Skip to Main content Skip to Navigation
Journal articles

Genome instability drives epistatic adaptation in the human pathogen Leishmania

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 , 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 2′- 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.
Document type :
Journal articles
Complete list of metadata

https://hal-pasteur.archives-ouvertes.fr/pasteur-03512631
Contributor : Christel Ricard Andraos Connect in order to contact the contributor
Submitted on : Wednesday, January 5, 2022 - 2:38:07 PM
Last modification on : Tuesday, May 31, 2022 - 10:20:18 AM
Long-term archiving on: : Wednesday, April 6, 2022 - 8:31:35 PM

File

e2113744118.full.pdf
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives 4.0 International License

Identifiers

Collections

Citation

Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata A. Domagalska, K. Shanmugha Rajan, et al.. Genome instability drives epistatic adaptation in the human pathogen Leishmania. Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2021, 118 (51), pp.e2113744118. ⟨10.1073/pnas.2113744118⟩. ⟨pasteur-03512631⟩

Share

Metrics

Record views

22

Files downloads

17