A Whole-genome Model of DNA Replication in Human Cells
DNA replication is a fundamental cellular process and its precise regulation is crucial for maintaining genomic integrity. Inspired by the mathematical parallelism between DNA replication and the nucleation problem in one-dimensional crystal growth kinetics, we introduce a model that maps whole-genome replication dynamics based on the firing rate profiles of replication origins and fork movement.
Overview
Abstract
DNA replication is a fundamental cellular process and its precise regulation is crucial for maintaining genomic integrity. Inspired by the mathematical parallelism between DNA replication and the nucleation problem in one-dimensional crystal growth kinetics, we introduce a model that maps whole-genome replication dynamics based on the firing rate profiles of replication origins and fork movement. We develop a fitting algorithm that efficiently maps firing rate distributions across various chromosomes and cell lines, revealing distinct patterns of early and late replication. Rigorously validated against high-resolution Repli-seq data, our model not only highlights the diversity in replication timing across various genomic regions but also accurately predicts the locations of common fragile sites, known for their susceptibility to replication stress. By identifying these zones, this comprehensive description of DNA replication further offers potential pathways for exploring therapeutic interventions in diseases driven by genomic instability. In this work, we present a combination of potential chemotherapeutic applications inspired directly by our model, alongside the fascinating mathematical framework upon which it is built.
Brief Biography
Francisco Berkemeier is a Postdoctoral Researcher at the University of Cambridge, and a member of the Boemo Group. The main focus of his research is understanding the implications of fork dynamics on DNA replication timing profiles on the genome of human cancer cells. Previously, he worked with Prof. Karen Page at UCL on the mathematical modelling of the Notch-Delta signalling pathway in different epithelial tissues of the Drosophila melanogaster fly.
He is interested in the mathematical applications of game theory and stochastic calculus in modelling the cell dynamics of living tissues. He is also an Artificial Intelligence enthusiast, specifically its applications in genomics. Some of his interests include DNA replication, pattern formation, stochastic calculus, wound healing and tumour dynamics.