We aim at combining automatic reasoning on biological sequences and networks with probabilistic approaches to manage, explore and integrate large sets of heterogeneous omics data into networks of interactions allowing to produce biomarkers of their behavior. We shall focus on the identification of a relevant set of biological components required to describe the complexity of a biological phenomenon. Starting from observations at several levels (genomics, transcriptomics, metabolomics) we shall select with products are relevant to the observed phenomena and complement this list with their regulators and those components that share the same metabolic and signalling pathways. Our long-term goal is to exhibit from the network obtained at the previous stage biomarkers for the different biological phenomena observed for an organism. Applications are mainly focused on biomining, based on the experience acquired at CMM in analysing several sets of data on biomining bacteria. Methods combine a fine tuning of sequence analysis, efficient constraint base programming and asymptotic study of Markov models properties.

Both groups are working in bioinformatics, more precisely in integrative biology. They have developed their own computational, statistical or mathematical tools to integrate heterogeneous information into networks of biological interactions, aiming to detect relevant biological signals in complete genomes. In Rennes, the team makes use of constraints based approaches and discrete dynamical systems to model the connections between several levels of cellular observations, in order to identify key regulators from the combination of data. In Chile,  The group develops methods of probabilistic, graph-theory and information- theory nature to analyze omics-data connected to industrial and academic programs of CMM, including biomining, salmon industry and agronomical sector. They have developed methods for biomonitoring systems of complex metagenomics biomining samples which was applied to detect bad-yeasts in the winery sector. Also, they have developed methods to reconstruct at a genomic level metabolic networks.

Anne Siegel (DR CNRS), Jacques Nicolas (DR Inria), François Coste (CR Inria), Dominique Lavenier (DR CNRS), Sylvain Prigent (ph-D student, end 12/14), Santiago Videla (ph-D student, end 09/2014), Sven Thiele (post-doc, end 08/2012). Jeanne Cambefort (IE CNRS). Marie Chevallier (IE ADT Inria, since 10/14). Jérémie Bourdon (Associate professor), Damien Eveillard (Associate professor)

Alejandro Masss (Professor, group leader), Mauricio Gonzalez (Associate Professor), Tomas Pérez (Researcher), Andrès Aravena (Ph-D student, end 10/14), Mauricio Latorre (postdoc, fondecyt), Marko Budinich (biotechnology engineer), Marìa Paz Cortès (biotechnology, PhD), Alex Di Genova (bioinformatics, PhD), Dante Travisany (bioinformatics engineer), Vicente Acuna (Researcher, CMM), Nicola Loira (Post-doc, Fondicyt).

Our main goal for 2014-2016 will be to prove that the bricks of integration listed above can be combined to evidence characteristic biomarkers of bacteria living in extreme environments: mining bacteria (A. ferrooxidans), metal-resistant bacteria (E. faecalis), and bacteria involved in salmon lethality (Piscirickettsia Salmonis). This question will be addressed by coupling proba- bilistic and static dynamical systems methods with constraint programming. For the three targeted applications, the chilean group strong collaborates with biological experts who can perform experimental validations. An important challenge will be to produce predictions of key regulators that could be validated with experimentations. Computationally, this means adding criteria on experimental design to our integration framework. The Chilean team has an expertise in this field through the development of oligos, based on probabilistic studies. Discretizing the criteria appearing in their analysis in order to scale to the size of problems raised by the integration of omics data will be an important issue. More generally, each “brick” of our workflow consists in solving difficult combinatorial optimization problems. The second challenge we will face is to propagate uncertainty throughout the steps of the analysis, by addressing sub-optimal problems without loosing in efficiency. This will be done first by using the new multi-optimization features of the most recent ASP solvers, and second by reducing the space of admissible models by integrating additional constraints (static analysis of biological systems, experimental design).

Experimental investigations. Functional identification of transcription factors ( Biometals 2012. Biotechnology and Bioengineering 2013 )

Lombarde. Constraints-based approach for the identification of core regulators implied in the response to several experimental stresses ( Preliminary results at the french Jobim conference, long papers submitted )

Caspo. Constraints-based approaches to investigate suboptimal solution to combinatorial optimization issues of high complexity ( best paper award. CMSB'2012 , Bioinformatics 2013 )

Theory. Constraints-based approaches to control a Boolean network (ICLP 2013)

Ongoing : application to mining bacteria.

Shogen: Constraints-based approaches for the alignments of genetic map, metabolic networks and gene expression data. ( Internship supervised by S. Thiele) ( Publication in LPNMR 013 )

Meneco: improving the gap-filling step of the reconstruction of a metabolic network ( other publication at LPNMR 2013 )

Pantograph: orthology-based reconstruction of a metabolic network ( BMC Systems Biology 2013 )

Study of minimal precursors sets (Bioinformatics 2012)

Experimental investigations. Metabolomic study of mining bacteria ( Metabolomics 2011, Biotechnology and Bioengineering 2013)

Ongoing: Application of shogen and meneco to mining bacteria and classification of functional modules

A. Aravena, V. Acuña, C. Guziolowski, M. Ostrowski, T. Schaub, D. Eveillard, A. Maass, A. Siegel, Deciphering transcriptional regulations in response to environmental stresses with a logic-based model of causality. Submitted 2015.

