Subcomplex.

  • A. Thiébaut, T. Delaveau, M. Benchouaia, J. Boeri, M. Garcia, G. Lelandais, et F. Devaux, « The CCAAT-Binding Complex Controls Respiratory Gene Expression and Iron Homeostasis in Candida Glabrata », Scientific Reports, vol. 7, nᵒ 1, p. 3531, juin 2017.
    Résumé : The CCAAT-binding complex (CBC) is a heterotrimeric transcription factor which is widely conserved in eukaryotes. In the model yeast S. cerevisiae, CBC positively controls the expression of respiratory pathway genes. This role involves interactions with the regulatory subunit Hap4. In many pathogenic fungi, CBC interacts with the HapX regulatory subunit to control iron homeostasis. HapX is a bZIP protein which only shares with Hap4 the Hap4Like domain (Hap4L) required for its interaction with CBC. Here, we show that CBC has a dual role in the pathogenic yeast C. glabrata. It is required, along with Hap4, for the constitutive expression of respiratory genes and it is also essential for the iron stress response, which is mediated by the Yap5 bZIP transcription factor. Interestingly, Yap5 contains a vestigial Hap4L domain. The mutagenesis of this domain severely reduced Yap5 binding to its targets and compromised its interaction with Hap5. Hence, Yap5, like HapX in other species, acts as a CBC regulatory subunit in the regulation of iron stress response. This work reveals new aspects of iron homeostasis in C. glabrata and of the evolution of the role of CBC and Hap4L-bZIP proteins in this process.
    Mots-clés : BIM, DBG.


  • S. Hacquard, B. Kracher, K. Hiruma, P. C. Münch, R. Garrido-Oter, M. R. Thon, A. Weimann, U. Damm, J. - F. Dallery, M. Hainaut, B. Henrissat, O. Lespinet, S. Sacristán, E. V. L. van Themaat, E. Kemen, A. C. McHardy, P. Schulze-Lefert, et R. J. O'Connell, « Erratum: Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi », Nature Communications, vol. 7, p. 13072, sept. 2016.

  • S. Hacquard, B. Kracher, K. Hiruma, P. C. Münch, R. Garrido-Oter, M. R. Thon, A. Weimann, U. Damm, J. - F. Dallery, M. Hainaut, B. Henrissat, O. Lespinet, S. Sacristán, E. Ver Loren van Themaat, E. Kemen, A. C. McHardy, P. Schulze-Lefert, et R. J. O'Connell, « Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi », Nature Communications, vol. 7, p. 11362, mai 2016.
    Résumé : The sessile nature of plants forced them to evolve mechanisms to prioritize their responses to simultaneous stresses, including colonization by microbes or nutrient starvation. Here, we compare the genomes of a beneficial root endophyte, Colletotrichum tofieldiae and its pathogenic relative C. incanum, and examine the transcriptomes of both fungi and their plant host Arabidopsis during phosphate starvation. Although the two species diverged only 8.8 million years ago and have similar gene arsenals, we identify genomic signatures indicative of an evolutionary transition from pathogenic to beneficial lifestyles, including a narrowed repertoire of secreted effector proteins, expanded families of chitin-binding and secondary metabolism-related proteins, and limited activation of pathogenicity-related genes in planta. We show that beneficial responses are prioritized in C. tofieldiae-colonized roots under phosphate-deficient conditions, whereas defense responses are activated under phosphate-sufficient conditions. These immune responses are retained in phosphate-starved roots colonized by pathogenic C. incanum, illustrating the ability of plants to maximize survival in response to conflicting stresses.
    Mots-clés : BIM, DBG.

