Inferring the DNA replication origin density landscape in human cells from replication timing and fork directionality data

Abstract

AbstractThe determinants of the locations and firing times of the multiple replication origins are still elusive in human and other metazoan organisms. Experiments can independently profile mean replication timing (MRT) and replication fork directionality (RFD) genome-wide. In the hypothesis of a constant replication fork speed, MRT and RFD are related to each other by an analytical formula so are a priori equivalent. However, we show here that experimental noises result in MRT and RFD profiles containing information at different spatial frequencies. We further demonstrate that one can compute an origin density landscape that, when inserted in an appropriate simulation framework, jointly predicts experimental MRT and RFD profiles with an unprecedented precision. We also extract an analytical formula linking intrinsic origin efficiency with observed origin efficiency and MRT. We then compare the computed origin density landscape with experimental distributions of potential origins (ORC, MCM) or actual initiation events (Bubble-seq, SNS-seq, OK-seq). The results indicate that MRT and RFD data are highly consistent with each other, that our simple model suffices to capture the replication dynamics during S phase given an appropriate initiation probability landscape, but that the density of potential origins is not the sole determinant of this landscape.