Comput Biol Chem - Large replication skew domains delimit GC-poor gene deserts in human.

Tópicos

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Resumo

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.

Resumo Limpo

besid largescal organ isochor mammalian genom display megabases region span gene intergen strand nucleotid composit asymmetri decreas linear possibl due replic activ socal skewn domain cover third human genom border two skew upward jump hypothes compos subset master replic origin activ germlin skewn domain shown exhibit particular gene organ gene cpgrich promot like express germlin repres near master replic origin larg gene coorient replic fork progress suggest coordin replic transcript studi describ anoth skew structur cover human genom border putat master replic origin similar one flank skewn domain skewsplitn domain shape reminisc n split half leav center region null skew whose length increas domain size central region median size kb homogen composit ie null constant skew constant low gc content correspond heterochromatin gene desert found lowgc isochor averag gene densiti promotersmb compar promotersmb genom wide analysi epigenet mark replic time data confirm late replic heterochomat region initi replic like random contrast transcript activ euchromatin state found around border well posit master replic origin altogeth skewn domain skewsplitn domain cover human genom

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