Dissecting aneuploidy phenotype by the synthesis and SCRaMbLE of synthetic disomic yeast

Aneuploidy compromises genomic stability, often leads to embryo viability, and is frequently associated with tumorigenesis and aging. Different aneuploid chromosome stoichiometry could lead to distinct transcriptomic and phenotypic changes, it is necessary to study aneuploidy in a tightly controlled genetic background. By exploiting the engineered SCRaMbLE system to the newly synthesized Sc2.0 chromosome VII (synVII), we built a synthetic disomic yeast and screened hundreds of SCRaMbLEd disomic yeasts with diverse chromosomal rearrangements of the megabase synVII. Phenotypic characterization and multi-omics analysis revealed that the fitness defect associated with aneuploidy could be restored by removing most extra copies of chromosome contents, or modifying specific regions in the target chromosome. These findings indicate that both chromosome copy number and chromosomal regions contribute to the aneuploidy-related phenotype.