Cell-to-cell variability and robustness in S-phase duration from genome replication kinetics

Genome replication, a key process for a cell, relies on stochastic initiation by replication origins, causing a variability of replication timing from cell to cell. While stochastic models of eukaryotic replication are widely available, the link between the key parameters and overall replication timing has not been addressed systematically. We use a combined analytical and computational approach to calculate how positions and strength of many origins lead to a given cell-to-cell variability of total duration of the replication of a large region, a chromosome or the entire genome. Specifically, the total replication timing can be framed as an extreme-value problem, since it is due to the last region that replicates in each cell. Our calculations identify two regimes based on the spread between characteristic completion times of all inter-origin regions of a genome. For widely different completion times, timing is set by the single specific region that is typically the last to replicate in all cells. Conversely, when the completion time of all regions are comparable, an extreme-value estimate shows that the cell-to-cell variability of genome replication timing has universal properties. Comparison with available data shows that the replication program of three yeast species falls in this extreme-value regime.