In this work, we investigated a large-scale organization of the human genes with respect to putative replication origins. We developed an appropriate multiscale method to analyze the nucleotide compositional skew along the genome and found that in more than one-quarter of the genome, the skew profile presents characteristic patterns consisting of successions of N-shaped structures, designated here N-domains, bordered by putative replication origins. Our analysis of recent experimental timing data confirmed that, in a number of cases, domain borders coincide with replication initiation zones active in the early S phase, whereas the central regions replicate in the late S phase. Around the putative origins, genes are abundant and broadly expressed, and their transcription is co-oriented with replication fork progression. These features weaken progressively with the distance from putative replication origins. At the center of domains, genes are rare and expressed in few tissues. We propose that this specific organization could result from the constraints of accommodating the replication and transcription initiation processes at chromatin level, and reducing head-on collisions between the two machineries. Our findings provide a new model of gene organization in the human genome, which integrates transcription, replication, and chromatin structure as coordinated determinants of genome architecture.

In the course of evolution, mutations do not affect both strands of genomic DNA equally. This imbalance mainly results from asymmetric DNA mutation and repair processes associated with replication and transcription. In prokaryotes, prevalence of G over C and T over A is frequently observed in the leading strand. The sign of the resulting TA and GC skews changes abruptly when crossing replication-origin and termination sites, producing characteristic step-like transitions. In mammals, transcription-coupled skews have been detected, but so far, no bias has been associated with replication. Here, analysis of intergenic and transcribed regions flanking experimentally identified human replication origins and the corresponding mouse and dog homologous regions demonstrates the existence of compositional strand asymmetries associated with replication. Multiscale analysis of human genome skew profiles reveals numerous transitions that allow us to identify a set of 1,000 putative replication initiation zones. Around these putative origins, the skew profile displays a characteristic jagged pattern also observed in mouse and dog genomes. We therefore propose that in mammalian cells, replication termination sites are randomly distributed between adjacent origins. Taken together, these analyses constitute a step toward genome-wide studies of replication mechanisms.replication termination ͉ wavelet transform ͉ compositional bias ͉ skewness C omprehensive knowledge of genome evolution relies on understanding mutational processes that shape DNA sequences. Nucleotide substitutions do not occur at similar rates, and, in particular, owing to strand asymmetries of the DNA mutation and repair processes, they can affect each of the two DNA strands differently. Asymmetries of substitution rates coupled to transcription have been observed in prokaryotes (1-3) and in eukaryotes (4-6). Strand asymmetries (i.e., G C and T A) associated with the polarity of replication have been found in bacterial, mitochondrial, and viral genomes, where they have been used to detect replication origins (7-9). In most cases, the leading replicating strand presents an excess of G over C and of T over A. Along one DNA strand, the sign of this bias changes abruptly at the replication origin and at the terminus. In eukaryotes, the situation is unclear. Several studies failed to show compositional biases related to replication, and analyses of nucleotide substitutions in the region of the ␤-globin replication origin did not support the existence of mutational bias between the leading and the lagging strands (8, 10, 11). In contrast, strand asymmetries associated with replication were observed in the subtelomeric regions of Saccharomyces cerevisiae chromosomes, supporting the existence of replication-coupled asymmetric mutational pressure in this organism (12). Here, we present analyses of strand asymmetries flanking experimentally determined human replication origins, as well as the corresponding mouse and dog homologous regions. Our results demonstrate the exis...

It is shown that a small subset of modes which are likely to be involved in protein functional motions of large amplitude can be determined by retaining the most robust normal modes obtained using different protein models. This result should prove helpful in the context of several applications proposed recently, like for solving difficult molecular replacement problems or for fitting atomic structures into lowresolution electron density maps. It may also pave the way for the development of methods allowing us to predict such motions accurately. DOI: 10.1103/PhysRevLett.96.078104 PACS numbers: 87.15.He, 46.40.ÿf, 87.15.ÿv For two-domain proteins, it is well known that a few low-frequency normal modes can provide a fair description of their large amplitude motion upon ligand binding [1][2][3]. Recently, it has been shown that this is also true for proteins with complex architectures [4 -8], as long as their functional motion is a collective one, i.e., if it concerns large parts of the structure [9][10][11]. For instance, a single mode of the T form of hemoglobin is enough to describe accurately its conformational change upon oxygen binding [5].This result has been successfully applied for exploiting fiber diffraction data [12,13], solving difficult molecular replacement problems [14,15], or fitting atomic structures into low-resolution electron density maps [15][16][17]. The principle of these applications is to perturb a known structure along its low-frequency modes so as to get a deformed structure that is consistent with low-resolution biophysical data, which are obtained after the protein has undergone some large amplitude conformational change. It was also shown that when variations of a few key distances are known, through spectroscopic measurements, for instance, it is possible, using linear response theory, to identify which modes are the most involved in the conformational change [18,19]. However, if such experimental data are missing, it is difficult to guess which low-frequency modes are the functional ones. Hereafter, we show that they are among the most robust ones, i.e., among the most conserved modes when different models are considered. The robustness of the functional modes was recognized when it was shown that they can be obtained [9][10][11] with simple protein descriptions, like elastic network (EN) models [20 -23]. Herein, this property is used so as to identify them.First, standard normal modes were calculated for a set of five proteins of different sizes and architectures after preliminary energy minimization. The CHARMM program [24] was used, with the EEF1.1 implicit solvent model [25], as done in recent studies performed at this level of detail [26]. Then, for each energy-minimized structure, low-frequency normal modes were calculated with the all-atom EN model proposed by Tirion [21], where the many-parameters empirical energy function E p used in programs like CHARMM is replaced by:where d ij is the distance between atoms i and j, d0 ij being their distance in the studied structure. ...

In order to assess the impact of the mid-tropospheric circulation over the Greenland ice sheet (GrIS) on surface melt, as simulated by the regional climate model MAR, an automatic Circulation type classification (CTC) based on 500 hPa geopotential height from reanalyses is developed. General circulation correlates significantly with the surface melt anomalies for the summers in the period 1958-2009. The record surface melt events observed during the summers of 2007-2009 are linked to the exceptional persistence of atmospheric circulations favouring warm air advection. The CTC emphasizes that summer 500 hPa circulation patterns have changed since the beginning of the 2000s; this process is partly responsible for the recent warming observed over the GrIS.