In 1995, Lobry and Sueoka demonstrated that, in the absence of selective or mutational differences between the two complementary strands of DNA, the composition of a single DNA strand at equilibrium should be such that G
, with A
representing the frequencies of adenine, cytosine, guanine and thymine, respectively 
. Several functions and processes, in particular protein coding and replication, induce asymmetries between complementary DNA strands. The resulting departure from the intrastrand parity rules G
can be quantified by computing the GC and TA skews as the ratios (G
) and (T
Replication induces differences between a leading and a lagging strand, which are synthesized continuously and discontinuously, respectively. The leading and the lagging strands were shown to have different substitution rates in several systems (e.g.
), which could be due to differences in the mutational spectrum of the leading- and the lagging-strand polymerases, to differential mismatch repair of leading-strand versus lagging-strand replication errors or to the difference in the frequency with which the leading and the lagging strands are in single-strand DNA conformation (for reviews, see 
The different substitution rates could be expected to lead to different values of GC and TA skews for the leading and the lagging strands, which would mark replication origins and termination sites as positions where these values abruptly change. Lobry found in 1996 that that was indeed the case: he showed that the values of GC and TA skews calculated along large fragments of several eubacterial genomes exhibit a sharp jump at the position of the replication origin, thus demonstrating the possibility of origin prediction through analysis of compositional biases 
. These observations were soon generalized 
and the analysis of GC and TA skews is now a standard method to predict replication origins in eubacteria 
Theoretically, the termination sites of eubacterial chromosomes should also appear as skew jumps, with an inverted orientation compared to origins. One sharp skew jump is often detected in the termination region of eubacterial genomes, suggesting that the fork convergence points are precisely located at this site, and not at the multiple unidirectional replication pause (Ter
) sites that may span a large portion of the genome (about half the Escherichia coli
chromosome for example) 
. The experimental detection in E. coli
of replication fork arrests and of converging forks at some Ter
sites (but not at the site of the skew jump) contradicts the hypothesis that the site of the skew jump would be currently used as a termination site 
, but could be explained by the recent appearance of a Ter
site-based termination mechanism which would have superseded a previous mechanism using the position of the skew jump as termination site. Alternatively, the skew jump in the termination region could be due to compositional biases unrelated to replication and possibly linked to chromosome recombination or segregation. The possibility to predict termination sites in eubacterial genomes through analysis of compositional skews thus remains unclear.
In contrast to eubacteria with their one unique origin per chromosome, replication is more complex in eukaryotes where stochasticity plays a large part 
. Multiple potential replication origins exist in eukaryotic genomes and, during a given S phase, only a minority of them fire while most are passively replicated (e.g.
). Since replication origins do not fire systematically in all S phases, a given sequence can be synthesized as a leading strand during some replication cycles and as a lagging strand in other cycles, thus reducing replication-related GC and TA skews.
Nevertheless, the existence of replication-associated GC and TA skews was recently proposed for the human genome 
and for the genomes of two yeast species, Saccharomyces cerevisiae
and Kluyveromyces lactis
. In the human genome, a sharp upward jump of the total skew S
, defined as (G
), was first detected at some experimentally-determined replication origins 
. This led to an origin-prediction method, which provided a set of ~1,500 upward skew jumps or putative origins. The skew S
calculated for intergenic regions (in order to eliminate transcription-associated skews) was found to decrease linearly along the interorigin intervals and no downward jumps that would have reflected the presence of precisely positioned termination sites were observed between two adjacent predicted origins 
. About 56% of these putative origins were subsequently found to be located at a distance less than 100 kb from a replication initiation zone in at least one of six different cell types, which indicates that upward jump positions correspond probably to replication origins active in germline cells 
. However, these putative origins represent only a fraction of the 30,000 to 100,000 origins expected in human germline cells, probably the earliest and the most efficient ones.
We and others have recently demonstrated in S. cerevisiae
and in K. lactis
the existence of replication-associated GC and TA skews and the enrichment of the leading strand in adenines and cytosines 
. In this work, I have first sought to further characterize skew variations around replication origins and termination sites in S. cerevisiae
, where they are the most documented. Asymmetry indices linked to GC and TA skews were subsequently defined and a global asymmetry index IGC,TA
was described. IGC,TA
was found to strongly correlate with origin efficiency and to allow the definition of sets of intergenes significantly enriched in origin loci in S. cerevisiae
. The generalized use of asymmetry indices for origin prediction in naive genomes implies the determination of the direction of the skews. In Candida albicans
and in related species, the centromeric regions contain early and efficient replication origins. It has been proposed that the skew jumps observed at these positions would reflect the activity of these origins, thus allowing to determine the direction of the skews in these genomes 
. However, I show here that the skew jumps at C. albicans
centromeres are not related to replication and that replication-associated GC and TA skews in C. albicans
have in fact the opposite directions of what was previously suggested.