  • G. Klein, C. Mathé, M. Biola-Clier, S. Devineau, E. Drouineau, E. Hatem, L. Marichal, B. Alonso, J. - C. Gaillard, G. Lagniel, J. Armengaud, M. Carrière, S. Chédin, Y. Boulard, S. Pin, J. - P. Renault, J. - C. Aude, et J. Labarre, « RNA-binding proteins are a major target of silica nanoparticles in cell extracts », Nanotoxicology, vol. 10, nᵒ 10, p. 1555-1564, déc. 2016.
    Résumé : Upon contact with biological fluids, nanoparticles (NPs) are readily coated by cellular compounds, particularly proteins, which are determining factors for the localization and toxicity of NPs in the organism. Here, we improved a methodological approach to identify proteins that adsorb on silica NPs with high affinity. Using large-scale proteomics and mixtures of soluble proteins prepared either from yeast cells or from alveolar human cells, we observed that proteins with large unstructured region(s) are more prone to bind on silica NPs. These disordered regions provide flexibility to proteins, a property that promotes their adsorption. The statistical analyses also pointed to a marked overrepresentation of RNA-binding proteins (RBPs) and of translation initiation factors among the adsorbed proteins. We propose that silica surfaces, which are mainly composed of Si-O(-) and Si-OH groups, mimic ribose-phosphate molecules (rich in -O(-) and -OH) and trap the proteins able to interact with ribose-phosphate containing molecules. Finally, using an in vitro assay, we showed that the sequestration of translation initiation factors by silica NPs results in an inhibition of the in vitro translational activity. This result demonstrates that characterizing the protein corona of various NPs would be a relevant approach to predict their potential toxicological effects.
    Mots-clés : B3S, BIM, DBG, IMAPP, intrinsically disordered protein, PEPS, Protein corona, proteomics, RNA binding protein, silica nanoparticles.

  • Z. Yi, M. Manil-Ségalen, L. Sago, A. Glatigny, V. Redeker, R. Legouis, et M. - H. Mucchielli-Giorgi, « SAFER, an Analysis Method of Quantitative Proteomic Data, Reveals New Interactors of the C. elegans Autophagic Protein LGG-1 », Journal of Proteome Research, vol. 15, nᵒ 5, p. 1515-1523, mai 2016.
    Résumé : Affinity purifications followed by mass spectrometric analysis are used to identify protein-protein interactions. Because quantitative proteomic data are noisy, it is necessary to develop statistical methods to eliminate false-positives and identify true partners. We present here a novel approach for filtering false interactors, named "SAFER" for mass Spectrometry data Analysis by Filtering of Experimental Replicates, which is based on the reproducibility of the replicates and the fold-change of the protein intensities between bait and control. To identify regulators or targets of autophagy, we characterized the interactors of LGG1, a ubiquitin-like protein involved in autophagosome formation in C. elegans. LGG-1 partners were purified by affinity, analyzed by nanoLC-MS/MS mass spectrometry, and quantified by a label-free proteomic approach based on the mass spectrometric signal intensity of peptide precursor ions. Because the selection of confident interactions depends on the method used for statistical analysis, we compared SAFER with several statistical tests and different scoring algorithms on this set of data. We show that SAFER recovers high-confidence interactors that have been ignored by the other methods and identified new candidates involved in the autophagy process. We further validated our method on a public data set and conclude that SAFER notably improves the identification of protein interactors.
    Mots-clés : atg-8/LC3, Autophagy, BIM, BIOCELL, C. elegans, DBG, label free mass spectrometry, OTOFAG, PF, proteomics, SICAPS, statistical methodology.


  • M. Boudard, J. Bernauer, D. Barth, J. Cohen, et A. Denise, « GARN: Sampling RNA 3D Structure Space with Game Theory and Knowledge-Based Scoring Strategies », PloS One, vol. 10, nᵒ 8, p. e0136444, 2015.
    Résumé : Cellular processes involve large numbers of RNA molecules. The functions of these RNA molecules and their binding to molecular machines are highly dependent on their 3D structures. One of the key challenges in RNA structure prediction and modeling is predicting the spatial arrangement of the various structural elements of RNA. As RNA folding is generally hierarchical, methods involving coarse-grained models hold great promise for this purpose. We present here a novel coarse-grained method for sampling, based on game theory and knowledge-based potentials. This strategy, GARN (Game Algorithm for RNa sampling), is often much faster than previously described techniques and generates large sets of solutions closely resembling the native structure. GARN is thus a suitable starting point for the molecular modeling of large RNAs, particularly those with experimental constraints. GARN is available from:
    Mots-clés : Algorithms, BIM, DBG, Game Theory, Knowledge Bases, Models, Molecular, RNA, RNA Folding.

