High-resolution genome replication profiles, modeling and single-cell imaging define the stochastic nature of replication initiation and termination

Eukaryotic genome replication is stochastic with each cell using a different cohort of replication origins. Interpreting high-resolution genome replication profiles with a mathematical model allowed us to quantify the stochastic nature of genome replication. This approach included estimation of the activity of every replication origin and the genome-wide location of replication termination events. Single-cell measurements verified the inferred values for stochastic origin replication time. Strains in which multiple origins had been inactivated, confirmed that the location of termination events is primarily dictated by the stochastic activation time of origins. Cell-to-cell variability in origin activity ensures that termination events are widely distributed across virtually the whole genome. We propose that the heterogeneity in origin usage contributes to genome stability by limiting potentially deleterious events from accumulating at particular loci. Overall design: Measurement of genome replication time for two S. cerevisiae strains. For each strain six S phase samples werecompared with a non-replicating sample.