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 asym-
metric DNA mutation and repair processes associated with repli-
cation 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 demon-
strates the existence of compositional strand asymmetries associ-
ated 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 puta-
tive 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.