"Matière et Systèmes Complexes"
Lundi 2 mars 2009 à 11h30
Bâtiment Condorcet, 4ème étage, salle 454 A.
(Laboratoire Joliot-Curie, ENS-Lyon)
Master replication origins at the heart of the organization and fragility of the human genome
During the course of evolution, mutations do not affect equally both strands of genomic DNA. This mainly results from asymmetric DNA mutation and repair processes associated with replication and transcription. In prokaryotes, prevalence of G over C and T over A is frequently observed in the leading replicating strand. The sign of the resulting TA and GC skews changes abruptly when crossing replication origin and termination sites, producing characteristic step-like transitions. In mammals, transcription-coupled skews have been detected but no bias had been associated with replication. In a first part, we present the analysis of intergenic and transcribed regions flanking experimentally identified human replication origins, demonstrating the existence of compositional strand asymmetries associated with replication. Wavelet-based multi-scale analysis of human genome skew profiles reveals numerous transitions allowing us to identify a set of one thousand putative replication initiation zones. Around these putative origins, the skew profiles display a remarkable pattern also observed in other mammalian genomes. Based on these results we propose a model of the mammalian replicon where termination sites are randomly distributed between adjacent origins. We report on DNA replication timing data that provide experimental verification of our in silico replication origin predictions. In a second part, we examine the organisation of the human genes around the replication origins. We show that replication origins, gene orientation and gene expression are not randomly distributed but on the opposite are at the heart of a strong organisation of human chromosomes. The analysis of open chromatin markers brings evidence of the existence of accessible open chromatin around the majority of the putative replication origins that replicate early in the S phase. We conclude by discussing the possibility that these “master’ replication origins also play a key role in genome dynamics during evolution and in pathological situations like cancer.