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

Area of Science:

• Cellular Biology
• Genetics
• Computational Biology

Background:

• Cellular replication relies on stochastic initiation from multiple origins, leading to cell-to-cell variability in replication timing.
• Existing stochastic models for eukaryotic replication lack systematic analysis of parameter links to overall replication timing.

Purpose of the Study:

• To systematically analyze how replication origin positions and strengths influence cell-to-cell variability in genome replication timing.
• To develop a framework connecting origin parameters to the duration of DNA replication for large genomic regions, chromosomes, or the entire genome.

Main Methods:

• Employed a combined analytical and computational approach to model genome replication.
• Framed the total replication timing as an extreme-value problem, focusing on the last region to replicate in each cell.
• Calculated replication timing based on the positions and strengths of numerous origins.

Main Results:

• Identified two distinct regimes of replication timing based on the spread of characteristic completion times across inter-origin regions.
• Demonstrated that timing is dictated by the single, typically last-replicating region when completion times vary widely.
• Showed that comparable completion times lead to universal properties in cell-to-cell replication timing variability, consistent with extreme-value statistics.

Conclusions:

• The study provides a quantitative link between replication origin characteristics and genome-wide replication timing variability.
• The findings suggest that replication timing can be understood through an extreme-value framework, particularly when origin completion times are similar.
• The replication programs of three yeast species align with the identified extreme-value regime, validating the model's predictions.