title: Large replication skew domains delimit GC-poor gene deserts in human.
abstract: Besides their large-scale organization in isochores, mammalian genomes display megabase-sized regions, spanning both genes and intergenes, where the strand nucleotide composition asymmetry decreases linearly, possibly due to replication activity. These so-called skew-N domains cover about a third of the human genome and are bordered by two skew upward jumps that were hypothesized to compose a subset of "master" replication origins active in the germline. Skew-N domains were shown to exhibit a particular gene organization. Genes with CpG-rich promoters likely expressed in the germline are over represented near the master replication origins, with large genes being co-oriented with replication fork progression, which suggests some coordination of replication and transcription. In this study, we describe another skew structure that covers ∼13% of the human genome and that is bordered by putative master replication origins similar to the ones flanking skew-N domains. These skew-split-N domains have a shape reminiscent of a N, but split in half, leaving in the center a region of null skew whose length increases with domain size. These central regions (median size ∼860 kb) have a homogeneous composition, i.e. both a null and constant skew and a constant and low GC content. They correspond to heterochromatin gene deserts found in low-GC isochores with an average gene density of 0.81 promoters/Mb as compared to 7.73 promoters/Mb genome wide. The analysis of epigenetic marks and replication timing data confirms that, in these late replicating heterochomatic regions, the initiation of replication is likely to be random. This contrasts with the transcriptionally active euchromatin state found around the bordering well positioned master replication origins. Altogether skew-N domains and skew-split-N domains cover about 50% of the human genome.
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Lamia
authors.initials: L
authors.lastname: Zaghloul
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Guénola
authors.initials: G
authors.lastname: Drillon
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Rasha E
authors.initials: RE
authors.lastname: Boulos
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Argoul
authors.affiliation: Centre de Génétique Moléculaire, CNRS UPR 3404, Gif-sur-Yvette, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Thermes
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Arneodo
authors.affiliation: Université de Lyon, F-69000 Lyon, France; Laboratoire de Physique, CNRS UMR 5672, Ecole Normale Supérieure de Lyon, F-69007 Lyon, France. Electronic address: benjamin.audit@ens-lyon.fr.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Audit
mesh_terms: D001482:Base Composition; D002843:Chromatin / Q000737:chemistry*; D002874:Chromosome Mapping; D018899:CpG Islands; D004261:DNA Replication; D044127:Epigenesis, Genetic; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin
keywords: Gene organization; Human genome; Master replication origins; Nucleotide composition strand asymmetry; Skew-N domains; Skew-split-N domains