Publication Date:
2015-01-28
Description:
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-alpha (Pol-alpha) 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-delta-mediated displacement of Pol-alpha-synthesized DNA, resulting in incorporation of such Pol-alpha 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374164/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374164/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reijns, Martin A M -- Kemp, Harriet -- Ding, James -- de Proce, Sophie Marion -- Jackson, Andrew P -- Taylor, Martin S -- MC_PC_U127580972/Medical Research Council/United Kingdom -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_U127597124/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Feb 26;518(7540):502-6. doi: 10.1038/nature14183. Epub 2015 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical and Developmental Genetics, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Biomedical Systems Analysis, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25624100" target="_blank"〉PubMed〈/a〉
Keywords:
Binding Sites
;
Chromatin/chemistry/metabolism
;
Conserved Sequence/genetics
;
DNA/*biosynthesis/*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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
