Biochemistry & MCB.

The final aim at this area of BIFI is to understand and to control biological systems depending on proteins that have interest for chemical, biotechnological, pharmacological and biomedical applications. Knowledge of protein behaviour at molecular and cellular levels allows interpretation of the macroscopic mechanisms of the cellular functions in which they are involved, but many of the parameters controlling these processes still remain unknown. Proteins adopt an organized three-dimensional structure closely related with their function that can be regulated by the interaction with other biomolecules and/or small organic molecules. Defective structural arrangements can prevent protein interaction with other molecules, provoking many different illnesses in human beings.

Many other illnesses are also produced by infectious viruses and microorganisms, and a way of stopping them could be to block a step of their vital cycle involving a protein or biomolecule. Moreover, small molecules from the environment can also be either toxic inhibitors or activatiors of particular activities in different organisms, and in many cases they might be used as effectors of the expression some genes, and the production or action of particular proteins.  The research lines in Biochemistry and Molecular and Cellular Biology at BIFI study different biological systems involved in key metabolic routes that serve as model for other systems combining classic methodologies from this area with biophysical and computational methods. Applications of the obtained knowledge are additionally being used to control and to modulate the behaviour of particular systems with benefits for the society.

Genetic and evolution of Mycobacterium tuberculosis

Genetic and evolution of Mycobacterium tuberculosis

Head of the Research Line:

Jesús Gonzalo-Asensio


Carlos Martín Montañés (Full Professor)
Esther Broset Blasco (Postdoc)
Irene Pérez Sanchez (DGA Grant)
Ana Picó Marco (Lab Technician)
Juan Calvet Seral (DGA Grant)
Elena Campos Pardos (FPU)



According to the last WHO report, Tuberculosis (TB) is responsible for 1.8 million deaths and causes 10.4 million new TB cases worldwide per year. Cumulative data indicate that TB has killed 1 billion people in the past 200 years, which turns it as the biggest killer compared to other infectious diseases as plague, influenza, smallpox, malaria, cholera or AIDS.

TB in humans is mainly caused by the Mycobacterium tuberculosis bacillus. However, other Mycobacterium species are also able to infect humans. These include M. canettii and M. africanum, responsible for human cases geographically restricted to East- and West-African countries respectively. In addition, a number of Mycobacterium species are also able to cause TB in mammals, which represents an economic problem as well as a zoonotic risk for humans. Overall, these species constitute the M. tuberculosis Complex (MTBC). (Figure 1)


Figure 1: Schematic phylogenetic relationships of the MTBC. Phylogenetic distribution of M. canettii, the L1-L7 lineages of M. tuberculosis and the animal-adapted species. The figure also shows the geographic distribution of each lineage and the preferred host. Adaptado de Broset et al. mBio 2015.

To gain a complete evolutionary perspective, it is highly recomended to extend genomic studies to the whole MTBC. Our cumulative knowledge in mycobacterial genomes indicates that mutations in the PhoPR two-component virulence system were acquired during the natural evolution of mycobacterial species probably to ensure adaptation to different hosts (Gonzalo-Asensio et al, PNAS 2014). PhoPR is a well-known regulator of pathogenic phenotypes in the Mycobacterium tuberculosis complex (MTBC) including secretion of the virulent factor ESAT-6 (Broset et al. mBio 2015), biosynthesis of acyltrehalose-based lipids (Gonzalo-Asensio et al. JBC 2008) or modulation of antigen export (Solans et al. PLoS pathogens 2014) (Figure 2).


Figure 2. Molecular characterization of the PhoPR Two-Component System. A. Positioning of the PhoP transcription factor relative to the RNA polymerase and its target genes measured as the most probable values from ChIP-seq data. The PhoP consensus motif (TCACAG-N5-TCACAG) is also indicated. B. ChIP-seq reads from representative promoters of PhoP-regulated genes. Note the significant increase in ChIP-seq peaks in the wild-type strain relative to its phoP mutant indicative of a specific interaction of PhoP with these regions. C. PhoP binding motifs elucidated from ChIP-seq data shown in panel B. Distance to the start codon of target genes is also indicated. D. Genomic location of relevant phoP polymorphisms in the MTBC. Insertions of IS6110 in the promoter region and their positions relative to the phoP start codon are shown. Amino acid positions of the Asp71 residue involved in the phosphotransfer reaction and the Ser219Leu substitution in H37Ra are also indicated. E. Ribbon model of the DNA-binding domain of PhoP superimposed on the structure of a PhoB-DNA complex. Solid spheres show the wild-type serine 219 in H37Rv (left) or the leucine residue that appears in H37Ra (right) (Adapted from Gonzalo-Asensio et al. J. Bacteriol 2008). The mutant leucine residue is expected to interfere with DNA binding and/or recognition. F. Secondary structure of the PhoR sensor kinase indicating its membrane topology. Each domain has been coloured individually indicating the presence of α-helices (“racetrack” ovals) and β-strands (arrows). Note the presence of PhoR polymorphisms in the sensor loop located in the periplasmic space. Position of the Histidine involved in the phosphotransfer reaction is also indicated. Adapted from Broset et al. mBio 2015.

Evolutionarily conserved polymorphisms in PhoPR from M. africanum and animal-adapted species result in loss of functional phenotypes. Interestingly, some members of the MTBC have acquired compensatory mutations to counteract these polymorphisms and likely to maintain their pathogenic potential. Some of these compensatory mutations include the insertion of the IS6110 element upstream phoPR in a particular M. bovis strain able to transmit between humans or polymorphisms in M. africanum and M. bovis affecting the regulatory region of the espACD operon, which allow PhoPR independent ESAT-6 secretion (Gonzalo-Asensio et al. PNAS 2014) (Figure 3).



Figure 3. Comparative illustration of PhoPR-regulated phenotypes in M. tuberculosis, M. bovis, M. africanum L6 and a M. tuberculosis phoP mutant. M. tuberculosis carrying a functional PhoR is able to sense its cognate stimulus and subsequently phosphorylate PhoP. Phosphorylated PhoP regulates three well-known phenotypes including synthesis of SL and DAT/PAT (via pks2 and pks3 regulation), secretion of ESAT-6 (through espA regulation) and post-transcriptional regulation of tatC (mediated by the mcr7 non-coding RNA). M. bovis and M. africanum L6 carrying a defective PhoR G71I allele are expected to have defects in PhoP phosphorylation, as a consequence these strains lacks SL, DAT and PAT. However, ESAT-6 secretion in these strains is restored by compensatory mutations in the espACD promoter region that include RD8 deletion and species-specific polymorphisms (asterisks). M. tuberculosis phoP mutants lack the aforementioned PhoP-regulated phenotypes and consequently does not synthesize SL, DAT and PAT or secrete ESAT-6. These mutants also have a deregulated TAT system and consequently secrete higher amounts of TAT substrates that include the antigens Ag85A and Ag85C. Consequently, adequately attenuated M. tuberculosis phoP-based vaccine strains, such as MTBVAC, are expected to induce long-lasting immunogenicity in clinical trials. Adapted de Broset et al. mBio 2015

Our research line is focused on the rising significance of PhoPR in the evolution of the MTBC and its potential application in the construction of new attenuated vaccines based on phoPR inactivation (Figure 3). In this context, the live-attenuated MTBVAC based on a phoP/fadD26 deletion mutant of M. tuberculosis is the first vaccine of this kind to successfully enter clinical development, representing a historic milestone in the field of vaccinology.


Relevant publications

1.- New insights into the transposition mechanisms of IS6110 and its dynamic distribution between Mycobacterium tuberculosis Complex lineages. Jesús Gonzalo-Asensio*, Irene Pérez, Nacho Aguiló, Santiago Uranga, Ana Picó, Carlos Lampreave, Alberto Cebollada, Isabel Otal, Sofía Samper, Carlos Martín. 2018.. PLoS Genetics, IF= 6,1, D1 Genética y Herencia

2.- Reactogenicity to major tuberculosis antigens absent in BCG is essential to improve protection against Mycobacterium tuberculosis. Nacho Aguiló, Jesús Gonzalo-Asensio, Samuel Alvarez-Arguedas, Dessislava Marinova, Ana Belen Gomez, Santiago Uranga, Ralf Spallek, Mahavir Singh, Régine Audran, François Spertini, Carlos Martin. 2017. “” Nature Communications, IF=12,124, D1 Ciencias Multidisciplinares

3.- Evolutionary landscape of the Mycobacterium tuberculosis complex from the viewpoint of PhoPR: implications in virulence regulation and application to vaccine development. Esther Broset, Carlos Martín and Jesús Gonzalo-Asensio*. 2015. mBio, IF=6.786, D1 microbiology.

4.- Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Jesús Gonzalo-Asensio, Wladimir Malaga, Alexandre Pawlik, Catherine Astarie-Dequeker, Charlotte Passemar, Flavie Moreau, Françoise Laval, Mamadou Daffé, Carlos Martin, Roland Brosch, Christophe Guilhot. 2014 PROC. NATL. ACAD. SCI. USA, IF=9.809, D1 multidisciplinary sciences.

5.- A specific polymorphism in Mycobacterium tuberculosis H37Rv causes differential ESAT-6 expression and identifies WhiB6 as a novel ESX-1 component. Luis Solans, Nacho Aguiló, Sofía Samper, Alexandre Pawlik, Wafa Frigui, Carlos Martín, Roland Brosch, Jesús Gonzalo-Asensio*. 2014. Infection And Immunity, IF=4,156, Q1 Infectious Diseases.

