The mutation spectrum in genomic late replication domains shapes mammalian GC content

Ephraim Kenigsberg, Yishai Yehuda, Lisette Marjavaara, Andrea Keszthelyi, Andrei Chabes, Amos Tanay*, Itamar Simon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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.

Original languageAmerican English
Pages (from-to)4222-4232
Number of pages11
JournalNucleic Acids Research
Issue number9
StatePublished - 19 May 2016

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© 2016 The Author(s).


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