Genome instability drives epistatic adaptation in the human pathogenLeishmania

• DOI: 10.1073/pnas.2113744118
• Publication Date: 2021-12-13T21:27:20Z
• Authors: Giovanni Bussotti; Laura Piel; Pascale Pescher; Malgorzata A. Dom...; K. Shanmugha Rajan; Smadar Cohen-Chal...; Tirza Doniger; Disha-Gajanan Hir...; Peter J. Myler; Ron Unger; Shulamit Michaeli; Gerald F. Späth
• Keywords: Leishmania; 0301 basic medicine; [SDV]Life Sciences [q-bio]; Gene Dosage; posttranscriptional regulation; Epistasis, Genetic; fitness gain; Biological Sciences; epistatic interactions; Adaptation, Physiological; genome instability; Genomic Instability; [SDV] Life Sciences [q-bio]; 03 medical and health sciences; evolutionary adaptation; Humans; Genetic Fitness; Genome, Protozoan; Leishmaniasis

SignificanceChromosome 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 pathogenLeishmaniaexploits 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 inLeishmania. 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.