6.- The PhoP-dependent ncRNA Mcr7 modulates the TAT secretion system in Mycobacterium tuberculosis. Luis Solans*, Jesús Gonzalo-Asensio*, Claudia Sala*, Andrej Benjak, Swapna Uplekar, Jacques Rougemont, Christophe Guilhot, Wladimir Malaga, Carlos Martín, Stewart T. Cole. 2014. PLoS PATHOGENS, IF=8,136 D1 Microbiology, Virology and Parasitology.

7.- Tuberculosis Vaccine. Carlos Martín, Brigitte Gicquel, Esther Pérez, Jesús Gonzalo Asensio, Ainhoa Arbués. INTERNATIONAL PATENT. PCT/ES 2007/070051. Spain (ES7730491) / Europe (1997881) / USA (US12/294,199) / Canada (CA2,647,287) / Japan (JP2009-500878) / China (CN200780010366.5) / Russia (RU2008142140 (0)) / India (IN8123/DELN/2008) / Brasil (BRPI-0709106-0).


Main research projects

1.- Advancing Novel and Promising TB Vaccine Candidates From Discovery to Preclinical and Early Clinical Development (Reference TBVAC2020) H2020, IP: Carlos Martín Montañés. Participant.

2.- Multiplex Iterative Genome Engineering (MIGE) in Mycobacterium. Applications to development of genetic tools for testing new antibiotics Myco-MIGE (Reference BFU2015-72190-EXP). Ministerio de Economía y Competitividad, IP: Jesús Gonzalo-Asensio.

3.- Análisis de las diferencias de IS6110 entre los miembros del complejo Mycobacterium tuberculosis y el papel de su localización en el origen de replicación. (Reference PI15/00317) FIS-Instituto de Salud Carlos III, IP: Sofía Samper Blasco. Participant.

4.- Polimorfismos genómicos y transcriptómicos en M. tuberculosis complex y su significado en la clínica. (Reference PI12/01970) FIS-Instituto de Salud Carlos III. IP: Sofía Samper. Participant



  • Roland Brosch. Institut Pasteur, Paris
  • Christophe Guilhot. IPBS-CNRS, Toulouse
  • Marcelo Guerin. Ikerbasque, Spain
  • Inmaculada Yruela, BiFi, Spain
  • Bruno Contreras-Moreira. BiFi, Spain

Genetic regulation and physiology of cyanobacteria

Genetic regulation and physiology of cyanobacteria

Head of the Research Line:

María F. Fillat Castejón
María Luisa Peleato Sánchez



Teresa Bes Fustero
Emma Sevilla Miguel
Andrés Sandoval
Cristina Sarasa Buil
Jorge Guío Martínez
Irene Oliván Muro



Cyanobacteria are microorganisms that perform oxygenic photosynthesis and are able to colonize the most extreme environments. Because of its abundance and ubiquity, cyanobacteria play a key role in the overall carbon and nitrogen cycles and constitute the basis of the food chain in aquatic ecosystems. Some species of cyanobacteria are able to fix atmospheric nitrogen and have been used in fertilizer production. Likewise, strategies to use cyanobacteria as biotechnological choice in the biodiesel production or in the removal of heavy metals from sewage are under development. However, cyanobacteria can also be harmful. Due to the increasing eutrophization of water reservoirs, it is becoming frequent the appearance of cyanobacterial blooms in water intended for consumption or recreative uses. Several cyanobacterial species proliferating in these blooms can produce toxins that have deleterious effects on the human health as well as in animals. Although at present the factors unleashing the cyanotoxin synthesis are unknown, iron availability seems to be a determinant factor.

Our works is aimed to get a better understanding of the regulation of iron metabolism in cyanobacteria and their relationship with nitrogen metabolism, oxidative stress, cyanotoxin production and the formation of biofilms. All these processes are interrelated by a family of transcriptional regulators called FUR (ferric uptake regulator). Most of cyanobacteria express three FUR paralogues called FurA (Fur), Zur (FurB) and PerR (FurC). While most studies about these proteins deal with its regulatory character in cyanobacteria FUR are multifunctional, acting through various strategies not well characterized, together with their activity as transcriptional regulators.

Moreover, FUR proteins are also involved in the expression of virulence factors and biofilm formation in many pathogens, such as Escherichia coli, Pseudomonas aeruginosa or Clostridium difficile, among others. Since Fur is an essential protein for many of these microorganisms it has been proposed that could constitute a new therapeutic target, as an alternative to traditional antibiotics mechanisms.

Our research group has two main objectives:

– Performance of a functional study of FUR proteins in cyanobacteria including their potential biotechnological applications. Note that although the best studied of these proteins facet is its regulatory action in cyanobacteria FUR proteins have a multifunctional character, acting through various strategies not well characterized, together with its activity as transcriptional regulators.

– Characterization of the FUR regulators from the pathogens Pseudomonas aeruginosa and Clostridium difficile. Evaluation of these proteins as potential therapeutic targets by altering their activity by screening chemical libraries.


Relevant publications

1.-Fur-like proteins: beyond the Fur uptake regulator (Fur) paralog. Sevilla E, Bes MT, Peleato Ml, Fillat MF.Archives in Biochemistry and Biophysics,701: 108770. doi: 10.1016/

2.-2-oxoglutarate modulates the affinity of FurA for the ntcA promoter in Anabaena sp. PCC 7120. Guio, Jorge; Saresa-Buisan, Cristina; Velazquez-Campoy, Adrian; et ál. FEBS LETTERS  Volumen: ‏ 594   Número: ‏ 2   Páginas: ‏ 278-289   Fecha de publicación: 2020

3.- Regulation by FurC in Anabaena Links the Oxidative Stress Response to Photosynthetic Metabolism. Sevilla E, Sarasa-Buisan C, González A, Cases R, Kufryk G, Peleato ML, Fillat MF. Plant Cell Physiol. 2019 Aug 1;60(8):1778-1789. doi: 10.1093/pcp/pcz094.2.

4.- Redox-Based Transcriptional Regulation in Prokaryotes: Revisiting Model Mechanisms. Sevilla E, Bes MT, González A, Peleato ML, Fillat MF. Antioxid Redox Signal. 2019 May 1;30(13):1651-1696. doi: 10.1089/ars.2017.7442. Epub 2018 Sep 18.

5.- Transcriptional regulators: valuable targets for novel antibacterial strategies. González A, Fillat MF, Lanas Á. Future Med Chem. 2018 Mar 1;10(5):541-560. doi: 10.4155/fmc-2017-0181. Epub 2018 Feb 20. Review.

6.- Molecular basis for the integration of environmental signals by FurB from Anabaena sp. PCC 7120. Sein-Echaluce VC, Pallarés MC, Lostao A, Yruela I, Velázquez-Campoy A, Luisa Peleato M, Fillat MF. Biochem J. 2018 Jan 5;475(1):151-168. doi: 10.1042/BCJ20170692.

7.- Microcystin-LR Binds Iron, and Iron Promotes Self-Assembly. Ceballos-Laita L, Marcuello C, Lostao A, Calvo-Begueria L, Velazquez-Campoy A, Bes MT, Fillat MF, Peleato ML. Environ Sci Technol. 2017 May 2;51(9):4841-4850. doi: 10.1021/acs.est.6b05939. Epub 2017 Apr 17.

8.- Pivotal Role of Iron in the Regulation of Cyanobacterial Electron Transport. González A, Sevilla E, Bes MT, Peleato ML, Fillat MF. Journal: Adv Microb Physiol. 2016;68:169-217.

9.- The genome-wide transcriptional response to FurA depletion unveils new roles for this essential cyanobacterial global regulator. González A, Bes MT, Peleato ML and Fillat MF. Journal: PlosOne. 2016 Mar 11;11(3):e0151384. doi: 10.1371/journal.pone.0151384. eCollection

10.- Cysteine mutational studies provide insight into a thiol-based redox switch mechanism of metal and DNA binding in FurA from Anabaena sp. Botello-Morte L, Pellicer S, Contreras LM, Neira JL, Abian O, Velázquez-Campoy A, Peleato ML, Fillat MF and Bes MT. PCC 7120. Journal: Antioxid Redox Signal (PMID:26414804) Fecha: 2015.

11.- The Pkn22 Ser/Thr kinase in Nostoc PCC 7120: role of FurA and NtcA regulators and transcript profiling under nitrogen starvation and oxidative stress. Yingping F, Lemeille S, González A, Risoul V, Denis Y, Richaud P, Lamrabet O, Fillat MF, Zhang CC and Latifi A. Journal: BMC Genomics  2015 Jul 29;16:557. doi: 10.1186/s12864-015-1703-1.

12.- Pivotal role of iron in the regulation of cyanobacterial electron transport. González A, Sevilla E, Bes MT, Peleato ML and Fillat MF. Adv Microb Physiol. 2016;68:169-217. doi: 10.1016/bs.ampbs.2016.02.005. Epub 2016 Mar 15.

13.- Iron homeostasis and environmental responses in cyanobacteria: regulatory networks involving Fur. Peleato ML, Bes MT and Fillat MF. Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria. Chapter 19. pp. 1067-1078. Frans de Bruijn ed., Wiley-Blackwell.

