The firing dynamics of replication origins affect their genome distribution

Abstract DNA replication in yeast and in many other organisms starts from replication origins with well-defined locations on the genome. The spatial distribution of the origins in the genome is particularly important in ensuring that replication is completed quickly. Cells are more vulnerable to DNA damage and other forms of stress while they are replicating their genome. This raises the possibility that the spatial distribution of origins is under selection pressure. In this work we investigate the hypothesis that natural selection favours origin distributions leading to shorter replication times. Using a simple mathematical model, we show that this hypothesis leads to two main predictions about the origin distributions: that neighbouring origins that are inefficient (less likely to fire) are more likely to be close to each other than efficient origins; and that neighbouring origins with larger differences in firing times are more likely to be close to each other than origins with similar firing times. We test these predictions using next-generation sequencing data, and show that they are both supported by the data. Author summary DNA replication in many organisms start from well-defined locations on the DNA called replication origins . It is important that replication is completed quickly, sice cells are more vulnerable to DNA damage and other forms of stress while they are replicating their genome. This raises the possibility that the spatial distribution of origins is under selection pressure. In this work we investigate the hypothesis that natural selection favours origin distributions leading to shorter replication times. Using a simple mathematical model, we show that this hypothesis leads to two main predictions about the origin distributions: that neighbouring origins that are inefficient (less likely to fire) are more likely to be close to each other than efficient origins; and that neighbouring origins with larger differences in the times they replicate are more likely to be close to each other than origins with similar starting times. We test these predictions using next-generation sequencing data for yeast, and show that they are both supported by the data.