Lagging-strand replication shapes the mutational landscape of the genome

Martin A M Reijns, Harriet Kemp, James Ding, Sophie Marion de Procé, Andrew P Jackson, Martin S Taylor

Research output: Contribution to journalArticlepeer-review

Abstract

The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5′ ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-δ-mediated displacement of Pol-α-synthesized DNA, resulting in incorporation of such Pol-α tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.

Original languageEnglish
Pages (from-to)502–506
Number of pages5
JournalNature
Volume518
Issue number7540
Early online date26 Jan 2015
DOIs
Publication statusPublished - 26 Feb 2015

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