14.- Zur (FurB) is a key factor in the control of the oxidative stress response in Anabaena sp. PCC 7120. Sein-Echaluce VC, González A, Napolitano M, Luque I, Barja F, Peleato ML, Fillat MF. Journal: Environ Microbiol. 17(6): 2006-2017 (2015). doi: 10.1111/1462-2920.12628.

15.- Mesoscopic Model and Free Energy Landscape for Protein-DNA Binding Sites: Analysis of Cyanobacterial Promoters. Tapia-Rojo R, Mazo JJ, Hernández JÁ, Peleato ML, Fillat MF, Falo F. JOURNAL: PLoS Comput Biol. 2014 Oct 2;10(10):e1003835. doi: 10.1371/journal.pcbi.1003835.

16.- The FUR (ferric uptake regulator) superfamily: diversity and versatility of key transcriptional regulators. Fillat MF. Journal: Arch Biochem Biophys. 546:41-52 (2014). doi: 10.1016/

17.- The FurA regulon in Anabaena sp. PCC 7120: in silico prediction and experimental validation of novel target genes. González A, Angarica VE, Sancho J, Fillat MF. Journal: Nucleic Acids Research. 42(8):4833-46 (2014). doi: 10.1093/nar/gku123

18.- Unraveling the Redox Properties of the Global Regulator FurA from Anabaena sp. PCC 7120: Disulfide Reductase Activity Based on Its CXXC Motifs. Botello-Morte L, Bes MT, Heras B, Fernández-Otal A, Peleato ML, Fillat MF. Journal: Antioxid Redox Signal. 20(9):1396-406 (2014). doi: 10.1089/ars.2013.5376

19.- FurA is the master regulator of iron homeostasis and modulates the expression of tetrapyrrole biosynthesis genes in Anabaena sp. PCC 7120. González, A., Bes, M.T., Valladares, A., Peleato, M.L. and Fillat M.F. Journal: Environ Microbiol. 14(12):3175-87 (2012) doi: 10.1111/j.1462-2920.2012.02897.x.

20.- Site-directed mutagenesis and spectral studies suggest a putative role of FurA from Anabaena sp. PCC 7120 as heme sensor protein. Pellicer S, González A, Peleato ML, Martínez JI, Fillat MF and Bes MT. Journal: The FEBS Journal, 279(12):2231-46 (2012). doi: 10.1111/j.1742-4658.2012.08606.x.

21.- Unravelling the regulatory function of FurA in Anabaena sp. PCC 7120 through 2-D DIGE proteomic analysis. González, A., Bes, M.T., Peleato, M.L. and Fillat M.F. Journal: Journal of Proteomics, 74:660-71 (2011) doi: 10.1016/j.jprot.2011.02.001.

22.- Overexpression of FurA in Anabaena sp. PCC 7120 reveals new targets for this regulator involved in photosynthesis, iron uptake and cellular morphology. González, A., Bes, M.T., Barja, F., Peleato, M.L. and Fillat M.F. Journal: Plant and cell Physiology. Vol 51 (11):1900-1914 (2010). doi: 10.1093/pcp/pcq148.


Main research projects

1.- Redes reguladoras implicadas en la respuesta a estrés y la formación de biofilms en cianobacterias. Identificación de nuevas rutas vinculadas a las proteínas FUR. Nombres investigadores principales): María Francisca Fillat Castejón. Nº de investigadores/as: 3. Agencia Estatal de Investigación. Fecha de inicio-fin: 01/06/2020 – 31/05/2024  Duración: 4 años

2.- Multifuncionalidad de las proteínas FUR en cianobacterias: mecanismos alternativos de regulación del metabolismo y contribución a la formación de biofilms. MINECO. Duración: 01/01/2017 – 31/12/2019. Subvención: 140.000 euros. PI: María F. Fillat Castejón. Investigadores: 5.

3.- BFU2012-31458: La superfamilia de reguladores Fur: análisis funcional en cianobacterias, potenciales aplicaciones en biotecnología y como diana terapeútica en patógenos. FONDOS FEDER. MINECO. MINISTERIO DE ECONOMIA Y COMPETITIVIDAD. Duración: 01/01/2013 – 31/12/2015. Subvención: 114.660 euros. PI: María Francisca Fillat Castejón. Investigadores: 5.

4.- B18 BIOLOGÍA ESTRUCTURAL. Gobierno de Aragón. Duración: 01/01/2014 – 31/12/2016. Subvención: 20.609 euros. PI: María Luisa Peleato Sánchez. Investigadores: 16.

5.- 2012/GA LC 003. Evaluación del riesgo asociado al impacto del cambio climático en aguas: proliferación de patógenos oportunistas y cianobacterias potencialmente tóxicas y alteración de la fijación de CO2 atmosférico. DGA-LA CAIXA. Duración: 01/05/2012 – 30/09/2013. Subvención: 42.208,18 euros. PI: María Francisca Fillat Castejón. Investigadores: 9.

6.- BFU2009-07424. Transducción de señales redox mediadas por FurA (ferric uptake regulator) en cianobacterias. Consecuencias en la fotosíntesis y la fijación de nitrógeno. FONDOS FEDER. MINISTERIO DE CIENCIA E INNOVACIÓN. Duración: 01/01/2010 – 31/12/2012. Subvención: 139.150 euros. PI: María Francisca Fillat Castejón. Investigadores: 5.

7.- B18 BIOLOGÍA ESTRUCTURAL. Gobierno de Aragón. Duración: 01/01/2011 – 31/12/2012. Subvención: 38.192 euros. PI: Carlos Gómez-Moreno. Investigadores: 23.

8.- Identificación de cianobacterias potencialmente tóxicas y microorganismos patógenos en amebas de vida libre en aguas de Aragón. Diputación general de Aragón-DGA. Duración: 01/10/2009 – 30/09/2011. Subvención: 49.000 euros. PI: María Francisca Fillat Castejón. Investigadores: 10.

9.- Equipo para análisis y cuantificación de interacciones moleculares mediante resonancia de plasmón de superficie (SPR) (UNZA08-4E-021). Gobierno de Aragón- FEDER. : Jan 2009 – Dec 2011. Subvención: 384.569,51 euros. PI: José Felix Saenz.

10.- INF2008-BIO-05. INCUBADOR ORBITAL CON ILUMINACIÓN. D.G.A./U.Z. Duración: 10/07/2008 – 31/12/2008. Subvención: 14.373 euros. PI: María Francisca Fillat Castejón. Investigadores: 1.

11.- Respuesta de un tapete microbiano de cianobacterias a la contaminación por hidrocarburos. Proyectos Interreg. Departamento de Economía, Hacienda y Empleo de la Diputación General de Aragón. Duración: 01/02/2006 – 31/12/2007. PI: María Francisca Fillat Castejón. Investigadores: 8.



  • Dr. I. Michaud-Soret (Institut de Recherche en Technologie et Science pour le Vivant. CEA, Grenoble)
  • Dr. R. Helm (Virginia Tech)
  • Dr. F. Barja (Université de Genève)
  • Dr. B. Heras (LaTrobe University, Melbourne)
  • Dr. B. Landeros (Universidad de Baja California)
  • Dr.J.M. Mulet (Univ. Politécnica de Valencia)
  • Dr. I. Luque (Instituto de Bioquímica vegetal y Fotosíntesis, CSIC, Sevilla)
  • Dr. A. Lostao (Instituto de Nanociencia de Aragón, Universidad de Zaragoza)
  • Dr. A. Lanas (Instituto Aragonés de Ciencias de la Salud, Zaragoza)
Plant evolutionary and genetic biology

Plant Evolutionary and genetic Biology

Head of the Research Line:

Pilar Catalán Rodríguez


Ernesto Pérez Collazos
Rubén Sancho Cohen
Antonio Díaz Pérez



Our research focuses on molecular systematics, population-genetics, bio/phylogeography, comparative genomics, diversity and conservation of plants. The group of species that constitute our primary interest are the temperate grasses (Poaceae, Festuca, Brachypodium), distributed in most continents and including many ecologically and economically important species, and other mountain, steppe and Mediterranean-type plant species. Our research emphasize on studies of functional genomics, phylogeny, speciation, hybridization, polyploidization, island and continental colonizations, reproductive biology, ecological adaptation, niche modelling, conservation genetics and taxonomy of wild plants. Our lab has implemented new approaches of genomic inheritance analysis in plant polyploids and cutting-edge plant phylogenomics and landscape genomics analyses. In collaboration with our colleagues of the Joint Genome Institute and the International Brachypodium Consortium, we use model plants of the grass genus Brachypodium to investigate the evolution and regulatory mechanisms of relevant biological and adaptive traits such as allopolyploidy, switches in annuality/perenniality and tolerance to environmental stresses.


Relevant publications

1.- Brachypodium: A monocot grass model genus for plant biology. Scholthof KB, Irigoyen S, Catalán P, Mandadi KK. Plant Cell. 2018. (early publication on line, July 2018), doi:

2.- Reconstructing the biogeography of species’ genomes in the highly reticulate allopolyploid-rich model grass genus Brachypodium using minimum evolution, coalescence and maximum likelihood approaches. Díaz-Pérez A, López-Álvarez D, Sancho R, Catalán P. Molecular Phylogenetics and Evolution. 2018. 127: 256-271. doi 10.1016/j.ympev.2018.06.003.

