Eukaryotic chromosomes replicate with defined timing patterns. However, the mechanism that regulates the timing of replication
is unknown. In particular, there is an apparent conflict between population experiments, which show defined average replication
times, and single-molecule experiments, which show that origins fire stochastically. Here, we provide a simple simulation
that demonstrates that stochastic origin firing can produce defined average patterns of replication firing if two criteria
are met. The first is that origins must have different relative firing probabilities, with origins that have relatively high
firing probability being likely to fire in early S phase and origins with relatively low firing probability being unlikely
to fire in early S phase. The second is that the firing probability of all origins must increase during S phase to ensure
that origins with relatively low firing probability, which are unlikely to fire in early S phase, become likely to fire in
late S phase. In addition, we propose biochemically plausible mechanisms for these criteria and point out how stochastic and
defined origin firing can be experimentally distinguished in population experiments.
Keywords replication timing - stochastic origin firing - origin regulation - origin efficiency
Responsible editors: Marie-Noëlle Prioleau and Dean Jackson.