A chromatin structure‐based model accurately predicts DNA replication timing in human cells

The metazoan genome is replicated in precise cell lineage-specific temporal order. However, the mechanism controlling this orchestrated process is poorly understood as no molecular mechanisms have been identified that actively regulate the firing sequence of genome replication. Here, we develop a mechanistic model of genome replication capable of predicting, with accuracy rivaling experimental repeats, observed empirical replication timing program in humans. In our model, replication is initiated in an uncoordinated (time-stochastic) manner at well-defined sites. The model contains, in addition to the choice of the genomic landmark that localizes initiation, only a single adjustable parameter of direct biological relevance: the number of replication forks. We find that DNase-hypersensitive sites are optimal and independent determinants of DNA replication initiation. We demonstrate that the DNA replication timing program in human cells is a robust emergent phenomenon that, by its very nature, does not require a regulatory mechanism determining a proper replication initiation firing sequence.