Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes
- Chun-Long Chen1,
- Aurélien Rappailles2,
- Lauranne Duquenne3,
- Maxime Huvet4,
- Guillaume Guilbaud2,
- Laurent Farinelli5,
- Benjamin Audit6,
- Yves d'Aubenton-Carafa1,
- Alain Arneodo6,
- Olivier Hyrien2 and
- Claude Thermes1,7
- 1 Centre de Génétique Moléculaire, CNRS;
- 2 Ecole Normale Supérieure de Paris;
- 3 UMR CNRS 5558;
- 4 Imperial College, London;
- 5 Fasteris SA;
- 6 Ecole Normale Supérieure de Lyon
- * Corresponding author; email: thermes{at}cgm.cnrs-gif.fr
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 on the neutral substitution pattern. We obtained a high-resolution replication timing profile of the whole human genome by massive 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. By 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.
Footnotes
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- Received July 25, 2009.
- Accepted January 15, 2010.
- Copyright © 2010, Cold Spring Harbor Laboratory Press
