Physics Colloquium - Fall 2007 - Low frequency rhythms in human DNA sequences: from genome-wide sequence analysis to the modeling of replication in higher eukaryotes
Dept of Physics & Astronomy
University of Maine, Orono, Maine
Presents
Dr. Alain Arneodo
Laboratoire Joliot Curie and Laboratoire de Physique
Ecole Normale Supérieure de Lyon
Low frequency rhythms in human DNA sequences: from genome-wide sequence analysis to the modeling of replication in higher eukaryotes
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. Recent technical progress in live cell imaging have confirmed that the structure and dynamics of chromatin play an essential role in regulating many biological processes, such as gene activity, DNA replication, recombination and DNA damage repair. The emerging view is that genomes are compartimentalized at the level of chromosome territories in mammalian nuclei, into subchromosal structural domains that are likely to be fundamental functional units that coordinate the spatial organization and timing of replication and transcription. To which extent one may learn about the higher order structure and dynamics of chromatin directly from the primary DNA sequence and its functional landmarks, is a question of fundamental and practical importance.
In this talk, we explore the large-scale compositional heterogeneity of human autosomal chromosomes through the optics of the wavelet transform (WT) microscope. We show that the GC content displays relaxational nonlinear oscillations with two main frequencies corresponding to 100 kb and 400 kb which are well recognized characteristic sizes of chromatin loops and loop domains involved in the hierarchical folding of the chromatin fiber. These frequencies are also remarkably similar to the size of mammalian replicons . When further investigating deviations from intrastrand equimolarities between A and T and between G and C, we corroborate the existence of these two fundamental frequencies as the footprints of the replication and/or transcription mutation biais and we show that the observed nonlinear oscillations enlighten a remarkable cooperative organization of gene location and orientation. When further investigating the intergenic and transcribed regions flanking experimentally identified human replication origins and the corresponding mouse and dog homologous regions, we reveal that for 7 of 9 of these known origins, 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 further use the singularity tracking ability of the WT to develop a methodology to detect the origins of replication. We report the discovery of 1024 putative origins of replications in the human genome. The statistical analysis of the distribution of sense and anti-sense genes around these origins strongly suggests that the origins of replication play a fundamental role in the organization of mammmalian genomes. Taken together, these analyses show that replication and gene expression are likely to be regulated by the structure and dynamics of the chromatin fiber.
Friday, October 19, 2007
3:10 pm
140 Bennett Hall
Refreshments will follow in Rm. 114, Bennett Hall
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