Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome

摘要: Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis DNA kinetics in several human cell types contradicts this view. combing HeLa cells sorted into four temporal compartments S phase shows origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant narrowly distributed through phase. However, multi-scale profile broad distribution gradients with practically no regions larger than 100 replicating less 2 kb/min. Therefore, lack unidirectional progression. Temporal replicated sequential activation rate set the delay spacing between successive firings rather single forks. Activation internal specific region is directly demonstrated IGH locus cells. Analysis published maps data other corroborate these findings, interesting exception embryonic stem where progression seem more abundant. These results can be explained if independently each but under control long-range chromatin structure, or forks progressing from early stimulate initiation nearby unreplicated DNA. findings shed new light on program genomes provide general model for their kinetics.