Replication timing and its emergence from stochastic processes

Abstract

The temporal organization of DNA replication has puzzled cell biologists since before the mechanism of replication was understood. The realization that replication timing correlates with important features, such as transcription, chromatin structure and genome evolution, and is misregulated in cancer and aging has only deepened the fascination. Many ideas about replication timing have been proposed, but most have been short on mechanistic detail. However, recent work has begun to elucidate basic principles of replication timing. In particular, mathematical modeling of replication kinetics in several systems has shown that the reproducible replication timing patterns seen in population studies can be explained by stochastic origin firing at the single-cell level. This work suggests that replication timing need not be controlled by a hierarchical mechanism that imposes replication timing from a central regulator, but instead results from simple rules that affect individual origins.

Figure 1

Replication fractions and initiation rates. (a,b) The relation between replication fractions f and initiation rates I, as illustrated for budding yeast. (a) Spatially resolved data, averaged over an asynchronous cell population. (b) Time course data, averaged over the genome. (c) Illustration of typical replication timing data for budding yeast (left) and a metazoan organism (right). Top-left image shows the replication fraction f(x,t), as it might be inferred from a microarray timing experiment with several time points of data from synchronized cell populations. Black represents low-replication levels and white represents high-replication levels. Averaging the replication fraction over the genome gives the curve f(t), depicted to the left of the f(x,t) image, which goes from 0 to 1. Averaging the replication fraction over time, as in an experiment on asynchronous cell populations, gives the curve above the f(x,t) image. The bottom-right group shows the inferred I(x,t) image, as well as the averaged curves I(t) and I(x). Note that, in budding yeast, replication origins are well localized, as indicated by the spikes in the function I(x). [When viewed or printed at low resolution, not all spikes in I(x,t) may be visible.] The right-hand groups illustrate similar concepts for a typical metazoan organism. The main difference is that origins are not well localized, so that the function I(x) has broad features, representing zones where initiations are more or less likely to occur.