Bifractality of human DNA strand-asymmetry profiles results from transcription.

We use the wavelet transform modulus maxima method to investigate the multifractal properties of strand-asymmetry DNA walk profiles in the human genome. This study reveals the bifractal nature of these profiles, which involve two competing scale-invariant (up to repeat-masked distances less, or similar 40 kbp) components characterized by Hölder exponents h{1}=0.78 and h{2}=1, respectively. The former corresponds to the long-range-correlated homogeneous fluctuations previously observed in DNA walks generated with structural codings. The latter is associated with the presence of jumps in the original strand-asymmetry noisy signal S. We show that a majority of upward (downward) jumps co-locate with gene transcription start (end) sites. Here 7228 human gene transcription start sites from the refGene database are found within 2 kbp from an upward jump of amplitude DeltaS > or = 0.1 which suggests that about 36% of annotated human genes present significant transcription-induced strand asymmetry and very likely high expression rate.

DNA replication timing data corroborate in silico human replication origin predictions.

We develop a wavelet-based multiscale pattern recognition methodology to disentangle the replication- from the transcription-associated compositional strand asymmetries observed in the human genome. Comparing replication skew profiles to recent high-resolution replication timing data reveals that most of the putative replication origins that border the so-identified replication domains are replicated earlier than their surroundings whereas the central regions replicate late in the S phase. We discuss the implications of this first experimental confirmation of these replication origin predictions that are likely to be early replicating and active in most tissues.

From DNA sequence analysis to modeling replication in the human genome.

We explore the large-scale behavior of nucleotide compositional strand asymmetries along human chromosomes. As we observe for 7 of 9 origins of replication experimentally identified so far, the (TA+GC) skew displays rather sharp upward jumps, with a linear decreasing profile in between two successive jumps. We present a model of replication with well positioned replication origins and random terminations that accounts for the observed characteristic serrated skew profiles. We succeed in identifying 287 pairs of putative adjacent replication origins with an origin spacing approximately 1-2 Mbp that are likely to correspond to replication foci observed in interphase nuclei and recognized as stable structures that persist throughout subsequent cell generations.

Low frequency rhythms in human DNA sequences: a key to the organization of gene location and orientation?

We explore large-scale nucleotide compositional fluctuations of the human genome using multiresolution techniques. Analysis of the GC content and of the AT and GC skews reveals the existence of rhythms with two main periods of 110+/-20 kb and 400+/-50 kb that enlighten a remarkable cooperative gene organization. We show that the observed nonlinear oscillations are likely to display all the characteristic features of chaotic strange attractors which suggests a very attractive deterministic picture: gene orientation and location, in relation with the structure and dynamics of chromatin, might be governed by a low-dimensional nonlinear dynamical system.

Transcription-coupled TA and GC strand asymmetries in the human genome.

Analysis of the whole set of human genes reveals that most of them present TA and GC skews, that these biases are correlated to each other and are specific to gene sequences, exhibiting sharp transitions between transcribed and non-transcribed regions. The GC asymmetries cannot be explained solely by a model previously proposed for (G+T) skew based on transitions measured in a small set of human genes. We propose that the GC skew results from additional transcription-coupled mutation process that would include transversions. During evolution, both processes acting on a large majority of genes in germline cells would have produced these transcription-coupled strand asymmetries.