  • B. Brancotte, B. Yang, G. Blin, S. Cohen-Boulakia, A. Denise, et S. Hamel, « Rank aggregation with ties: experiments and analysis », Proceedings of the VLDB Endowment, vol. 8, nᵒ 11, p. 1202-1213, juill. 2015.

  • U. Gophna, D. M. Kristensen, Y. I. Wolf, O. Popa, C. Drevet, et E. V. Koonin, « No evidence of inhibition of horizontal gene transfer by CRISPR-Cas on evolutionary timescales », The ISME journal, vol. 9, nᵒ 9, p. 2021-2027, sept. 2015.
    Résumé : The CRISPR (clustered, regularly, interspaced, short, palindromic repeats)-Cas (CRISPR-associated genes) systems of archaea and bacteria provide adaptive immunity against viruses and other selfish elements and are believed to curtail horizontal gene transfer (HGT). Limiting acquisition of new genetic material could be one of the sources of the fitness cost of CRISPR-Cas maintenance and one of the causes of the patchy distribution of CRISPR-Cas among bacteria, and across environments. We sought to test the hypothesis that the activity of CRISPR-Cas in microbes is negatively correlated with the extent of recent HGT. Using three independent measures of HGT, we found no significant dependence between the length of CRISPR arrays, which reflects the activity of the immune system, and the estimated number of recent HGT events. In contrast, we observed a significant negative dependence between the estimated extent of HGT and growth temperature of microbes, which could be explained by the lower genetic diversity in hotter environments. We hypothesize that the relevant events in the evolution of resistance to mobile elements and proclivity for HGT, to which CRISPR-Cas systems seem to substantially contribute, occur on the population scale rather than on the timescale of species evolution.
    Mots-clés : Adaptive Immunity, Archaea, bacteria, BIM, Biological Evolution, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, DBG, Gene Transfer, Horizontal, Genome, Bacterial, Models, Genetic, Temperature, Viruses.

  • S. Ithurbide, E. Bentchikou, G. Coste, B. Bost, P. Servant, et S. Sommer, « Single Strand Annealing Plays a Major Role in RecA-Independent Recombination between Repeated Sequences in the Radioresistant Deinococcus radiodurans Bacterium », PLoS genetics, vol. 11, nᵒ 10, p. e1005636, oct. 2015.
    Résumé : The bacterium Deinococcus radiodurans is one of the most radioresistant organisms known. It is able to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Our work aims to highlight the genes involved in recombination between 438 bp direct repeats separated by intervening sequences of various lengths ranging from 1,479 bp to 10,500 bp to restore a functional tetA gene in the presence or absence of radiation-induced DNA double strand breaks. The frequency of spontaneous deletion events between the chromosomal direct repeats were the same in recA+ and in ΔrecA, ΔrecF, and ΔrecO bacteria, whereas recombination between chromosomal and plasmid DNA was shown to be strictly dependent on the RecA and RecF proteins. The presence of mutations in one of the repeated sequence reduced, in a MutS-dependent manner, the frequency of the deletion events. The distance between the repeats did not influence the frequencies of deletion events in recA+ as well in ΔrecA bacteria. The absence of the UvrD protein stimulated the recombination between the direct repeats whereas the absence of the DdrB protein, previously shown to be involved in DNA double strand break repair through a single strand annealing (SSA) pathway, strongly reduces the frequency of RecA- (and RecO-) independent deletions events. The absence of the DdrB protein also increased the lethal sectoring of cells devoid of RecA or RecO protein. γ-irradiation of recA+ cells increased about 10-fold the frequencies of the deletion events, but at a lesser extend in cells devoid of the DdrB protein. Altogether, our results suggest a major role of single strand annealing in DNA repeat deletion events in bacteria devoid of the RecA protein, and also in recA+ bacteria exposed to ionizing radiation.
    Mots-clés : BIM, DBG, Deinococcus, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Gamma Rays, Genome, Mutation, Radiation Tolerance, RBA, Rec A Recombinases, Recombination, Genetic.