3.- Comparative plastome genomics and phylogenomics of Brachypodium: flowering time signatures, introgression and recombination in recently diverged ecotypes. Sancho R, Cantalapiedra CP, López-Álvarez D, Gordon SP, Vogel JP, Catalán P, Contreras-Moreira B. New Phytologist. 2018. 218: 1631-1644. doi:10.1111/nph.14926.

4.- Phylogeny of highly hybridogenous Iberian Centaurea L. (Asteraceae) taxa and its taxonomic implications. Arnelas I, Pérez-Collazos E, Devesa JA, López E, Catalán P. Plant Biosystems. 2018. 152:5, 1182-1190. doi:10.1080/11263504.2018.1435569.

5.- Extensive gene content variation in the Brachypodium distachyon pan-genome correlates with phenotypic variation. Gordon SP, Contreras-Moreira B, Daniel Woods D, Des Marais DL, Burgess D, Shu S, Stritt C, Roulin A, Schackwitz W, Tyler L, Martin J, Lipzen A, Dochy N, Phillips J, Barry K, Geuten K, Juenger TE, Amasino R, Caicedo AL, Goodstein D, Davidson P, Mur L, Figueroa M, Freeling M, Catalan P, Vogel JP. Nature Communications. 2017. 19; 8(1): 2184. doi: 10.1038/s41467-017-02292-8.

6.- Contrasting dispersal histories of broad- and fine-leaved temperate Loliinae grasses: range expansion, founder events, and the roles of distance and barriers. Minaya M, Hackel J, Namaganda M, Brochmann C, Vorontsova MS, Besnard G, Catalán P. Journal of Biogeography. 2017. 44: 1980-1993. doi:10.1111/jbi.13012.

7.- Diversity and association of phenotypic and metabolomic traits in the close model grasses Brachypodium distachyon, B. stacei and B. hybridum. López-Alvarez D, Zubair H, Beckmann M, Draper J, Catalán P. Annals of Botany. 2017. 119: 545-561. doi:101093/aob/mcw239.

8.- Past climate changes facilitated homoploid speciation in three mountain spiny fescues (Festuca, Poaceae).  Marques I, Draper D, López-Herranz ML, Segarra-Moragues JG, Catalán P.  Sci Rep. 2016. 6:36283. doi: 10.1038/srep36283.

9.- Recreating stable Brachypodium hybridum allotetraploids by uniting the divergent genomes of B. distachyon and B. stacei. Dinh Thi VA, Coriton O, Le Clainche I, Arnaud D, Gordon SP, Linc G, Catalán P, Hasterok R, Vogel JP, Jahier J, Chalhoub B. PLOsOne 2016. 11(12): e0167171. doi: 10.1371/journal.pone.0167171.

10.- Ant pollination promotes spatial genetic structure in the long-lived Borderea pyrenaica (Dioscoreaceae).  Pérez-Collazos E, Segarra-Moragues JG, Villar L, Catalán P.  Biol J Linnean Soc . 2015. 116: 144-155. doi: 10.1111/bij.12562.



Main research projects

1.- Integrative genomic characterization of the Brachypodium polyploid model to unravel bases of success of polyploidy in flowering plants.  Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez. JOINT GENOME INSTITUTE – CSP. 2018-2022.

2.- Evolución de caracteres biológicos y procesos de especiación en el género modelo Brachypodium (Poaceae) mediante análisis de genómica comparada y funcional. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez, Ernesto Pérez Collazos, Rubén Sancho Cohen y Antonio Díaz Pérez. MINECO. 2017-2019.

3.- Perenniality, abiotic stress tolerance, and biomass allocation in Brachypodium, a model grass genus for bioenergy.  Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez. JOINT GENOME INSTITUTE – CSP. 2017-2021.

4.- Origin: The model plant system Trithuria (Hydatellaceae), a new window into the origin of flowering plants and gene function. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez (host researcher). MARIE CURIE IOF. 2013-2016.

5.- Genómica comparada, biogeografía y evolución floral y adaptativa de gramíneas modelo. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez, Ernesto Pérez Collazos y Rubén Sancho Cohen. CICYT. 2013-2015.

6.- Brachypodium adaptation to drought stress across different geographic and ecological clines. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez y Ernesto Pérez Collazos. EPPN. 2013-2014.

7.- Genética y ecología del paisaje de pastos subalpinos pirenaico-cantábricos (Festuca, Gramineae): Conservación de la biodiversidad y restauración vegetal. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez y Ernesto Pérez Collazos. MMAMRM-OAPN. 2010-2012.

8.- Evolución multigenómica de las gramíneas templadas (Pooideae, Poaceae). Biogeografía y filogeografía de especies modelo de pooideas. Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez y Ernesto Pérez Collazos. CICYT. 2010-2012.

9.- Sistemática, evolución y biogeografía de los linajes basales de la subtribu Loliinae y transferencia horizontal de genes en la supertribu Aveneae-Poeae (Gramineae). Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez, Ernesto Pérez Collazos y Antonio Díez Pérez. CICYT. 2006-2009.

10.- Convergencia evolutiva transcontinental y genética de la conservación de los ñames enanos (Dioscoreaceae) críticamente amenazados (Borderea, Epipetrum). Departamento de Ciencias Agrarias y del Medio Natural. Escuela Politécnica Superior de Huesca – Universidad de Zaragoza. Pilar Catalán Rodríguez y Ernesto Pérez Collazos. FBBVA. 2006-2009.




  • John Vogel. Joint Genome Institute. Walnut Creek CA USA.
  • David Des Marais. Massachusetts Institute of Technology. Boston MA USA.
  • Richard Amasino. University of Wisconsin-Madison. Madison WI USA.
  • Bruno Contreras-Moreira. Estación Experimental de Aula Dei – CSIC. Zaragoza Spain.
  • Isabel Marques. Universidade de Lisboa. Lisboa Portugal.
  • Antonio Manzaneda. Universidad de Jaén. Jaén Spain.
  • Robert Hasterok and Alexander Betekhtin. University of Silesia. Katowice Poland.
  • Luis Mur and John Doonan. Aberystwyth University. Aberystwyth UK.
  • Liliana Giussani. Instituto Botánico Darwinion – CONICET. Buenos Aires Argentina.
  • Marina Olonova. Tomsk State University. Tomsk Russia.
  • Teresa Garnatje. Instituto Botánico de Barcelona – CSIC. Barcelona Spain.

Functional genomics of the OXPHOS system (GENOXPHOS)

Functional genomics of the OXPHOS system (GENOXPHOS)

Head of the Research Line:

Patricio Fernández Silva


Patricio Fernández Silva
Patricia Meade Huerta
Raquel Moreno Loshuertos



Our group is dedicated to the study of biogenesis, structural organization and pathology of the oxidative phosphorylation system (OXPHOS system) using molecular biology and functional genetics techniques. Our main objectives are:

  • Functional genetics of mouse mitochondrial DNA (mtDNA). In order to have a greater number of cellular models with functional alterations in the OXPHOS system, we have developed a mutagenesis technology which has allowed us to obtain a collection of mouse cell lines harbouring mutations in their mtDNA. Thus, we have managed to generate mutants in all respiratory complexes with mtDNA encoded subunits (complexes I, III, IV and V) and also a mutant in mitocondrial protein synthesis. These models allow studying the role of the affected genes by structural and functional analysis.
  • Animal models of mtDNA associated pathologies and potential therapies. We are developing mouse models carrying mtDNA mutations by transferring mitochondria harbouring mutations selected from those generated in our laboratory to embryos. Moreover, we have generated knock-in mice expressing the exogenous protein AOX (alternative oxidase, from fungus Emericella nidulans) and we are crossing them with knock-out mice for complex IV nuclear genes in muscle, which present severe myopathy. In this way, we try to evaluate the potential of the AOX protein as a therapeutic approach for failures in respiratory complexes III and IV.
  • Effect of mtDNA polymorphic variants. To evaluate the influence of mtDNA genotypes (mitocondrial haplogroups) on complex phenotypes such as aging, we have generated conplastic mice, which carry different mtDNA variants in the same nuclear background. Through different methodological approaches such as transcriptomics or metabolomics, we have demonstrated how different combinations of mitochondrial and nuclear genomes are responsible for differences in metabolism or quality of aging in these individuals.
  • Structural organization of the OXPHOS system. We have proposed a new model of organization of the mitochondrial electron transport chain (the plasticity model) and we have identified the first supercomplexes assembly factor (SCAF1). Currently, we are interested in analyzing both genetic and environmental factors involved in the formation of these superstructures as well as in the regulation of their levels and their functional implications on energy metabolism.


Relevant publications

1.- Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Latorre-Pellicer A, Moreno-Loshuertos R, Lechuga-Vieco AV, Sánchez-Cabo F, Torroja C, Acín-Pérez R, Calvo E, Aix E, González-Guerra A, Logan A, Bernad-Miana ML, Romanos E, Cruz R, Cogliati S, Sobrino B, Carracedo Á, Pérez-Martos A, Fernández-Silva P, Ruíz-Cabello J, Murphy MP, Flores I, Vázquez J, Enríquez JA. Nature 2016 Jul 28; 535(7613):561-5.

