Human gene organization driven by the coordination of replication and transcription

Factory-roof pattern of the skew profile. (A) Skew (S) profile around an experimentally identified replication origin. The skew is computed along a DNA fragment containing the experimentally determined replication origin associated with the MYC gene (Vassilev and Johnson 1990) (red arrow). S is computed in 1-kbp adjacent windows of masked sequences; (red) + genes (coding strand identical to the Watson strand); (blue) − genes (opposite direction); (black) intergenic regions (the color of each point is defined by the majority rule). In abscissa, the position on the sequence; in ordinate, the skew, S, in percent. (Red vertical lines) Putative replication origins associated with upward transitions of the S profile. (B–E) Working model of the factory-roof pattern of the S profile. We propose that this pattern results from the superimposition, in germ-line cells, of strand asymmetries associated with replication and transcription. (B) Model of the replication-associated skew profiles corresponding to two fixed putative adjacent replication origins, Ori1 and Ori2, and to a replication termination site (Ter) occurring with equal probability between Ori1 and Ori2 (adapted from Touchon et al. 2005). Upward or downward jumps of the S profile correspond to the origin and termination positions, respectively. (Left) Three elementary skew profiles, S_i, S_j, and S_k, are associated with three successive replication cycles and display three different Ter positions. (Middle) Superimposition of the S_i, S_j, and S_k profiles. (Right) Superimposition of a large number of elementary skew profiles, ultimately leading to a pattern decreasing linearly in the 5′ to 3′ direction; note that reverse complementation of the sequence leaves the factory roof structure intact. (C) Final replication-associated skew profile. (D) Transcription-associated skew profile showing positive step-like blocks at + gene positions and negative step-like blocks at − gene positions. (E) Superimposition of the replication- and transcription-associated skew profiles producing the final factory-roof pattern that defines the N-domains.