Biomedical subjects

B Audit

Publications and source records attributed to B Audit.

7 recordsLinked to original sources

PubMed2006

Formation and positioning of nucleosomes: effect of sequence-dependent long-range correlated structural disorder.

The understanding of the long-range correlations (LRC) observed in DNA sequences is still an open and very challenging problem. In this paper, we start reviewing recent results obtained when exploring the scaling properties of eucaryotic, eubacterial and archaeal genomic sequences using the space-scale decomposition provided by the wavelet transform (WT). These results suggest that the existence of LRC up to distances approximately 20-30 kbp is the signature of the nucleosomal structure and dynamics of the chromatin fiber. Actually the LRC are mainly observed in the DNA bending profiles obtained when using some structural coding of the DNA sequences that accounts for the fluctuations of the local double-helix curvature within the nucleosome complex. Because of the approximate planarity of nucleosomal DNA loops, we then study the influence of the LRC structural disorder on the thermodynamical properties of 2D elastic chains submitted locally to mechanical/topological constraint as loops. The equilibrium properties of the one-loop system are derived numerically and analytically in the quite realistic weak-disorder limit. The LRC are shown to favor the spontaneous formation of small loops, the larger the LRC, the smaller the size of the loop. We further investigate the dynamical behavior of such a loop using the mean first passage time (MFPT) formalism. We show that the typical short-time loop dynamics is superdiffusive in the presence of LRC. For displacements larger than the loop size, we use large-deviation theory to derive a LRC-dependent anomalous-diffusion rule that accounts for the lack of disorder self-averaging. Potential biological implications on DNA loops involved in nucleosome positioning and dynamics in eucaryotic chromatin are discussed.

Base Sequence↗

PubMed2005

Thermodynamics of DNA loops with long-range correlated structural disorder.

We study the influence of a structural disorder on the thermodynamical properties of 2D-elastic chains submitted to mechanical/topological constraint as loops. The disorder is introduced via a spontaneous curvature whose distribution along the chain presents either no correlation or long-range correlations (LRC). The equilibrium properties of the one-loop system are derived numerically and analytically for weak disorder. LRC are shown to favor the formation of small loop, larger the LRC, smaller the loop size. We use the mean first passage time formalism to show that the typical short time loop dynamics is superdiffusive in the presence of LRC. Potential biological implications on nucleosome positioning and dynamics in eukaryotic chromatin are discussed.

Chromatin↗

PubMed2005

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.

DNA Replication↗

PubMed2003

Influence of the sequence on elastic properties of long DNA chains.

We revisit the results of single-molecule DNA stretching experiments using a rodlike chain (RLC) model that explicitly includes some intrinsic structural disorder induced by the sequence. The investigation of artificial and real genomic sequences shows that the wormlike chain model reproduces quite well the data but with an effective bend stiffness A(eff), which underestimates the true elastic bend stiffness A, independently of the elastic twist stiffness C. Mainly dominated by the amplitude of the structural disorder, this correction seems rather insensitive to the presence of long-range correlations. This RLC model is shown to remarkably fit the experimental data for lambda-DNA when considering A approximately 70+/-10 nm (>A(eff) approximately 50 nm), in good agreement with previous experimental estimates of the "dynamic" persistent length. From the analysis of large human contigs, we speculate about the possible dependence of A(eff) and/or A upon the (G+C) content of the considered sequence.

Biophysical Phenomena↗

PubMed2001

Strain-specific genes of Helicobacter pylori: distribution, function and dynamics.

Whole-genome clustering of the two available genome sequences of Helicobacter pylori strains 26695 and J99 allows the detection of 110 and 52 strain-specific genes, respectively. This set of strain-specific genes was compared with the sets obtained with other computational approaches of direct genome comparison as well as experimental data from microarray analysis. A considerable number of novel function assignments is possible using database-driven sequence annotation, although the function of the majority of the identified genes remains unknown. Using whole-genome clustering, it is also possible to detect species-specific genes by comparing the two H.pylori strains against the genome sequence of Campylobacter jejuni. It is interesting that the majority of strain-specific genes appear to be species specific. Finally, we introduce a novel approach to gene position analysis by employing measures from directional statistics. We show that although the two strains exhibit differences with respect to strain-specific gene distributions, this is due to the extensive genome rearrangements. If these are taken into account, a common pattern for the genome dynamics of the two Helicobacter strains emerges, suggestive of certain spatial constraints that may act as control mechanisms of gene flux.

Amino Acid Sequence↗

PubMed2001

Long-range correlations in genomic DNA: a signature of the nucleosomal structure.

We use the "wavelet transform microscope" to carry out a comparative statistical analysis of DNA bending profiles and of the corresponding DNA texts. In the three kingdoms, one reveals on both signals a characteristic scale of 100-200 bp that separates two different regimes of power-law correlations (PLC). In the small-scale regime, PLC are observed in eukaryotic, in double-strand DNA viral, and in archaeal genomes, which contrasts with their total absence in the genomes of eubacteria and their viruses. This strongly suggests that small-scale PLC are related to the mechanisms underlying the wrapping of DNA in the nucleosomal structure. We further speculate that the large scale PLC are the signature of the higher-order structure and dynamics of chromatin.

Biophysical Phenomena↗

PubMed2000

Genome sequences and great expectations.

To assess how automatic function assignment will contribute to genome annotation in the next five years, we have performed an analysis of 31 available genome sequences. An emerging pattern is that function can be predicted for almost two-thirds of the 73,500 genes that were analyzed. Despite progress in computational biology, there will always be a great need for large-scale experimental determination of protein function.

Animals↗