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Post-transcriptional regulation of Leishmania fitness gain

Laura Piel, K. Shanmugha Rajan, Giovanni Bussotti, Hugo Varet, Rachel Legendre, Caroline Proux, Thibaut Douché, Quentin Giai-Gianetto, Thibault Chaze, Barbora Vojtkova, Nadav Gordon-Bar, Tirza Doniger, Smadar Cohen-Chalamish, Praveenkumar Rengaraj, Céline Besse, Anne Boland, Jovana Sadlova, Jean-François Deleuze, Mariette Matondo, Ron Unger, Petr Volf, Shulamit Michaeli, Pascale Pescher, Gerald F. Späth
doi: https://doi.org/10.1101/2021.03.22.436378
Laura Piel
1Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, 75015 Paris, France
2Université de Paris, 75013 Paris, France
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K. Shanmugha Rajan
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Giovanni Bussotti
1Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, 75015 Paris, France
4Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, 75015 Paris, France
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Hugo Varet
4Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, 75015 Paris, France
5Institut Pasteur, Biomics, 75015 Paris, France; Institut Pasteur, UTechS MSBio, 75015 Paris, France
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Rachel Legendre
4Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, 75015 Paris, France
5Institut Pasteur, Biomics, 75015 Paris, France; Institut Pasteur, UTechS MSBio, 75015 Paris, France
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Caroline Proux
5Institut Pasteur, Biomics, 75015 Paris, France; Institut Pasteur, UTechS MSBio, 75015 Paris, France
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Thibaut Douché
6Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, 75015 Paris, France
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Quentin Giai-Gianetto
4Institut Pasteur, Bioinformatics and Biostatistics Hub, Department of Computational Biology, USR 3756 IP CNRS, 75015 Paris, France
6Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, 75015 Paris, France
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Thibault Chaze
6Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, 75015 Paris, France
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Barbora Vojtkova
7Department of Parasitology, Faculty of Science, Charles University, Prague 2, 128 44, Czech Republic
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Nadav Gordon-Bar
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Tirza Doniger
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Smadar Cohen-Chalamish
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Praveenkumar Rengaraj
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Céline Besse
8Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France
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Anne Boland
8Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France
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Jovana Sadlova
7Department of Parasitology, Faculty of Science, Charles University, Prague 2, 128 44, Czech Republic
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Jean-François Deleuze
8Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France
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Mariette Matondo
6Institut Pasteur, Proteomics Platform Mass Spectrometry for Biology UTechS, C2RT, USR2000 CNRS, 75015 Paris, France
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Ron Unger
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Petr Volf
7Department of Parasitology, Faculty of Science, Charles University, Prague 2, 128 44, Czech Republic
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Shulamit Michaeli
3The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel
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Pascale Pescher
1Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, 75015 Paris, France
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  • For correspondence: gerald.spaeth@pasteur.fr pascale.pescher@pasteur.fr
Gerald F. Späth
1Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, 75015 Paris, France
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  • For correspondence: gerald.spaeth@pasteur.fr pascale.pescher@pasteur.fr
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Abstract

The protozoan parasite Leishmania donovani causes fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network driving parasite fitness, with genome instability causing highly reproducible, gene dosage-dependent changes in protein linked to post-transcriptional regulation. These in turn were associated with a gene dosage-independent reduction in flagellar transcripts and a coordinated increase in abundance of coding and non-coding RNAs known to regulate ribosomal biogenesis and protein translation. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence that Leishmania fitness gain may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model for Leishmania fitness gain, where differential regulation of mRNA stability and the generation of fitness-adapted ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach to Leishmania epidemiology and identifies the Leishmania non-coding small RNome as a potential novel source for biomarker discovery.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 22, 2021.
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Post-transcriptional regulation of Leishmania fitness gain
Laura Piel, K. Shanmugha Rajan, Giovanni Bussotti, Hugo Varet, Rachel Legendre, Caroline Proux, Thibaut Douché, Quentin Giai-Gianetto, Thibault Chaze, Barbora Vojtkova, Nadav Gordon-Bar, Tirza Doniger, Smadar Cohen-Chalamish, Praveenkumar Rengaraj, Céline Besse, Anne Boland, Jovana Sadlova, Jean-François Deleuze, Mariette Matondo, Ron Unger, Petr Volf, Shulamit Michaeli, Pascale Pescher, Gerald F. Späth
bioRxiv 2021.03.22.436378; doi: https://doi.org/10.1101/2021.03.22.436378
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Post-transcriptional regulation of Leishmania fitness gain
Laura Piel, K. Shanmugha Rajan, Giovanni Bussotti, Hugo Varet, Rachel Legendre, Caroline Proux, Thibaut Douché, Quentin Giai-Gianetto, Thibault Chaze, Barbora Vojtkova, Nadav Gordon-Bar, Tirza Doniger, Smadar Cohen-Chalamish, Praveenkumar Rengaraj, Céline Besse, Anne Boland, Jovana Sadlova, Jean-François Deleuze, Mariette Matondo, Ron Unger, Petr Volf, Shulamit Michaeli, Pascale Pescher, Gerald F. Späth
bioRxiv 2021.03.22.436378; doi: https://doi.org/10.1101/2021.03.22.436378

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