  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.