 P. Bordron, M. Latorre, M.P. Cortés, M. González, A. Siegel, A. Maass, D. Eveillard, A constraint-based integrative systems ecology approach to decipher bacterial interactions from metagenomic knowledge. Microbiology Open, 2015.

Complete genome sequence of Piscirickettsia salmonis LF-89 (ATCC VR-1361) a major pathogen of farmed salmonid fish R Pulgar, D Travisany, A Zuñiga, A Maass, V Cambiazo Journal of biotechnology 212, 30-31

Global transcriptional responses of Acidithiobacillus ferrooxidans Wenelen under different sulfide minerals M Latorre, N Ehrenfeld, MP Cortés, D Travisany, M Budinich, A Aravena, ... Bioresource Technology

 R. Pulgar, C. Hödar, D. Travisany, A. Zuñiga, C. Domínguez, A. Maass, M. González, V. Cambiazo, Transcriptional response of Atlantic salmon families to/Piscirickettsia salmonis/infection highlights the relevance of the iron-deprivation defence system. Submitted 2014.

A. Aravana, V. Acuna, A. Maass, A. Siegel (2014). Modeling parsimonious putative regulatory networks: complexity and heuristic approach. 15th International Conference on Verification, Model Checking, and Abstract Interpretation (VMCAI) January 19–21, 2014, San Diego, USA. Lecture Notes in Computer Science 8318, 322–336 (2014)

ylvain Prigent, Guillaume Collet, Simon M Dittami, Ludovic Delage, Floriane Ethis De Corny, Olivier Dameron, Damien Eveillard, Sven Thiele, Jeanne Cambefort, Catherine Boyen, Anne Siegel, Thierry Tonon (2014) The genome-scale metabolic network of Ectocarpus siliculosus (EctoGEM): a resource to study brown algal physiology and beyond. Plant Journal, Wiley-Blackwell.

D. Travisany, M. P. Cortés, M. Latorre. A. Di Genova, M. Budinich, R.A. Bobadilla-Fazzini, P. Parada, M. González, A. Maass (2014) A new genome of Acidithiobacillus thiooxidans provides insights into adaptation to bioleaching environment. Research in Microbiology.

P. Bordron, D. Eveillard, A. Maass, A. Siegel and S. Thiele (2013). An ASP application in integrative biology: identification of functional gene units. LPNMR - 12th International Conference on Logic Programming and Nonmonotonic Reasoning.

C. Guziolowski, S. Videla, F. Eduati, S. Thiele, A. Siegel and J. Saez-Rodriguez (2013). Exhaustively characterizing feasible logic models of a signaling network using Answer Set Programming. Bioinformatics.

G. Collet, M. Gebser, S. Prigent, T. Schaub, A. Siegel and S. Thiele (2013). Extending the Metabolic Network of Ectocarpus Siliculosus using Answer Set Programming. LPNMR -12th International Conference on Logic Programming and Nonmonotonic Reasoning.

R. Bobadilla-Fazzini, M. P. Corts, L. Padilla, D. Maturana, M. Budinich, A. Maass, P. Parada (2013) Stoichiometric Modeling of Oxidation of Reduced Inorganic Sulfur Com- pounds (RISCs) in Acidithiobacillus thiooxidans. Biotechnology and Bioengineering 110 (8) 2242-2251.

Loira, N., Dulermo, T., Nicaud, J.-M., and Sherman, D. J. (2012). A genome-scale metabolic model of the lipid-accumulating yeast Yarrowia lipolytica. BMC systems biology, 6(1), 35.

V. Acuna, P. V. Milreu, L. Cottret, A. Marchetti-Spaccamela, L. Stougie, M.-F. Sagot (2012) Algorithms and complexity of enumerating minimal precursor sets in genome-wide metabolic networks, Bioinformatics, Volume 28, Issue 19, 2012, Pages 2474-2483.

Andres Aravena, Carito Guziolowski, Anne Siegel and Alejandro Maass. Using Mutual Information and Answer Set Programming to refine PWM based transcription regulation network . JOBIM Conference. 2012

D. Travisany, A. Di Genova, A. Sepu ́lveda, R. Bobadilla, P. Parada, A. Maass, Draft genome sequence of Sulfobacillus thermosulfidooxidans Cutipay strain, indigenous bacteria isolated from naturally extreme mining environment in the north of Chile . Accepted Journal of Bacteriology 2012

Santiago Videla, Carito Guziolowski, Federica Eduati, Sven Thiele, Niels Grabe, Julio Saez-Rodriguez and Anne Siegel. Revisiting the Training of Logic Models of Protein Signaling Networks with a Formal Approach based on Answer Set Programming CMSB 2012 Best paper award

P. Mart ́ınez, S. G ́alvez, N. Ohtsuka, M. Budinich, M.P. Cort ́es, C. Serpell, K. Nakahi- gashi, A. Hirayama, M. Tomita, T. Soga, S. Mart ́ınez, A. Maass, P. Parada, Metabolomic study of Chilean biomining bacteria Acidithiobacillus ferrooxidans strain Wenelen and Acidithiobacillus thiooxidans strain Licanantay. Metabolomics July 2012

C. Hodar, P. Moreno, A. di Genova, M. Latorre, A. Reyes-Jara, A. Maass, M. Gonz ́alez, V. Cambiazo, Genome wide identification of A. ferrooxidans (ATCC 23270) transcription factors and comparative analysis of ArsR and MerR metal regulators , Biometals 25 (2012) 75-93.

