Large-scale analysis of the human genome: From DNA sequence analysis to the modeling of replication in higher eukaryotes

We explore large-scale nucleotide compositional fluctuations along the human genome through the optics of the wavelet transform microscope. Analysis of the TA and GC skews reveals the existence of strand asymmetries associated to transcription and/or replication. The investigation of 14854 intron-containing genes shows that both skews display a characteristic step-like profile exhibiting sharp transitions between transcribed (finite bias) and non-transcribed (zero bias) regions. As we observe for 7 out of 9 origins of replication experimentally identified so far, the (AT+GC) skew exhibits rather sharp upward jumps, with a linear decreasing profile in between two successive jumps. We describe a multi-scale methodology that allows us to predict 1012 replication origins in the 22 human autosomal chromosomes. We present a model of replication with well-positioned replication origins and random termination sites that accounts for the observed characteristic serrated skew profiles. We emphasize these putative replication initiation zones as regions where the chromatin fiber is likely to be more open so that DNA be easily accessible. In the crowded environment of the cell nucleus, these intrinsic decondensed structural defects actually predisposes the fiber to spontaneously form rosette-like structures that provide an attractive description of genome organization into replication foci that are observed in interphase mammalian nuclei.