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Nature. 2015 Feb 26;518(7540):502-506. doi: 10.1038/nature14183. Epub 2015 Jan 26.

Lagging-strand replication shapes the mutational landscape of the genome.

Author information

1
MRC Human Genetics Unit, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, UK.
#
Contributed equally

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.

PMID:
25624100
PMCID:
PMC4374164
DOI:
10.1038/nature14183
[Indexed for MEDLINE]
Free PMC Article

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