Wavelet-based method to disentangle transcription-and replication-associated strand asymmetries in mammalian genomes

in Applied & Computational Harmonic Analysis (2010), 28

During genome evolution, the two strands of the DNA double helix are not subjected to the same mutation patterns. This mutation bias is considered as a by-product of replicative and transcriptional ... [more ▼]

During genome evolution, the two strands of the DNA double helix are not subjected to the same mutation patterns. This mutation bias is considered as a by-product of replicative and transcriptional activities. In this paper, we develop a wavelet-based methodology to analyze the DNA strand asymmetry profiles with the specific goal to extract the contributions associated with replication and transcription respectively. In a first step, we use an adapted N-shaped analyzing wavelet to perform a multi-scale pattern recognition analysis of the sum of the TA and GC skews along human chromosomes. This method provides an 1 Mbp characteristic objective segmentation of the human genome in skew domains of size, bordered by two putative replication origins recognized as large amplitude upward jumps in the noisy skew profile. In a second step, we use a least-square fitting procedure to disentangle, in these skew domains, the small-scale (the mean human gene size 30 kbp) square-like transcription component from the global N-shaped component induced by replication. When applying this procedure to the 22 human autosomes, we delineate 678 replication domains of mean length L = 1.2 ± 0.6 Mbp spanning 33.8% of the human genome and we predict 1062 replication origins. When investigating the distribution of transcription-associated skew inside the replication N-domains, we reveal some dependence upon the distance to the putative replication origins located at N- domain extremities, the closer the genes to the origin, the larger their transcription bias as the signature of a higher transcriptional activity in the germ-line. As a comparative analysis, we further apply our wavelet-based methodology to skew profiles along the mouse chromosomes. The striking similarity of the results in human and mouse indicates that the remarkable gene organization observed inside the human replication N-domains is likely to be a general feature of mammalian genomes. [less ▲]

Bifractality of human DNA strand-asymmetry profiles results from transcription

in Physical Review E (2007), 75(3), 032902

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 ... [more ▼]

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 than or similar to 40 kbp) components characterized by Holder 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 colocate 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 Delta S >= 0.1 which suggests that about 36% of annotated human genes present significant transcription-induced strand asymmetry and very likely high expression rate. [less ▲]

DNA in chromatin: from genome-wide sequence analysis to the modelling of replication in mammals

in Advances in Chemical Physics (2006), 135

Understanding how chromatin is spatially and dynamically organized in the nucleus of eukaryotic cells and how this affects genome functions is one of the main challenges of cell biology. In that context ... [more ▼]

Understanding how chromatin is spatially and dynamically organized in the nucleus of eukaryotic cells and how this affects genome functions is one of the main challenges of cell biology. In that context the role of the DNA sequence itself in these condensation- decondensation processes is still debated. In this chapter, we explore large-scale nucleotide compositional fluctuations along the human genome through the optics of the wavelet transform microscope. Analysis of the GC content and of the TA and GC skews re- veals the existence of rhythms with characteristic fundamental frequencies that enlighten a remarkable cooperative organization of gene location and orientation. We describe a multi-scale methodology that allows us to predict 1012 replication origins in the 22 hu- man autosomal chromosomes. We present a model of replication with well-positioned replication origins and random termination sites that accounts for the highly relaxational nature of the oscillations observed in the 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 more easily accessible. We show that, in the crowded environment of the cell nucleus, the presence of these intrinsic decondensed structural defects actually pre- disposes the fiber to spontaneously form multi-looped rosette-like structures that provide an attractive description of genome organization into replication foci that are observed in interphase mammalian nuclei as stable autonomous chromatin domains favoring com- partmentalized DNA replication and gene expression. New experimental perspectives are discussed. [less ▲]

From DNA sequence analysis to modeling replication in the human genome

in Physical Review Letters (2005), 94

We explore the large-scale behavior of nucleotide compositional strand asymmetries along hum chromosomes. As we observe for 7 of 9 origins of replication experimentally identified so far, the (TA GC) skew ... [more ▼]

We explore the large-scale behavior of nucleotide compositional strand asymmetries along hum 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 successi jumps. We present a model of replication with well positioned replication origins and random terminatio that accounts for the observed characteristic serrated skew profiles. We succeed in identifying 287 pairs putative adjacent replication origins with an origin spacing 1­2 Mbp that are likely to correspond replication foci observed in interphase nuclei and recognized as stable structures that persist througho subsequent cell generations. [less ▲]