A unified model of aneuploid karyotype dynamics

Aneuploidies--whole-chromosome copy number imbalances arising from nondisjunction--underlie numerous congenital and somatic disorders, but unlike many other disease-causing variants, they can readily revert back to euploidy through subsequent errors of the same type. The extent to which this inherent plasticity impacts the stability and persistence of aneuploid karyotypes in populations remains poorly understood, a gap in knowledge that continues to limit our understanding of aneuploidy-driven disease incidence, penetrance, and progression. To assess how reversion shapes aneuploid population dynamics, we developed a budding yeast system to systematically measure the rates at which aneuploidies arise and revert, and quantify the relative fitness differences between these karyotypic states. We integrated these data into a computational framework encompassing the broad physiological range of aneuploid karyotype dynamics captured in our experiments. The resulting models reveal that canonical reversion (i.e., subsequent nondisjunction) occurs rarely, conferring a negligible effect on the population dynamics of most chromosomal aneuploidies. However, our models also identified that the reversion dynamics of some chromosomes--those that revert at extremely high rates--were more consistent with an alternative mechanism in which nondisjunction and reversion are directly coupled. Whole-genome sequencing and live-cell microscopy demonstrates that this coupled mechanism is facilitated by unresolved intermolecular linkages that disrupt chromosome segregation, leading to chromosome breakage and recombination-mediated repair over subsequent cell divisions. Collectively, this work establishes a unified model of aneuploid population genetics and expands our perspective of the diverse, and chromosome-specific mutational mechanisms shaping genome architecture.