Genome-wide mapping of human DNA-replication origins: levels of transcription at Orc1 sites regulate origin selection and replication timing

We report the genome-wide mapping of Orc1 binding-sites in mammals and their validation as active DNA-replication origins (ORIs). Orc1 sites are universally associated with transcription start sites (TSSs) of coding or non-coding RNAs. Transcription levels at the Orc1 sites directly correlate with replication timing, suggesting the existence of two classes of ORIs: those associated with moderate/high transcription levels (=1 RNA copy/cell), replicating in early S and mapping to the TSSs of coding RNAs, and those associated with low transcription levels (<1 RNA copy/cell), replicating throughout the entire S and mapping to TSSs of non-coding RNAs. These findings are compatible with a scenario whereby TSS expression-levels influence the efficiency of Orc1 recruitment at G1 and the probability of firing during S. Overall design: Identification of Orc1 binding sites in human cells