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Genome instability drives epistatic adaptation in the human pathogen Leishmania

View ORCID ProfileGiovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, Tirza Doniger, Disha-Gajanan Hiregange, View ORCID ProfilePeter J. Myler, Ron Unger, Shulamit Michaeli, Gerald F. Späth
doi: https://doi.org/10.1101/2021.06.15.448517
Giovanni Bussotti
1Institut Pasteur – Bioinformatics and Biostatistics Hub – C3BI, USR 3756 IP CNRS – Paris, France
2Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
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  • ORCID record for Giovanni Bussotti
Laura Piel
2Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
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Pascale Pescher
2Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
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Malgorzata A. Domagalska
3Institute of Tropical Medicine, Molecular Parasitology Unit, B-2000, Antwerp, Belgium
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K. Shanmugha Rajan
4The 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
4The 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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Disha-Gajanan Hiregange
5Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, 7610001 Israel
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Peter J. Myler
6Seattle Structural Genomics Center for Infectious Disease, Seattle, Washington, USA
7Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, Washington, USA
8Department of Pediatrics, University of Washington, Seattle, Washington, USA
9Department of Global Health, University of Washington, Seattle, Washington, USA
10Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, USA
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  • For correspondence: peter.myler@seattlechildrens.org
Ron Unger
4The 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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Shulamit Michaeli
4The 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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Gerald F. Späth
2Institut Pasteur, INSERM U1201, Unité de Parasitologie moléculaire et Signalisation, Paris, France
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  • For correspondence: Gerald.spaeth@pasteur.fr
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Abstract

How genome instability is harnessed for fitness gain despite its potential deleterious effects is largely elusive. An ideal system to address this important open question is provided by the protozoan pathogen Leishmania that exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches we provide first evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations that can inform on pathways driving fitness gain in a given environment. We further uncover post-transcriptional regulation as a key mechanism that compensates for deleterious gene dosage effects and provides phenotypic robustness to genetically heterogenous parasite populations. Finally, we correlate dynamic variations in snoRNA gene dosage to changes in rRNA 2’-O-methylation and pseudouridylation, proposing translational control as an additional layer of parasite adaptation. Leishmania genome instability is thus harnessed for fitness gain by genome-dependent variations in gene expression, and genome-independent, compensatory mechanisms. This allows for polyclonal adaptation and maintenance of genetic heterogeneity despite strong selection. Epistatic adaptation described here needs to be considered in Leishmania epidemiology and biomarker discovery, and may be relevant to other fast evolving, eukaryotic cells that exploit genome instability for adaptation, such as fungal pathogens or cancer.

One Sentence Summary Epistatic interactions harness genome instability for Leishmania fitness gain.

Competing Interest Statement

The authors have declared no competing interest.

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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 June 15, 2021.
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Genome instability drives epistatic adaptation in the human pathogen Leishmania
Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, Tirza Doniger, Disha-Gajanan Hiregange, Peter J. Myler, Ron Unger, Shulamit Michaeli, Gerald F. Späth
bioRxiv 2021.06.15.448517; doi: https://doi.org/10.1101/2021.06.15.448517
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Genome instability drives epistatic adaptation in the human pathogen Leishmania
Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, Tirza Doniger, Disha-Gajanan Hiregange, Peter J. Myler, Ron Unger, Shulamit Michaeli, Gerald F. Späth
bioRxiv 2021.06.15.448517; doi: https://doi.org/10.1101/2021.06.15.448517

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