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Bacteria and archaea are at risk for both cell death and genomic invasion by a diverse set of genetic parasites (e.g. phages), and as a result have developed an array of sophisticated lines of active defense that can collectively be referred to as the prokaryotic anti-phage defensome. Based on their action modes, the defensome components can be divided into two major groups: immunity and programmed cell death. The immunity group comprises: i) restriction-modification (R-M) systems that target specific sequences on the invading phage1,2; ii) clustered regularly interspaced short palindromic repeats and adjacent cas genes (CRISPR-Cas) systems3, which provide acquired immunity through memorization of previous phage attacks; iii) DNA phosphorothioation (PT) systems4 that replace non-bridging oxygen by sulphur on the DNA sugar-phosphate backbone; iv) and additional systems such as BREX5, prokaryotic Argonautes (pAgos)6, DISARM7, DRUANTIA, GABIJA, and ZORYA8 whose mechanisms of action are not yet clear. On the other hand, the programmed cell death group includes: i) toxin-antitoxin (T-A) systems which play roles in phage defense, virulence, or as DNA maintenance modules9; and ii) abortive infection (ABI) systems that lead to cell death or metabolic arrest upon infection10.
The past few decades have revealed extensive insights on how biotic interactions, such as competition, symbioses, horizontal gene transfer (HGT), and predation, play a role in the distribution and diversity of microbial communities across multiple biomes. The presence of phages in these communities adds an extra layer of complexity as it can lead to escalation, (similar to an arms-race), where each party invests in a greater number of weapons and/or defenses, resulting in mutual directional natural selection. And while the abundance, distribution, and diversity of anti-phage defense systems has been well characterized on genomic data, we currently lack a holistic view of the defensome across distinct environmental and host-associated microbial populations.
Here we aim to perform a large-scale mapping of the defensomes of >30,000 high-quality metagenome-assembled genomes (MAGs) obtained from environmental (e.g.: oceans) and human-associated (e.g.: gut) metagenomic datasets. We will then use comparative genomics to evaluate the variability and distribution of defensome components, and test their association with mechanisms of genetic mobility. The presence of previously unidentified genes enriched in defense islands will also be assessed. Ultimately, this project will deepen our understanding on the extent to which phage-host interactions play a role in shaping diversity and structure of complex microbial communities, as well as pinpoint previously unappreciated mechanisms by which immunity spreads.
The ideal candidate will have a strong interest in working in the integration, interpretation and visualization of large biological datasets. Proficiency in UNIX-Linux shell is expected as well as proficiency in at least one of the following programming languages (R/Bioconductor, Python, Perl, C++). Experience in working on high performance computing/cluster platforms will be a plus. The candidate will benefit from a highly dynamic and interdisciplinary environment, including biologists, microbiologists, computer scientists, and bioinformaticians. The Genoscope (French National Sequencing Centre) has a long-standing tradition in the broad field of genomics. After having been one of the players in the human genome project, and supporting more than 650 projects serving the national scientific community, it currently focuses on the genomics of environmental organisms (e.g. TARA project), bacterial flora of the human digestive tract, among others.
1 Oliveira, P. H., Touchon, M. & Rocha, E. P. Regulation of genetic flux between bacteria by restriction-modification systems. Proc Natl Acad Sci U S A 113, 5658-5663, (2016).
2 Oliveira, P. H., Touchon, M. & Rocha, E. P. The interplay of restriction-modification systems with mobile genetic elements and their prokaryotic hosts. Nucleic Acids Res 42, 10618-10631, (2014).
3 Koonin, E. V., Makarova, K. S. & Zhang, F. Diversity, classification and evolution of CRISPR-Cas systems. Curr Opin Microbiol 37, 67-78, (2017).
4 Wang, L. et al. DNA phosphorothioation is widespread and quantized in bacterial genomes. Proc Natl Acad Sci U S A 108, 2963-2968, (2011).
5 Goldfarb, T. et al. BREX is a novel phage resistance system widespread in microbial genomes. EMBO J 34, 169-183, (2015).
6 Makarova, K. S., Wolf, Y. I., van der Oost, J. & Koonin, E. V. Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements. Biol Direct 4, 29, (2009).
7 Ofir, G. et al. DISARM is a widespread bacterial defence system with broad anti-phage activities. Nat Microbiol 3, 90-98, (2018).
8 Doron, S. et al. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359, (2018).
9 Unterholzner, S. J., Poppenberger, B. & Rozhon, W. Toxin-antitoxin systems: Biology, identification, and application. Mob Genet Elements 3, e26219, (2013).
10 Dy, R. L., Przybilski, R., Semeijn, K., Salmond, G. P. & Fineran, P. C. A widespread bacteriophage abortive infection system functions through a Type IV toxin-antitoxin mechanism. Nucleic Acids Res 42, 4590-4605, (2014).