Andres Aravena starts a co-supervised Phd within CMM and the Dyliss project team (july 2010). Defense : december 2013.

Santiago Videla starts a ph-D thesis in the Dyliss team on the associated team scientific project (ANR support) (september 2011). Defense: july 2014.

Tristan Charrier starts a two monthes internship in the team with S. Thiele, D. Eveillard and P. Bordron (june 2012)

Marko Budinich joined France for a six monthes internship (january 2013), followed by a ph-D thesis funded by Univ. Nantes.

A. Di Genova, M.P. Cortes and D. Travisani started a ph-D in Chile (january 2013)

V. Acuna got a 5-years researcher position at CMM (automn 2013)

N. Loira obtained a contract funded by fundycit (automn 2013)

Data and knowledge integration application. All ASP-based tools are freely available as python package on the bioASP webserver: meneco, lombarde, ...

Workflow & webserver: bricks develops within the framework of the associated teams are accessible on line on several webservers using the Mobyle plateform technology. (Santiago de Chile) (Rennes/Bioinformatics) (Nantes/Systems biology)

Integration in dynamical studies Biotempo ANR project

Participation to patent (A. Aravena, A. Maass) Arrangement of nucleotide sequences for the detection and identification of transcripts associated with the resistance or susceptibility to infection of Salmo salar with Piscirickettsia salmonis.

February 2011. Three weeks visit from A. Maass in Rennes

February to July 2011. Five month visit from A. Aravena in Rennes (co-funded by Universite Europeenne de Bretagne and Conicyt). Methods for the construction of transcriptional biological networks

May 2011. One month visit of Marko Budinich (engineer) in Rennes. Reconstruction and study of metabolic network with reduction methods.

June 2011. One month visit of Alex Di Genova (engineer) in Rennes. Detection of structural variations in genomes.

July 2011. Two weeks visit of Damien Eveillard (assistant professor) in Santiago. Co-funded by conycit. Reduction methods for the analysis of metabolic networks.

October 2011. Two weeks visit of François Coste (researcher) in Santiago. Co-funded by conycit.

October 2011. Two weeks visit of Jérémie Bourdon (assistant professor) in Santiago

November 2011. 10 days visit of Anne Siegel (researcher) in Santiago

November-December 2011. One month visit of Sylvain Prigent (ph-D student) in Santiago. Co-funded by conycit.

January to July 2012. Six month visit from A. Aravena (co-supervised ph-D student) in Rennes.

March 2012. Two weeks visit of Santiago Videla (ph-D student) in Santiago.

April 2012. One week visit of Pierre Peterlongo (Inria junior researcher) in Santiago.

April 2012. One week visit of Claire Lemaitre (Inria junior researcher) in Santiago.

September 2012. Two weeks visit of Alejandro Maass (Inria junior researcher) in Rennes and Lyon.

September 2012. Meeting in Lyon.

October 2012. One month visit of Sven Thiele (post-doc Inria) in Santiago.

November 2012. 10 days visit of Damien Eveillard (Associate professor) in Santiago.

November 2012. 1 week visit of Anne Siegel (researcher) in Santiago.

January to July 2013. Six month of Andres Aravena (co-supervised ph-D student) in Rennes.

January to July 2013. Six month of Marko Budinich (internship) in Nantes.

March 2013. Visit of A. Maass in Rennes.

Aprim 2013. 1 week visit of S. Videla in Chile

May 2013. Visit of S. Thiele in Lyon to meet MF Sagot and V. Acuna

June 2013. 2 weeks visit of N. Loira in France

September 2013. Visit of A. Maass in Rennes

June 2014. One month visit of P. Bordron in Rennes.

August 2014. One week visit of O. Sallou in Santiago.

September & October 2014. 6 weeks visit of Maria-Paz Cortes in Rennes.

November 2014. 1/2 week visit of A. Siegel, M. Chevallier, D. Eveillard and J. Bourdon in Santiago de Chile.

August 2015. 2 weeks visit of M. Chevallier in Santiago. Working group for the design of a demo of the integrative workflow applied to A. Ferroxidans.

September 2015. 2 weeks visit of M. Latorre in Rennes. Metabolic network reconstruction workflow applied E. Faecalis.

October 2015. Short visit of A. Maass in Rennes .

November 2015. One week visit of N. Loira in Rennes. Improvments to the meneco tool.

November 2015. Two weeks visit of A. Aravena in Rennes. Implementation of the lombarde tool in the integrative worflow.

December 2015. 10 days visit of A. Siegel, J. Bourdon, M. Chevallier and C. Frioux in Santiago de Chile. Formalisation of metrics used for biochip design, improvement of the integrative workflow demo