Chun-Long Chen1, Aurélien Rappailles2, Lauranne Duquenne1,6, Maxime Huvet1,7, Guillaume Guilbaud2, Laurent Farinelli3, Benjamin Audit4,5, Yves d'Aubenton-Carafa1, Alain Arneodo4,5, Olivier Hyrien2 and
Claude Thermes1,8
-Author Affiliations
1Centre de Génétique Moléculaire (CNRS), Allée de la Terrasse, 91198 Gif-sur-Yvette, France;
2Institut de Biologie de l'Ecole Normale Supérieure (IBENS), CNRS UMR 8197, INSERM U1024, 75005 Paris, France;
3Fasteris SA, CH-1228 Plan-les-Ouates, Switzerland;
4Université de Lyon, F-69000 Lyon, France;
5Laboratoire Joliot Curie et Laboratoire de Physique, Ecole Normale Supérieure de Lyon, CNRS, F-69007 Lyon, France
↵6 Present addresses: UMR CNRS 5558, LBBE, UCB Lyon1, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France;
↵7 Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
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.
Footnotes
↵8 Corresponding author.
E-mail thermes@cgm.cnrs-gif.fr; fax 33-169823828.
[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra) under accession no. SRA010799.]
Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.098947.109.
Received July 25, 2009.
Accepted January 15, 2010.
Copyright © 2010 by Cold Spring Harbor Laboratory Press
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.
Footnotes
↵8 Corresponding author.
E-mail thermes@cgm.cnrs-gif.fr; fax 33-169823828.
[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra) under accession no. SRA010799.]
Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.098947.109.
Received July 25, 2009.
Accepted January 15, 2010.
Copyright © 2010 by Cold Spring Harbor Laboratory Press
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