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标题：Genome instability drives epistatic adaptation in the human pathogen Leishmania
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作者：Giovanni Bussotti ; Laura Piel ; Pascale Pescher 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：51
DOI：10.1073/pnas.2113744118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Chromosome and gene copy number variations often correlate with the evolution of microbial and cancer drug resistance, thus causing important human mortality. How genome instability is harnessed to generate beneficial phenotypes and how deleterious gene dosage effects are compensated remain open questions. The protist pathogen Leishmania exploits genome instability to regulate expression via gene dosage changes. Using these parasites as a unique model system, we uncover complex epistatic interactions between gene copy number variations and compensatory transcriptomic responses as key processes that harness genome instability for adaptive evolution in Leishmania. Our results propose a model of eukaryotic fitness gain that may be broadly applicable to pathogenic fungi or tumor cells known to exploit genome instability for adaptation. 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.
关键词：genome instability; epistatic interactions; posttranscriptional regulation; evolutionary adaptation; fitness gain