2.- The CoQH2/CoQ ratio serves as a sensor of respiratory chain efficiency. Guarás, E. Perales-Clemente, E. Calvo, R. Acín-Pérez, E. Nuñez, C. Pujol, I. Martínez-Carrascoso, M. Loureiro-Lopez, F. García-Marqués, M. A. Rodríguez-Hernández, A. Cortés, F. Diaz, A. Pérez-Martos, C. T. Moraes, P. Fernández-Silva, A. Trifunovic, P. Navas, J. Vázquez and J.A. Enríquez. Cell Reports 2016 Apr 5;15 (1), 197-209.

3.- ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use.  Acín-Pérez R, Carrascoso I, Baixauli F, Roche-Molina M, Latorre-Pellicer A, Fernández-Silva P, Mittelbrunn M, Sanchez-Madrid F, Pérez-Martos A, Lowell CA, Manfredi G, Enríquez JA. Cell Metab. 2014 Jun 3;19(6):1020-33.

4.- Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L. Cell, 2013 Sep 26;155(1):160-71.

5.- Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Lapuente-Brun E, Moreno-Loshuertos R, Acín-Pérez R, Latorre-Pellicer A, Colás C, Balsa E, Perales-Clemente E, Quirós PM, Calvo E, Rodríguez-Hernández MA, Navas P, Cruz R, Carracedo Á, López-Otín C, Pérez-Martos A, Fernández-Silva P, Fernández-Vizarra E, Enríquez JA. Science, 2013 Jun 28;340(6140):1567-70.

6.- Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. Moreno-Loshuertos R, Ferrín G, Acín-Pérez R, Gallardo ME, Viscomi C, Pérez-Martos A, Zeviani M, Fernández-Silva P, Enríquez JA. PLoS Genet. 2011 Apr;7(4):e1001379.

7.- A genome-wide shRNA screen for new OxPhos related genes. Bayona-Bafaluy MP, Sánchez-Cabo F, Fernández-Silva P, Pérez-Martos A, Enríquez JA. Mitochondrion. 2011 May; 11(3):467-75.

8.- Tissue-specific differences in mitochondrial activity and biogenesis. Fernández-Vizarra E, Enríquez JA, Pérez-Martos A, Montoya J, Fernández-Silva P. Mitochondrion. 2011 Jan; 11(1):207-13.

9.- Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? Perales-Clemente E, Fernández-Silva P, Acín-Pérez R, Pérez-Martos A, Enríquez JA.  Nucleic Acids Res. 2011 Jan; 39(1):225-34.

10.- Five entry points of the mitochondrially encoded subunits in mammalian complex I assembly. Perales-Clemente E, Fernández-Vizarra E, Acín-Pérez R, Movilla N, Bayona-Bafaluy MP, Moreno-Loshuertos R, Pérez-Martos A, Fernández-Silva P, Enríquez JA. Mol Cell Biol. 2010 Jun; 30(12):3038-47.

11.- Respiratory active mitochondrial supercomplexes. Acín-Pérez R, Fernández-Silva P, Peleato ML, Pérez-Martos A, Enriquez JA. Mol Cell. 2008 Nov 21; 32(4):529-39.

12.- Functional genetic analysis of the mammalian mitochondrial DNA encoded peptides: a mutagenesis approach. Bayona-Bafaluy MP, Movilla N, Pérez-Martos A, Fernández-Silva P, Enriquez JA. Methods Mol Biol. 2008; 457:379-90.

13.- Restoration of electron transport without proton pumping in mammalian mitochondria. Perales-Clemente E, Bayona-Bafaluy MP, Pérez-Martos A, Barrientos A, Fernández-Silva P,Enriquez JA. Proc Natl Acad Sci U S A. 2008 Dec 2; 105(48):18735-9.

14.- Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Moreno-Loshuertos R, Acín-Pérez R, Fernández-Silva P, Movilla N, Pérez-Martos A, Rodriguez de Cordoba S, Gallardo ME, Enríquez JA. Nat Genet. 2006 Nov; 38(11):1261-8.

15.- Respiratory complex III is required to maintain complex I in mammalian mitochondria. Acín-Pérez R, Bayona-Bafaluy MP, Fernández-Silva P, Moreno-Loshuertos R, Pérez-Martos A, Bruno C, Moraes CT, Enríquez JA. Mol Cell. 2004 Mar 26; 13(6):805-15.


Main research projects

1.- Generación de modelos y ensayo de terapia génica para enfermedades oxphos. FIS (PI12/0129). Investigador principal: Patricio Fernández Silva.

2.- Estudio de factores genéticos y ambientales implicados en el ensamblaje y la estabilidad de los complejos y supercomplejos respiratorios. Universidad de Zaragoza/Ibercaja(JIUZ-2015-BIO-06). Investigador principal: Raquel Moreno Loshuertos.

3.- Estudio del efecto de la modulación del estado Redox y los ROS sobre la formación y estabilidad de los supercomplejos respiratorios. Universidad de Zaragoza (UZ2016-BIO-04). Investigador principal: Raquel Moreno Loshuertos.

4.- B55 genómica funcional del sistema de fosforilación oxidativa (GENOXPHOS). Diputación General de Aragón 2013. Investigador principal: Patricio Fernández Silva.

5.- Grupo Consolidado Biología Estructural (B18). Diputación General de Aragón (B18). Investigador principal: María Luisa Peleato.

6.- Ensayo de la xenoexpresión como terapia génica para las enfermedades mitocondriales. Fundación Ramón Areces (212328). Investigador principal: Patricio Fernández Silva.

7.- Terapia génica de las enfermedades mitocondriales mediante xenoexpresión. FIS (PI09/00946). Investigador principal: Patricio Fernández Silva.

8.- CONSOLIDER. Papel funcional del estrés oxidativo y nitrosativo en grandes sistemas biológicos. Ministerio de Ciencia y Tecnología (CSD2007-00020). Investigador principal: José Antonio Enríquez.

9.- Efecto de los fallos en el sistema OXPHOS sobre la expresión génica y la diferenciación de células ES. Instituto Aragonés de Ciencias de la Salud (PIPAMER09/05). Investigador principal: Patricio Fernández Silva.

10.- EUMITOCOMBAT: rational treatment strategies combating mitocondrial oxidative phosphorilation (OXPHOS) disorders. Unión Europea (LSHM-CT-2004-503116). Investigador principal: José Antonio Enríquez.



  • Dr. José Antonio Enriquez. Centro Nacional de Investigaciones Cardiovasculares (CNIC). Madrid-Spain
  • Massimo Zeviani. MBU-MRC. Cambridge-UK
  • Eva Monleón. Dtpo. de Anatomía e Histología Humanas- UZ
Development of antimicrobials and mechanisms of resistance (D2AMR)

Development of Antimicrobials and Mechanisms of Resistance


Head of the Research Line:

José Antonio Aínsa Claver
Santiago Ramón-García


José Antonio Aínsa Claver, PI
Santiago Ramón-García, PI
Ainhoa Lucía Quintana, Postdoc
Clara Aguilar Pérez, PhD Student
Ernesto Anoz Carbonell, PhD Student
Ana Cristina Millán Placer, PhD Student
Marta María Gómara Lomero, PhD Student
María Pilar Arenaz Callao, PhD Student
Lara Muñoz Muñoz, PhD Student
Begoña Gracia Díaz, Laboratory Technician



Research line Development of Antimicrobials and Mechanisms of Resistance is committed to study mechanisms of resistance to antimicrobial agents in diverse microbial pathogens and to use this information for identifying novel molecules with antimicrobial activity and characterise their mechanisms of action and resistance. This work is funded by public grants got in competitive calls at the national and international level.

In recent years, we have characterised several efflux pumps from Mycobacterium tuberculosis and we have contributed to identify compounds that evading resistance mediated by efflux pumps have an increased antimicrobial activity. We are characterising novel drug targets, not only in Mycobacterium but also in other bacterial pathogens, and exploring novel molecules (peptides,…) as alternatives to conventional antibiotics.

During the last 7 years, we have published 15 scientific articles, we have got a patent related with the diagnostic value of a specific resistance gene and have made a number of communications to national and international conferences.

Our research is getting insight into novel perspectives, such as the use of nanoparticles for administering antibiotics, or combination of molecules with antimicrobial activity.



