Abstract
Faithful chromosome segregation, driven by the mitotic spindle, is essential for organismal survival. Neopolyploid cells from diverse species exhibit a significant increase in mitotic errors relative to their diploid progenitors, resulting in chromosome nondisjunction. In the model system Saccharomyces cerevisiae, the rate of chromosome loss in haploid and diploid cells is measured to be one thousand times lower than the rate of loss in isogenic tetraploid cells. Currently it is unknown what constrains the number of chromosomes that can be segregated with high fidelity in an organism. Here we developed a simple mathematical model to study how different rates of chromosome loss in cells with different ploidy can arise from changes in (1) spindle dynamics and (2) a maximum duration of mitotic arrest, after which cells enter anaphase. We apply this model to S. cerevisiae to show that this model can explain the observed rates of chromosome loss in S. cerevisiae cells of different ploidy. Our model describes how small increases in spindle assembly time can result in dramatic differences in the rate of chromosomes loss between cells of increasing ploidy and predicts the maximum duration of mitotic arrest.
Highlights
Chromosome segregation is an important, highly conserved cellular function
In our model we describe the dynamics of spindle assembly including KC attachment and detachment (Figure 1A), silencing of the spindle assembly checkpoint and the maximum duration of mitotic arrest after which cells enter anaphase regardless of whether all KCs are attached, allowing for chromosome loss in our model
When we plot the fraction of cells with lost kinetochores against spindle assembly time, we find that linear-scale changes in spindle assembly time result in exponential-scale changes in the rate of chromosome loss (Figure 2E)
Summary
Chromosome segregation is an important, highly conserved cellular function. Rare errors in chromosome segregation are observed, and the error rate generally increases when the number of sets of chromosomes (ploidy, n) increases within the cell (Comai, 2005). Increased rates of chromosome loss are observed in autopolyploid cells, within yeasts, plants, and human cells (Mayer and Aguilera, 1990; Song et al, 1995; Ganem et al, 2009). Autopolyploidization can cause tumorigenesis, and these tumors are marked by significant chromosome gain/loss events (Fujiwara et al, 2005; Zack et al, 2013). The general observation is that many newly formed polyploid cells have increased chromosome segregation errors relative to isogenic diploid cells, and the cause of these errors is not known
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