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Asymmetry indices for analysis and prediction of replication origins in eukaryotic genomes.

ABSTRACT: DNA replication was recently shown to induce the formation of compositional skews in the genomes of the yeasts Saccharomyces cerevisiae and Kluyveromyces lactis. In this work, I have characterized further GC and TA skew variations in the vicinity of S. cerevisiae replication origins and termination sites, and defined asymmetry indices for origin analysis and prediction. The presence of skew jumps at some termination sites in the S. cerevisiae genome was established. The majority of S. cerevisiae replication origins are marked by an oriented consensus sequence called ACS, but no evidence could be found for asymmetric origin firing that would be linked to ACS orientation. Asymmetry indices related to GC and TA skews were defined, and a global asymmetry index I(GC,TA) was described. I(GC,TA) was found to strongly correlate with origin efficiency in S. cerevisiae and to allow the determination of sets of intergenes significantly enriched in origin loci. The generalized use of asymmetry indices for origin prediction in naive genomes implies the determination of the direction of the skews, i.e. the identification of which strand, leading or lagging, is enriched in G and which one is enriched in T. Recent work indicates that in Candida albicans and in several related species, centromeres 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 proposed.

SUBMITTER: Marsolier-Kergoat MC

PROVIDER: S-EPMC3459929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:DNA replication initiates from multiple replication origins (ORIs) in eukaryotes. Discovery and characterization of replication origins are essential for a better understanding of the molecular mechanism of DNA replication. In this study, the features of autonomously replicating sequences (ARSs) in Saccharomyces cerevisiae have been comprehensively analyzed as follows. Firstly, we carried out the analysis of the ARSs available in S. cerevisiae S288C. By evaluating the sequence similarity of experimentally established ARSs, we found that 94.32% of ARSs are unique across the whole genome of S. cerevisiae S288C and those with high sequence similarity are prone to locate in subtelomeres. Subsequently, we built a non-redundant dataset with a total of 520 ARSs, which are based on ARSs annotation of S. cerevisiae S288C from SGD and then supplemented with those from OriDB and DeOri databases. We conducted a large-scale comparison of ORIs among the diverse budding yeast strains from a population genomics perspective. We found that 82.7% of ARSs are not only conserved in genomic sequence but also relatively conserved in chromosomal position. The non-conserved ARSs tend to distribute in the subtelomeric regions. We also conducted a pan-genome analysis of ARSs among the S. cerevisiae strains, and a total of 183 core ARSs existing in all yeast strains were determined. We extracted the genes adjacent to replication origins among the 104 yeast strains to examine whether there are differences in their gene functions. The result showed that the genes involved in the initiation of DNA replication, such as orc3, mcm2, mcm4, mcm6, and cdc45, are conservatively located adjacent to the replication origins. Furthermore, we found the genes adjacent to conserved ARSs are significantly enriched in DNA binding, enzyme activity, transportation, and energy, whereas for the genes adjacent to non-conserved ARSs are significantly enriched in response to environmental stress, metabolites biosynthetic process and biosynthesis of antibiotics. In general, we characterized the replication origins from the genome-wide and population genomics perspectives, which would provide new insights into the replication mechanism of S. cerevisiae and facilitate the design of algorithms to identify genome-wide replication origins in yeast.

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Asymmetry indices for analysis and prediction of replication origins in eukaryotic genomes.

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