Relevant publications

1.- Discovery of antimicrobial compounds targeting bacterial type FAD synthetases. Sebastián M, Anoz-Carbonell E, Gracia B, Cossio P, Aínsa JA, Lans I, Medina M. J Enzyme Inhib Med Chem. 2018 Dec;33(1):241-254. doi: 10.1080/14756366.2017.1411910. PMID: 29258359

2.- The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. Mori G, Orena BS, Franch C, Mitchenall LA, Godbole AA, Rodrigues L, Aguilar-Pérez C, Zemanová J, Huszár S, Forbak M, Lane TR, Sabbah M, Deboosere N, Frita R, Vandeputte A, Hoffmann E, Russo R, Connell N, Veilleux C, Jha RK, Kumar P, Freundlich JS, Brodin P, Aínsa JA, Nagaraja V, Maxwell A, Mikušová K, Pasca MR, Ekins S. Tuberculosis (Edinb). 2018 Sep;112:98-109. doi: 10.1016/ PMID: 30205975

3.- Synergy between Circular Bacteriocin AS-48 and Ethambutol against Mycobacterium tuberculosis. Aguilar-Pérez C, Gracia B, Rodrigues L, Vitoria A, Cebrián R, Deboosère N, Song OR, Brodin P, Maqueda M, Aínsa JA. Antimicrob Agents Chemother. 2018 Aug 27;62(9). pii: e00359-18. doi: 10.1128/AAC.00359-18. PMID: 29987141

4.- Boldine-Derived Alkaloids Inhibit the Activity of DNA Topoisomerase I and Growth of Mycobacterium tuberculosis. García MT, Carreño D, Tirado-Vélez JM, Ferrándiz MJ, Rodrigues L, Gracia B, Amblar M, Ainsa JA, de la Campa AG. Front Microbiol. 2018 Jul 24;9:1659. doi: 10.3389/fmicb.2018.01659. PMID: 30087665

5.- Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs. Glaus F, Dedić D, Tare P, Nagaraja V, Rodrigues L, Aínsa JA, Kunze J, Schneider G, Hartkoorn RC, Cole ST, Altmann KH. J Org Chem. 2018 Jul 6;83(13):7150-7172. doi: 10.1021/acs.joc.8b00193. PMID: 29542926

6.- New active formulations against M. tuberculosis: Bedaquiline encapsulation in lipid nanoparticles and chitosan nanocapsules. L.De Matteis, D.Jary, A.Lucía, S.García-Embid, I.Serrano-Sevilla, D.Pérez, J.A.Ainsa, F.P.Navarro, J.M. de la Fuente. Chemical Engineering Journal. Volume 340, 15 May 2018, Pages 181-191.

7.- Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors. Song L, Merceron R, Gracia B, Quintana AL, Risseeuw MDP, Hulpia F, Cos P, Aínsa JA, Munier-Lehmann H, Savvides SN, Van Calenbergh S. J Med Chem. 2018 Apr 12;61(7):2753-2775. doi: 10.1021/acs.jmedchem.7b01570. PMID: 29510037

8.- Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem. Huang W, Briffotaux J, Wang X, Liu L, Hao P, Cimino M, Buchieri MV, Namouchi A, Ainsa JA, Gicquel B. Tuberculosis (Edinb). 2017 Dec;107:111-118. doi: 10.1016/ PMID: 29050757

9.- How can nanoparticles contribute to antituberculosis therapy? Costa-Gouveia J, Aínsa JA, Brodin P, Lucía A. Drug Discov Today. 2017 Mar;22(3):600-607. doi: 10.1016/j.drudis.2017.01.011. PMID: 28137645

10.- Antituberculosis drugs: reducing efflux=increasing activity. Rodrigues L, Parish T, Balganesh M, Ainsa JA. Drug Discov Today. 2017 Mar;22(3):592-599. doi: 10.1016/j.drudis.2017.01.002. PMID: 28089787

11.- Structure-Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions. Liu J, Bruhn DF, Lee RB, Zheng Z, Janusic T, Scherbakov D, Scherman MS, Boshoff HI, Das S, Rakesh, Waidyarachchi SL, Brewer TA, Gracia B, Yang L, Bollinger J, Robertson GT, Meibohm B, Lenaerts AJ, Ainsa J, Böttger EC, Lee RE. ACS Infect Dis. 2017 Jan 13;3(1):72-88. doi: 10.1021/acsinfecdis.6b00158. PMID: 28081607

12.- Identification of Aminopyrimidine-Sulfonamides as Potent Modulators of Wag31-mediated Cell Elongation in Mycobacteria. Vinayak Singh, Neeraj Dhar, János Pató, Gaëlle S. Kolly, Jana Korduláková, Martin Forbak, Joanna C. Evans, Rita Székely, Jan Rybniker, Zuzana Palčeková, Júlia Zemanová, Isabella Santi, François Signorino-Gelo, Liliana Rodrigues, Anthony Vocat, Adrian S. Covarrubias, Monica G. Rengifo, Kai Johnsson, Sherry Mowbray, Joseph Buechler, Vincent Delorme, Priscille Brodin, Graham W. Knott, José A. Aínsa, Digby F. Warner, György Kéri, Katarína Mikušová, John D. McKinney, Stewart T. Cole, Valerie Mizrahi, Ruben C. Hartkoorn. Mol Microbiol. 2017 Jan;103(1):13-25. doi: 10.1111/mmi.13535. PMID: 27677649

13.- Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development. Bailo R, Bhatt A, Aínsa JA. Biochem Pharmacol. 2015 Aug 1;96(3):159-67. doi: 10.1016/j.bcp.2015.05.001. PMID: 25986884.

14.- Measuring efflux and permeability in mycobacteria. Rodrigues L, Viveiros M, Aínsa JA. Methods Mol Biol. 2015;1285:227-39. doi: 10.1007/978-1-4939-2450-9_13. PMID: 25779319.

15.- Spectinamides: a new class of semisynthetic antituberculosis agents that overcome native drug efflux. Lee RE, Hurdle JG, Liu J, Bruhn DF, Matt T, Scherman MS, Vaddady PK, Zheng Z, Qi J, Akbergenov R, Das S, Madhura DB, Rathi C, Trivedi A, Villellas C, Lee RB, Rakesh, Waidyarachchi SL, Sun D, McNeil MR, Ainsa JA, Boshoff HI, Gonzalez-Juarrero M, Meibohm B, Böttger EC, Lenaerts AJ. Nat Med. 2014 Feb;20(2):152-8. doi: 10.1038/nm.3458. PMID: 24464186.



Main research projects

1.- El fenotipo silente de Mycobacterium tuberculosis: persistencia y latencia. Ministerio de Economía y Competitividad. Universidad de Zaragoza. SAF2017-84839-C2-1-R. 01/01/2018 – 31/12/2020. IP  José Antonio Aínsa Claver.

2.- Identification of novel therapies for difficult to treat cystic fibrosis pulmonary infections caused by mycobacteria using an innovative technology: synergy screens of clinically approved drugs. Unión Europea. Universidad de Zaragoza. 01/04/2018 – 31/03/2019. IP: Santiago Ramon Garcia.

3.- NAREB – Nanotherapeutics for antibiotic resistant emerging bacterial pathogens. Unión Europea. Universidad de Zaragoza. 01/02/2014 – 31/07/2018. IP: José Antonio Aínsa Claver.

4.- SAF-2013-48971-C2-2-R: Aplicaciones biomédicas de AS-48: una proteína con amplio espectro de actividad antimicrobiana. MINECO – Ministerio de Economia y Competitividad. Universidad de Zaragoza. 01/01/2014 – 31/07/2018. IP: José Antonio Aínsa Claver.

5.- MM4TB – More medicines for tuberculosis. Unión Europea. Universidad de Zaragoza. 01/02/2011 – 31/01/2016. IP: José Antonio Aínsa Claver.



  • Adela G. De la Campa, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Majadahonda, Madrid, Spain). Desarrollo de inhibidores frente a la topoisomerasa de  tuberculosis.
  • Mercedes Maqueda, Universidad de Granada (Granada, Spain). Estudio de actividad antimicrobiana de la bacteriocina AS-48.
  • Serge van Calenbergh, Universidad de Gent (Gent, Belgium). Nuevos inhibidores de timidilato kinasa de tuberculosis.
  • Concepción González-Bello (Universidad de Santiago de Compostela, Santiago de Compostela, Spain). Inhibidores de dehidroquinasas en tuberculosis.

Apoptosis and metabolism

Apoptosis and metabolism

Head of the Research Line:

José Alberto Carrodeguas Villar


Diego de la Fuente Herreruela/CPIF
Beatriz Sáenz de Buruaga/PhD
Laura Bueno Martínez/Student TFG
Sara García Gadea/Student TFG
Carlos Matute Lamana/Student TFM



Our work has focused in different lines during the last years, as stated next:

1- Studying PSAP/Mtch1 function (Presenilin 1-associated protein/mitochondrial carrier homolog 1). PSAP interacts with presenilin 1, part of the gamma secretase complex, involved in Alzheimer’s disease. It is also known as mitochondrial carrier homolog 1 (Mtch1), since it contains a domain conserved in outer mitochondrial membrane carriers, although it is located in the inner membrane. Mtch1 induces cell death upon overexpression in culture.

We have identified two isoforms generated by alternative splicing that localize into the inner membrane through inner targeting sequences and that contain two proapoptotic domains. Mtch1 can induce apoptosis in the absence of Bax and Bak, two proapoptotic members of the Bcl-2 family. It does not appear to have a role in transport, but it could function as a receptor for yet-to-be-identified ligands in the surface of mitochondria.

We have studied the Drosophila knockout of mtch1 and we are preparing a publication in this respect, in collaboration with researchers from the Biomedical Research Institute, CSIC-UAM, Madrid.

2- Bcl-2 proteins. Proteins from this family are essential for the fulfillment of cell death, integrating several cellular signals. Their major known roles depend on protein-protein interactions for the induction or the inhibition of initial steps in cell death. Nevertheless, recent evidence suggests alternative functions of this family of protein in metabolism regulation. In this line, we have described the involvement of the transmembrane domain of Bcl-XL in dimerization.

3- PEPCK. Together with Dr. Pascual López Buesa, we have studied several genetic polymorphisms with effect on pig meat quality, focusing in recent years on both cytosolic and mitochondrial isoforms of phosphoenolpyruvate carboxykinase. This work has evolved towards the study of post-translational regulation of this enzyme, essential for gluconeogenesis and involved in pathologies like diabetes and cancer.  In a recent work, together with Dr. John Denu, from the Wisconsin Institute for Discovery, and the Universidad de Wisconsin-Madison as well as researchers from Australia, La Rioja and Harvard, we have discovered novel post-translational mechanisms of regulation of PEPCK activity in mammals. This work has been recently published in the journal Molecular Cell. We hare concluding another set of studies in this same line.

