Lagging-strand replication shapes the mutational landscape of the genome

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Conserved Sequence / genetics
  • DNA / biosynthesis*
  • DNA / genetics*
  • DNA Polymerase I / metabolism
  • DNA Polymerase III / metabolism
  • DNA Replication / genetics*
  • DNA-Binding Proteins / metabolism
  • Evolution, Molecular
  • Genome, Human / genetics*
  • Humans
  • Models, Biological
  • Mutagenesis / genetics
  • Mutation / genetics*
  • Protein Binding
  • Saccharomyces cerevisiae / genetics
  • Transcription Factors / metabolism


  • Chromatin
  • DNA-Binding Proteins
  • Okazaki fragments
  • Transcription Factors
  • DNA
  • DNA Polymerase I
  • DNA Polymerase III

Associated data

  • GEO/GSE64521