  • J. - P. Lasserre, A. Dautant, R. S. Aiyar, R. Kucharczyk, A. Glatigny, D. Tribouillard-Tanvier, J. Rytka, M. Blondel, N. Skoczen, P. Reynier, L. Pitayu, A. Rotig, A. Delahodde, L. M. Steinmetz, G. Dujardin, V. Procaccio, et J. - P. di Rago, « Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies », Disease Models & Mechanisms, vol. 8, nᵒ 6, p. 509-526, juin 2015.
    Mots-clés : Animals, BIM, BIOCELL, BIOMIT, DBG, DNA, Fungal, Drug screening, FDMITO, Genetic suppressors, Humans, mitochondria, Mitochondrial disease, Mitochondrial Diseases, Models, Biological, OXPHOS, Saccharomyces cerevisiae, Translational Medical Research, Yeast.
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Publications Principales avant 2015

-  Bost B, Veitia R (2014). Dominance and interloci interactions in transcriptional activation cascades : A model explaining compensatory mutations and inheritance patterns. BioEssays 36(1) : 84–92.

-  Darty K, Denise A and Ponty Y (2009). VARNA : Interactive drawing and editing of the RNA secondary structure. Bioinformatics 25(15):1974-1975.

-  Dufresne M, Lespinet O, Daboussi MJ, Hua-Van A (2011) Genome-Wide Comparative Analysis of pogo-Like Transposable Elements in Different Fusarium Species. Journal of Molecular Evolution 73 : 230-243.

-  Espagne E, Lespinet O, Malagnac F, Da Silva C, Jaillon O, Porcel BM, Couloux A, Aury JM, Ségurens B, Poulain J, Anthouard V, Grossetete S, Khalili H, Coppin E, Déquard-Chablat M, Picard M, Contamine V, Arnaise S, Bourdais A, Berteaux-Lecellier V, Gautheret D, de Vries RP, Battaglia E, Coutinho PM, Danchin EG, Henrissat B, Khoury RE, Sainsard-Chanet A, Boivin A, Pinan-Lucarré B, Sellem CH, Debuchy R, Wincker P, Weissenbach J, Silar P. (2008) The genome sequence of the model ascomycete fungus Podospora anserina. Genome Biol. 9(5):R77.

-  Glatigny A, Mathieu L, Herbert CJ, Dujardin J, Meunier B, Mucchielli-Giorgi MH (2011) An in silico approach combined with in vivo experiments enables the identification of a new protein controlling the biogenesis of respiratory complexes in Saccharomyces cerevisiae. BMC System Biology, 5 : 173-185.

-  Grossetête S, Labedan B, Lespinet O. (2010) FUNGIpath : a tool to assess fungal metabolic pathways predicted by orthology. BMC Genomics,11:81.

-  Lamiable A, Quessette F, Vial S, Barth D, Denise A, (2012), An algorithmic game-theory approach for coarse-grain prediction of RNA 3D structure, IEEE/ACM Transactions on Computational Biology and Bioinformatics, 10(1) : 193-199.

-  Lopes A, Sacquin-Mora S, Dimitrova V, Laine E, Ponty Y, Carbone A (2013). Protein-protein interactions in a crowded environment : an analysis via cross-docking simulations and evolutionary information. PLoS Comput Biol. 9(12):e1003369

-  Lopes A, Tavares P, Petit MA, Guérois R, Zinn-Justin S (2014). Automated classification of tailed bacteriophages according to their neck organization. BMC Genomics, in press.

-  Pereira C, Denise A, Lespinet O (2014). A meta-approach for improving the prediction and the functional annotation of ortholog groups. BMC Genomics

-  Mathé C, Devineau S, Aude J-C, Lagniel G, Chédin S, Legros V, Mathon M-H, Renault J-P, Pin S, Boulard Y, Labarre J : Structural determinants for protein adsorption/non-adsorption to silica surface. PLoS ONE 2013, 8:e81346.

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