DNA replication timing reveals genome-wide features of transcription and fragility

DNA replication in humans requires precise regulation to ensure accurate genome duplication and maintain genome integrity. A key indicator of this regulation is replication timing, which reflects the interplay between origin firing and fork dynamics. We present a high-resolution (1-kilobase) mathematical model that maps firing rate distributions to replication timing profiles across various cell lines, validated using Repli-seq data. The model effectively captures genome-wide replication patterns while identifying local discrepancies. Notably, regions where the model and data diverge often overlap with fragile sites and large genes, highlighting the influence of genomic architecture on replication dynamics. Conversely, regions of high concordance are associated with open chromatin and active promoters, where elevated firing rates facilitate timely fork progression and reduce replication stress. By establishing these correlations, our model provides a valuable framework for exploring the structural interplay between replication timing, transcription, and chromatin organisation, offering new insights into the mechanisms underlying replication stress and its implications for genome stability and disease.