High-Resolution Replication Profiles Define the Stochastic Nature of Genome Replication Initiation and Termination

• Deep sequencing reveals a high-resolution view of genome replication dynamics
• Genome-wide modeling and single-cell imaging reveal stochastic origin activity
• Origin activity determines the location of replication termination events
• Termination events are widely distributed across the whole genome

SummaryEukaryotic genome replication is stochastic, and each cell uses a different cohort of replication origins. We demonstrate that interpreting high-resolution Saccharomyces cerevisiae genome replication data with a mathematical model allows quantification of the stochastic nature of genome replication, including the efficiency of each origin and the distribution of termination events. Single-cell measurements support the inferred values for stochastic origin activation time. A strain, in which three origins were inactivated, confirmed that the distribution 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.

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