Replication-associated strand asymmetries in mammalian genomes: Toward detection of replication origins

In the course of evolution, mutations do not affect both strands of genomic DNA equally. This imbalance mainly results from asymmetric DNA mutation and repair processes associated with replication and transcription. In prokaryotes, prevalence of G over C and T over A is frequently observed in the leading strand. The sign of the resulting TA and GC skews changes abruptly when crossing replication-origin and termination sites, producing characteristic step-like transitions. In mammals, transcription-coupled skews have been detected, but so far, no bias has been associated with replication. Here, analysis of intergenic and transcribed regions flanking experimentally identified human replication origins and the corresponding mouse and dog homologous regions demonstrates the existence of compositional strand asymmetries associated with replication. Multiscale analysis of human genome skew profiles reveals numerous transitions that allow us to identify a set of 1,000 putative replication initiation zones. Around these putative origins, the skew profile displays a characteristic jagged pattern also observed in mouse and dog genomes. We therefore propose that in mammalian cells, replication termination sites are randomly distributed between adjacent origins. Taken together, these analyses constitute a step toward genome-wide studies of replication mechanisms.