On the rate of aneuploidy reversion in a wild yeast model

Aneuploidy, arising from the gain or loss of chromosomes due to nondisjunction, is a special class of mutation. It can create significant phenotypic changes by altering the abundance of hundreds of genes in a single event, providing material for adaptive evolution. But it can also incur large fitness costs relative to other types of mutations. Understanding the mutational dynamics of aneuploidy is important for modeling its impact in nature, but aneuploidy rates are difficult to measure accurately. One challenge is that aneuploid karyotypes may revert back to euploidy, biasing forward mutation rate estimates-yet the rate of aneuploidy reversion is largely uncharacterized. Furthermore, current rate estimates are confounded because fitness differences between euploids and aneuploids are typically not accounted for in rate calculations. We developed a unique fluctuation assay in a wild-yeast model to measure the rate of extra-chromosome loss across 3 aneuploid chromosomes while accounting for fitness differences between aneuploid and euploid cells. We show that incorporating fitness effects is essential to obtain accurate estimates of aneuploidy rates. Furthermore, the rate of extra-chromosome loss, separate from karyotype fitness differences, varies across chromosomes. We also measured rates in a strain lacking RNA-binding protein Ssd1, important for aneuploidy tolerance and implicated in chromosome segregation. We found no role for Ssd1 in the loss of native aneuploid chromosomes, although it did impact an engineered chromosome XV with a perturbed centromeric sequence. We discuss the impacts and challenges of modeling aneuploidy dynamics in real-world situations.