4- Parkinson´s disease. Together with Dr. Nunilo Cremades, at BIFI, we are starting a research project about Parkinson´s using a multidisciplinary approach, biophysical (Dr. Cremades) and cellular (Dr. Carrodeguas), focused on the development of novel cellular models and the use of state-of-the-art biophysical techniques with the aim of determining the initial mechanisms leading to aggregation of a-synuclein in this pathology.

5- Stem cells. We have also worked on the differentiation and death of stem cells and we are going to apply this knowledge in the development of cellular models for Parkinson´s disease.

We also collaborate with several researchers at BIFI in different research lines.


Relevant publications

  1. Latorre-Muro P, Baeza J, Armstrong, EA, Hurtado-Guerrero R, Corzana F, Wus LE, Sinclair DA, López-Buesa P, Carrodeguas JA, Denu JM (2018). Dynamic acetylation of cytosolic phosphoenolpyruvate carboxykinase toggles enzyme activity between gluconeogenic and anaplerotic reactions. Mol. Cell. 71: 718-732. doi: 10.1016/j.molcel.2018.07.031.
  2. Latorre P, Varona L, Burgos C, Carrodeguas JA, López-Buesa P. (2017). O-GlcNAcylation mediates the control of cytosolic phosphoenolpyruvate carboxykinase activity via Pgc1α. PLoS One 12: e0179988. doi: 10.1371/journal.pone.0179988.
  3. Hidalgo J, Latorre P, Carrodeguas JA, Velázquez-Campoy A, Sancho J, López-Buesa P. (2016). Inhibition of Pig Phosphoenolpyruvate Carboxykinase Isoenzymes by 3-Mercaptopicolinic Acid and Novel Inhibitors. PLoS One. 11: e0159002. doi: 10.1371/journal.pone.0159002.
  4. Escós M, Latorre P, Hidalgo J, Hurtado-Guerrero R, Carrodeguas JA, López-Buesa P. (2016). Kinetic and functional properties of human mitochondrial phosphoenolpyruvate carboxykinase. Biochem Biophys Rep. 7: 124-129. doi: 10.1016/j.bbrep.2016.06.007. Co-corresponding author.
  5. Latorre P, Burgos C, Hidalgo J, Varona L, Carrodeguas JA, López-Buesa P. (2016). c.A2456C-substitution in Pck1 changes the enzyme kinetic and functional properties modifying fat distribution in pigs. Sci Rep. 6: 19617. doi: 10.1038/srep19617. Co-corresponding author.
  6. Nelo-Bazán MA, Latorre P, Bolado-Carrancio A, Pérez-Campo FM, Echenique-Robba P, Rodríguez-Rey JC, Carrodeguas JA. (2015). Early growth response 1 (EGR-1) is a transcriptional regulator of mitochondrial carrier homolog 1 (MTCH 1)/presenilin 1-associated protein (PSAP). Gene 578:52-62. doi: 10.1016/j.gene.2015.12.014.
  7. Echenique-Robba P, Nelo-Bazán MA, Carrodeguas JA. (2013). Reducing the standard deviation in multiple-assay experiments where the variation matters but the absolute value does not. PLoS One 8: e78205. doi: 10.1371/journal.pone.0078205.
  8. Ospina A, Lagunas-Martínez A, Pardo J, Carrodeguas JA (2011). Protein oligomerization mediated by the transmembrane carboxyl terminal domain of Bcl-XL. FEBS Lett. 585: 2935-42. doi: 10.1016/j.febslet.2011.08.012.
  9. Conesa C, Doss MX, Antzelevitch C, Sachinidis A, Sancho J, Carrodeguas JA (2012). Identification of specific pluripotent stem cell death–inducing small molecules by chemical screening. Stem. Cell Rev. 2012 Mar;8(1):116-27. doi: 10.1007/s12015-011-9248-4.
  10. Lamarca V, Marzo I, Sanz-Clemente A, Carrodeguas JA (2008). Exposure of any of two proapoptotic domains of presenilin 1-associated protein/mitochondrial carrier homolog 1 on the surface of mitochondria is sufficient for induction of apoptosis in a Bax/Bak-independent manner. Eur. J. Cell. Biol. 87: 325-34. doi: 10.1016/j.ejcb.2008.02.004.


Main research projects

1.- Modulación de las características del músculo esquelético por la fosfoenolpiruvato carboxiquinasa. Facultad de Veterinaria – Universidad de Zaragoza. Pascual López Buesa y José Alberto Carrodeguas Villar. CICYT. 2016-1018.

2.- Modulación de las características del músculo esquelético por la fosfoenolpiruvato carboxiquinasa. Instituto Universitario De Investigación De Biocomputación y Física De Sistemas Complejos – Universidad de Zaragoza. José Alberto Carrodeguas Villar. VIC. INV. – APOYO INV. 2016.

3.- PEPCK y sus efectos sobre el metabolismo, los caracteres productivos y la calidad de la carne y la canal del ganado porcino. Facultad De Veterinaria – Universidad de Zaragoza. Pascual Luis López Buesa. VIC. INV. – APOYO INV. 2015.

4.- Identificación de moléculas bioactivas en células troncales mediante cribado funcional de quimiotecas: herramientas para terapias seguras. Instituto de Biocomputación y Física de Sistemas Complejos. José Alberto Carrodeguas Villar. Universidad de Zaragoza/Ibercaja. 2012-2013.

5.- Proteínas Mtch: regulación transcripcional en humanos y efectos fenotípicos del mutante en Drosophila. Instituto Universitario De Investigación De Biocomputación y Física De Sistemas Complejos. José Alberto Carrodeguas Villar. Universidad de Zaragoza. 2011.

6.- Genética química para la identificación de compuestos bioactivos que promueven diferenciación específica, proliferación o apoptosis en células madre. Instituto de Biocomputación y Física de Sistemas Complejos. Departamento de Bioquímica y Biología Molecular y Celular. Facultad de Ciencias. Universidad de Zaragoza. José Alberto Carrodeguas Villar. Instituto Aragonés de Ciencias de la Salud. 2011.

7.- Regulación de la actividad de proteínas proapoptóticas mitocondriales. Instituto de Biocomputación y Física de Sistemas Complejos. Departamento de Bioquímica y Biología Molecular y Celular. Facultad de Ciencias. Universidad de Zaragoza. José Alberto Carrodeguas Villar. Ministerio de Ciencia e Innovación. 2010.

8.- Identificación de compuestos químicos que inducen diferenciación celular específica o muerte celular apoptótica en células madre embrionarias de ratón (continuación). Instituto de Biocomputación y Física de Sistemas Complejos. Departamento de Bioquímica y Biología Molecular y Celular. Facultad de Ciencias. José Alberto Carrodeguas Villar. Instituto Aragonés de Ciencias de la Salud. 2009-2010.

9.- Identificación de compuestos químicos que inducen diferenciación celular específica o muerte celular apoptótica en células madre embrionarias de ratón (continuación). Instituto de Biocomputación y Física de Sistemas Complejos. Departamento de Bioquímica y Biología Molecular y Celular. Facultad de Ciencias. José Alberto Carrodeguas Villar. Instituto Aragonés de Ciencias de la Salud. 2008-2010.

10.- Mecanismos moleculares de proteínas de la membrana externa mitocondrial similares a transportadores implicadas en apoptosis. Papel en enfermedades degenerativas y en cáncer. Facultad de Veterinaria. Universidad de Zaragoza. José Alberto Carrodeguas Villar. MEC. 2006-2009.



  • Miguel Fernández Moreno and Juan José Arredondo. Instituto de Investigaciones Biomédicas. CSIC-UAM. Madrid.
  • Javier Sancho, Milagros Medina, Adrián Velázquez Campoy, Ramón Hurtado-Guerrero, Patricio Fernández Silva, Raquel Moreno Loshuertos. Instituto de Biocomputación y Física de Sistemas Complejos. Departamento de Bioquímica y Biología Molecular y Celular. Facultad de Ciencias. Universidad de Zaragoza.
  • José Carlos Rodríguez-Rey. Department of Molecular Biology, University of Cantabria, IDIVAL, Santander, Cantabria, Spain.
  • Flor Pérez Campo. Department of Internal Medicine, Hospital U. Marqués de Valdecilla-IDIVAL University of Cantabria, 39008 Santander, Cantabria, Spain.
  • John M. . Wisconsin Institute for Discovery, Morgridge Institute for Research, and the Department of 12 Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, USA.
  • Francisco Corzana. Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja.
Computational genomics and systems BioMedicine

Computational Genomics and Systems Bio-medicine

Head of the Research Line:

Joaquín Sanz


PhD students:
Mario Tovar
Jorge Cárdenas

Master students:
Ignacio Marchante

Undergrad students:
Santiago Royo
Pablo Pérez
Pilar Cobos.

Jessica Moreira Batista Da Silva
Regina Santesteban Azanza



In our lab, we use mathematical models to describe infectious and auto-immune diseases at a variety of scales: from cells & genes to individuals & populations. Our main goal is to pinpoint the causal factors -both genetic and environmental- shaping variation in immune responses to pathogens, as well as to characterize the drivers of functional vs. pathological responses and learn how do they relate to epidemiological observations.

