title: The mutation spectrum in genomic late replication domains shapes mammalian GC content.
abstract: Genome sequence compositions and epigenetic organizations are correlated extensively across multiple length scales. Replication dynamics, in particular, is highly correlated with GC content. We combine genome-wide time of replication (ToR) data, topological domains maps and detailed functional epigenetic annotations to study the correlations between replication timing and GC content at multiple scales. We find that the decrease in genomic GC content at large scale late replicating regions can be explained by mutation bias favoring A/T nucleotide, without selection or biased gene conversion. Quantification of the free dNTP pool during the cell cycle is consistent with a mechanism involving replication-coupled mutation spectrum that favors AT nucleotides at late S-phase. We suggest that mammalian GC content composition is shaped by independent forces, globally modulating mutation bias and locally selecting on functional element. Deconvoluting these forces and analyzing them on their native scales is important for proper characterization of complex genomic correlations.
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ephraim
authors.initials: E
authors.lastname: Kenigsberg
authors.affiliation: Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Yishai
authors.identifier: 0000-0001-9079-9335
authors.initials: Y
authors.lastname: Yehuda
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
authors.forename: Lisette
authors.initials: L
authors.lastname: Marjavaara
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Keszthelyi
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden andrei.chabes@umu.se.
authors.forename: Andrei
authors.initials: A
authors.lastname: Chabes
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel amos.tanay@weizmann.ac.il.
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
authors.affiliation: Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel itamarsi@ekmd.huji.ac.il.
authors.forename: Itamar
authors.initials: I
authors.lastname: Simon
mesh_terms: D001482:Base Composition; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D004261:DNA Replication; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D009154:Mutation
chemical_list: D002843:Chromatin