Genome instability drives epistatic adaptation in the human pathogen Leishmania .
Autor: | Bussotti G; Bioinformatics and Biostatistics Hub C3BI, Institut Pasteur, Université de Paris, Unité de Service et de Recherche (USR) 3756 Institut Pasteur CNRS, Paris 75015, France.; Unité de Parasitologie moléculaire et Signalisation, Institut Pasteur, Université de Paris, INSERM U1201, Paris 75015, France., Piel L; Unité de Parasitologie moléculaire et Signalisation, Institut Pasteur, Université de Paris, INSERM U1201, Paris 75015, France., Pescher P; Unité de Parasitologie moléculaire et Signalisation, Institut Pasteur, Université de Paris, INSERM U1201, Paris 75015, France., Domagalska MA; Molecular Parasitology Unit, Institute of Tropical Medicine B-2000 Antwerp, Belgium., Rajan KS; The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel., Cohen-Chalamish S; The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel., Doniger T; The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel., Hiregange DG; Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel., Myler PJ; Seattle Structural Genomics Center for Infectious Disease, Seattle, WA 98195.; Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA 98195.; Department of Pediatrics, University of Washington, Seattle, WA 98195.; Department of Global Health, University of Washington, Seattle, WA 98195.; Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98195., Unger R; The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel., Michaeli S; The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel., Späth GF; Unité de Parasitologie moléculaire et Signalisation, Institut Pasteur, Université de Paris, INSERM U1201, Paris 75015, France; gerald.spaeth@pasteur.fr. |
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Jazyk: | angličtina |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Dec 21; Vol. 118 (51). |
DOI: | 10.1073/pnas.2113744118 |
Abstrakt: | 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. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.) |
Databáze: | MEDLINE |
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