A new method for assessing the effect of replication on DNA base composition asymmetry.

DNA base composition asymmetry is at the basis of numerous in silico methods for the detection of the origin and terminus of replication in prokaryotes. However, most of these methods are unable to identify the evolutionary mechanisms that cause the base composition asymmetry. In prokaryotic chromosomes, due to the tendency for coorientation between replication and transcription, compositional biases that discriminate the leading strand from the lagging strand can be produced by 2 superposing mechanisms: replication-associated mutation bias and coding sequence-associated bias (such as transcription-related mutational processes or selective pressures on codon usage). We propose here a new method for the analysis of nucleotide composition asymmetry that allows the decoupling of replication-related and coding sequence-related mechanisms. This method is inspired by a recent work (Nikolaou and Almirantis 2005) that proposed an artificial chromosomal rearrangement meant to create a perfect gene orientation bias. We show that the study of nucleotide skews on the artificially rearranged chromosomes is a powerful means to assess the contributions of the 2 types of mechanisms in generating the base composition asymmetry. We applied our method to all completely sequenced prokaryotic chromosomes available. Our results confirm that in most species the replication mechanism has an important effect on base composition asymmetry but also that it has different impacts on GC and AT skews. We also analyzed the variability in AT skew direction encountered in prokaryotes. In disagreement with a recent report (Worning et al. 2006), we find that the polymerase-alpha subunits encoded in a genome are not sufficient to predict the sign of the AT skew on its leading strand for replication.