Genome instability drives epistatic adaptation in the human pathogen Leishmania

Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, Smadar Cohen-Chalamish, Tirza Doniger, Disha Gajanan Hiregange, Peter J. Myler, Ron Unger, Shulamit Michaeli, Gerald F. Spath

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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, which exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches, we provide evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations in pathways driving fitness gain in a given environment. We further uncover posttranscriptional 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 small nucleolar RNA (snoRNA) gene dosage with changes in ribosomal RNA 20-O-methylation and pseudouridylation, suggesting 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 selective pressure. The 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.

Original languageEnglish
Article numbere2113744118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - 21 Dec 2021

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This study was supported by a seeding grant from the Institut Pasteur International Department to the LeiSHield Consortium, the EU H2020 project LeiSHield-MATI-REP-778298-1, the Fondation pour la Recherche Médicale (Grant FDT201805005619), the Flemish Ministry of Science and Innovation (MADLEI, SOFI Grant 754204), and a grant from CAMPUS France and the Israeli Ministry of Science and Technology PHC MAIMONIDE 2018-2019-Projet 41131ZD. We thank Cedric Notredame and Jean-Claude Dujardin for critical reading of the manuscript.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.


  • Epistatic interactions
  • Evolutionary adaptation
  • Fitness gain
  • Genome instability
  • Posttranscriptional regulation


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