Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

Abstract

AbstractAneuploidy causes system-wide disruptions in the stochiometric balances of transcripts, proteins, and metabolites, often resulting in detrimental effects for the organism. The protozoan parasite Leishmania has an unusually high tolerance for aneuploidy, but its molecular consequences remain poorly understood. Here, we present the first integrated analysis of the genome, transcriptome, proteome, and metabolome of highly aneuploid Leishmania donovani strains. Our analysis unambiguously establishes that, despite this tolerance, aneuploidy in Leishmania globally and proportionally impacts the transcriptome and proteome of affected chromosomes, ultimately explaining the degree of metabolic differences between strains. This impact was present in both proliferative and infectious life stages. Protein complex subunits, secreted proteins, and non-cytoplasmic proteins, responded less or even not at all to aneuploidy-induced dosage changes. In contrast to other Eukaryotes, widespread transcript regulation modulating aneuploidy-related stress was absent. Further, the majority of regulated proteins was encoded by non-aneuploid chromosomes and had no underlying transcript change, suggesting that aneuploidy induces extensive post-transcriptional protein-level modulation. This makes Leishmania a unique Eukaryotic model for elucidating post-transcriptional protein-abundance modulation in the context of aneuploidy.