Replication origins are organized in a functional hierarchical manner along the chromosome. (A) DNA combing analysis performed in Drosophila Kc (top panel) and mouse (bottom panel) cells after two consecutive labeling pulses of IdU and CldU. (B) Summary of the experimental and simulated inter-origin distance distributions for MEF cells. For the “Increasing Ori efficiency” model, the values for the firing efficiency represent the initial and final origin firing efficiency during simulations. (C) “Random Ori firing” model. In this model, origins are completely independent and are activated randomly (red circles). Very short and long inter-origin distances are observed. (D) In the “Increasing Ori efficiency” model, origins are completely independent and activated randomly, but with increasing firing efficiency throughout S phase progression. (E) “Flexible Replicon” model. In this model, origins are linked within functional units where activation of one origin silences the others in the same group. The bottom panels present the computer-simulated results for each model. The gray profile is the distribution of inter-origin distances obtained by DNA combing of MEF cells. The red line represents the simulated distribution of inter-origin distances according to each model. The “Flexible Replicon” model is the only model to yield a simulated distribution of inter-origin distances that is statistically indistinguishable from the DNA combing data.
