Post-transcriptional regulation can harness genome instability and provide phenotypic robustness during fitness gain in the human parasite Leishmania donovani

Genome instability has been recognized as a driver in Leishmania fitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting to in vitro culture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth (fitness gain) impairing differentiation of infectious metacyclic parasites, hence infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network driving parasite fitness, with genome instability causing gene dosage-dependent changes in proteins linked to post-transcriptional regulation. These in turn caused gene dosage-independent changes in transcripts associated with fitness tradeoff, including coordinated degradation of flagellar transcripts and stabilization of coding and non-coding RNAs regulating ribosomal biogenesis and protein translation, including small nucleolar RNAs (snoRNAs). Overall design: Comparative genomic, transcriptomic and proteomic analyses to study fitness gain and fitness cost of Leishmania donovani during culture adaptation