To do that, NGS genomic data constitutes our main raw material. That includes genetic variation data on large human cohorts, as well as host & pathogen transcriptomes and epigenomes, both in human & animal models at bulk and single-cell resolution. On the epidemiological side, we develop transmission models to interpret data such as trans-national burden registers, prevalence surveys and clinical trials outcomes. In pursuing these goals, our methods integrate tools from computational genomics, systems Bio-Medicine, biostatistics, data & network science, Bayesian inference, mathematical epidemiology and Physics of complex systems.

Nowadays, there is three main research thread open in the line, which was created in 2019. These include the Systems Biology of host-pathogen interactions in tuberculosis; the development of computational tools for single-cell -omics data analysis, and the development of computational applications to the study of the genomics of the immune system.


Systems biology of tuberculosis.

Tuberculosis (TB) is  one of the most ancient infectious diseases affecting humans, and, with an estimated number of 1.4 million deaths in 2019, it remains among the deadliest ones. Its causative agent, the bacillus Mycobacterium tuberculosis, is arguably the most successful among all human pathogens, considering its striking ability to coexist with its host (circa. 24% of contemporary humans are estimated to be infected with M.tb.) without compromising their fitness. Among all possible epidemiological interventions under consideration in the fight against TB, the introduction of a new vaccine able to complement, or outperform the current vaccine of the Bacillus Calmette-Guerin (BCG) holds the promise of a greatest impact against the disease.

In our lab, we use Systems Biology, Bio-informatics & Mathematical Epidemiology techniques to model Tuberculosis infection and TB vaccine properties at different levels of complexity. That includes the genomic characterization of the regulatory mechanisms underlying mycobacterial-induced trained innate immunity, and the epidemiological modelling of TB transmission at a trans-national level to evaluate the impact of epidemiological interventions and assist the analysis and interpretation of vaccine-efficacy clinical trials.

Fig. 1: Systems Biology of TB. The recent activity of the group in this topic includes the characterization of transcriptional regulatory networks, at the level of single bacteria; the study of innate trained immunity in collaboration with M. Divangahi (McGill) and his team  (at the level of one host); the ongoing characterization of the genetic architecture of the response of human macrophages to M.tb. infection (at the level of one population), and the development of mathematical models of TB transmission, at supranational scales (many populations).


Single-cell -omics data modelling and analysis

In 2009, Fuchou Tang and collaborators were the first to use single cell RNA-seq, from a four-cell stage mouse blastomere. Since then, the field has witnessed spectacular progress in microfluidic techniques, automation of library preparation and multiplexing, to the point that now it is possible, and relatively affordable, to compile datasets containing hundreds of thousands of cells. These experimental improvements unlock the possibility of addressing deeper Biological problems through the usage of complex experimental designs.

In the lab, we combine data-science, statistical modeling and complex networks methods to propose improved pipelines for single cell transcriptomic data, with a special focus on characterizing transcriptional responses to infection, immune training, and vaccination in immune cells and their hematopoietic precursors.

Computational immuno-genomics

Immune responses to immunological insults are complex, and highly variable across individuals. The adequacy of the immune response to an infection challenge can be often evaluated by observing its strength, promptness and specificity; and all these are dynamical features that emerge from a complex interplay between many different causal factors. These factors equally stem from the genetics of both host and pathogen as well as from the environmental context wherein they meet.

In the lab we study the causality links that connect genotypes and environmental variables with immune responses to infection. Our main objective is the identification of the components of such responses that are more strongly affected by those causal factors, as well as their evolutionary and clinical implications.

Fig. 2. Computational immunogenomics. Graphical scheme of the experimental approaches implemented in some of the last projects we have been reciently involved with, in collaboration with professors L. Barreiro (U. Chicago), and J. Tung (Duke), and their teams.


Relevant publications

  1. Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity. Hawash, M., Sanz, J, Grenier, J. C., Kohn, J., Yotova, V., Johnson, Z., … & Barreiro, L. B. (2020). Proceedings of the National Academy of Sciences, 2021.
  2. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Khan1, Downey, Sanz, J., Kaufmann, Blankenhaus, Pacis, … & Divangahi (2020). Cell, 183(3), 752-770.
  3. Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques. Sanz, J., Maurizio, P. L., Snyder-Mackler, N., Simons, N. D., Voyles, T., Kohn, J., … & Barreiro, L. B. (2020). Proceedings of the National Academy of Sciences117(38), 23317-23322.
  4. Bridging the gap between efficacy trials and model-based impact evaluation for new tuberculosis vaccines. Tovar, M., Arregui, S., Marinova, D., Martín, C., Sanz, J., & Moreno, Y. Nature Communications10(1), 1-10. (co-last author) (2019).
  5. Natural selection contributed to immunological differences between hunter-gatherers and agriculturalists. Harrison, G.F., Sanz, J., Boulais, J., Mina, M.J., Grenier, J.C., Leng, Y., Dumaine, A., Yotova, V., Bergey, C. M., Nsobya, S.L., Elledge, S.J., Schurr, E., Quintana-Murci, L., Perry, G.H., Barreiro, L.B. Nature Ecology and Evolution 1253-1264 3(8) (2019).
  6. Spotting the old foe—revisiting the case definition for TB. Houben, R.M., Esmail, H., Emery, J.C., Joslyn, L.R., McQuaid, C.F., Menzies, N.A., Sanz, J., Shrestha, S., White, R.G., Yang, C. and Cobelens, F., 2019. The Lancet Respiratory Medicine7(3), pp.199-201.
  7. Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques. Snyder-Mackler, N., Sanz, J., Kohn, J. N., Voyles, T., Pique-Regi, R., Wilson, M. E., … & Tung, J. (2019). Proceedings of the National Academy of Sciences116(4), 1219-1228.
  8. Genetic and evolutionary determinants of human population variation in immune responses. Sanz, J., Randolph, H. E., & Barreiro, L. B. (2018). Current opinion in genetics & development53, 28-35.
  9. Data-driven model for the assessment of Mycobacterium tuberculosis transmission in evolving demographic structures. Arregui, S., Iglesias, M. J., Samper, S., Marinova, D., Martin, C., Sanz, J. , & Moreno, Y. 1 . (co-last author). (2018). Proceedings of the National Academy of Sciences115(14), E3238-E3245.
  10. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Kaufmann, E. 1, Sanz, J. 1, Dunn, J. L. 1, Khan, N., Mendonça, L. E., Pacis, A., … & Mailhot-Léonard, F. (co-first author). (2018). Cell172(1-2), 176-190.
  11. Social status alters immune regulation and response to infection in macaques. N. Snyder-Mackler1, J. Sanz1, J.N. Kohn, J.F. Brinkworth, S. Morrow, A.O. Shaver, J.C. Grenier, R. Pique-Regi, Z.P. Johnson, M.E. Wilson, L.B. Barreiro2 & J. Tung2 (co-first author; co-last author); Science, 354 (6315), 1041-1045.
  12. Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Y. Nédéléc1, J. Sanz1, G. Baharian1, Z.A. Szpiech, A. Pacis, A. Dumaine, J.C. Grenier, A. Freiman, J. Sams, S. Hebert, A. Pagé-Sabourin, F. Luca, R. Blekhman, R.D. Hernández, R. Piqué-Regi, J. Tung, V. Yotova & L.B.B. Barreiro, (co-first author). Cell 167-3, p657–669.e21 (2016) (The paper was selected for the Issue cover).


Main research projects

  • PID2019-106859GA-I00: Enfoques sistémicos a los mecanismos de defensa del hospedador ante enfermedad e infección en M. tuberculosis: causas genéticas y evaluación de impacto en nuevas vacunas, 2020-2023 Spanish Ministry of Science and Innovation (MICINN), Principal Investigator: Joaquín Sanz.
  • Bio-computational approaches applied to the development of TB vaccines: epidemiological modeling, efficacy simulations and immunogenetics analyses. Government of Aragon, Spain. Grant LMP117-18. 2019-2020. PI: Yamir Moreno.
  • Multi-scale approaches to Tuberculosis infection: mathematical epidemiology and functional genomics. National Programme for Recruitment and Incorporation of Human Resources 2018, subprogramme “Ramón y Cajal”. RYC-2017-23560. 2019-2024. Principal Investigator: Joaquín Sanz.
  • Stress and the Genome: Testing the Impact of Social Effects on Gene Regulation. National Institute of Health NIH (USA) Project # 1R01GM102562-01. (2012-2022). Principal Investigator: Dr. Jenny Tung. (Duke University)


  • Maziar Divangahi, McGill University, Canada.
  • Eva Kaufmann, McGill University, Canada.
  • Luis Barreiro, University of Chicago, USA.
  • Genelle Harrison, University of Colorado, USA.
  • Jenny Tung, Duke University, Durham, USA.
  • Bana Jabri, University of Chicago, USA.
  • Valentina Discepolo, Universitá Federico II, Naples, Italy.
  • Carlos Martín, unizar.
  • Nacho Aguiló, unizar.
  • Jesús Gonzalo-Asensio, unizar.
  • Yamir Moreno, unizar.
  • Pierpaolo Bruscolini, unizar.
  • Mario Floría, unizar.
  • Jesús Gómez-Gardeñes, unizar.
  • Sandro Meloni, IFISC, Palma de Mallorca.



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