title: Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes.
abstract: Neutral nucleotide substitutions occur at varying rates along genomes, and it remains a major issue to unravel the mechanisms that cause these variations and to analyze their evolutionary consequences. Here, we study the role of replication in the neutral substitution pattern. We obtained a high-resolution replication timing profile of the whole human genome by massively parallel sequencing of nascent BrdU-labeled replicating DNA. These data were compared to the neutral substitution rates along the human genome, obtained by aligning human and chimpanzee genomes using macaque and orangutan as outgroups. All substitution rates increase monotonously with replication timing even after controlling for local or regional nucleotide composition, crossover rate, distance to telomeres, and chromatin compaction. The increase in non-CpG substitution rates might result from several mechanisms including the increase in mutation-prone activities or the decrease in efficiency of DNA repair during the S phase. In contrast, the rate of C --> T transitions in CpG dinucleotides increases in later-replicating regions due to increasing DNA methylation level that reflects a negative correlation between timing and gene expression. Similar results are observed in the mouse, which indicates that replication timing is a main factor affecting nucleotide substitution dynamics at non-CpG sites and constitutes a major neutral process driving mammalian genome evolution.
authors.affiliation: Centre de Génétique Moléculaire, Allée de la Terrasse, 91198 Gif-sur-Yvette, France.
authors.forename: Chun-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Aurélien
authors.initials: A
authors.lastname: Rappailles
authors.forename: Lauranne
authors.initials: L
authors.lastname: Duquenne
authors.forename: Maxime
authors.initials: M
authors.lastname: Huvet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Guilbaud
authors.forename: Laurent
authors.initials: L
authors.lastname: Farinelli
authors.forename: Benjamin
authors.initials: B
authors.lastname: Audit
authors.forename: Yves
authors.initials: Y
authors.lastname: d'Aubenton-Carafa
authors.forename: Alain
authors.initials: A
authors.lastname: Arneodo
authors.forename: Olivier
authors.initials: O
authors.lastname: Hyrien
authors.forename: Claude
authors.initials: C
authors.lastname: Thermes
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D042522:DNA Replication Timing / Q000502:physiology*; D004330:Drosophila; D019143:Evolution, Molecular; D016678:Genome / Q000235:genetics; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D008251:Macaca / Q000235:genetics; D008322:Mammals / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense / Q000502:physiology; D002679:Pan troglodytes / Q000235:genetics; D011148:Pongo pygmaeus / Q000235:genetics; D051381:Rats