DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes

Lin Liu, Subhajyoti De, Franziska Michor

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Single-nucleotide substitutions are a defining characteristic of cancer genomes. Many single-nucleotide substitutions in cancer genomes arise because of errors in DNA replication, which is spatio-temporally stratified. Here we propose that DNA replication patterns help shape the mutational landscapes of normal and cancer genomes. Using data on five fully sequenced cancer types and two personal genomes, we determined that the frequency of intergenic single-nucleotide substitution is significantly higher in late DNA replication timing regions, even after controlling for a number of genomic features. Furthermore, some substitution signatures are more frequent in certain DNA replication timing zones. Finally, integrating data on higher-order nuclear organization, we found that genomic regions in close spatial proximity to late-replicating domains display similar mutation spectra as the late-replicating regions themselves. These data suggest that DNA replication timing together with higher-order genomic organization contribute to the patterns of single-nucleotide substitution in normal and cancer genomes.

Original languageEnglish (US)
Article number1502
JournalNature communications
Volume4
DOIs
StatePublished - 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes'. Together they form a unique fingerprint.

Cite this