Two key cellular processes, namely transcription and replication, require the opening of the DNA double helix and act differently on the two DNA strands, generating different mutational patterns (mutational asymmetry) that may result, after long evolutionary time, in different nucleotide compositions on the two DNA strands (compositional asymmetry). Here, we propose to model the spatio-temporal program of DNA replication and its impact on the DNA sequence evolution. The mutational and compositional asymmetries observed in the human genome are shown to decompose into transcription- and replication-associated components. The replication-associated asymmetry is related to the replication fork polarity, which is also shown to be proportional to the derivative of the mean replication timing. The large-scale variation of the replication fork polarity delineate Mbp scale replication domains where the replication timing is shaped as a U. Such replication domains are also observed in the germline, where they are revealed by a N-shaped compositional asymmetry, which indicates the conservation of this replication program over several hundred million years. The replication domains borders are enriched in open chromatin markers, and correspond to regions permissive to transcription and replication initiation. The analysis of chromatin interaction data suggests that these replication domains correspond to self-interacting chromatin structural units, at the heart of a highly parallelized organization of the replication program in the human genome.
