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PMID: 23422670 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Nature communications ·Vol. 4 ·2013-00-00 ·Pages 1502

Liu L, De S, Michor F

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.

MeSH Terms
Amino Acid Substitution/genetics Cell Nucleus/genetics DNA Replication Timing/genetics Databases, Genetic Evolution, Molecular Genome, Human/genetics Humans Mutation/genetics Mutation Rate Neoplasms/genetics,pathology Nucleotides/genetics Polymorphism, Single Nucleotide/genetics
Chemicals
Nucleotides
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Liu Lin
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Instituteh, Boston, Massachusetts 02215, USA.
De Subhajyoti
Michor Franziska
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms2502
Published
2013-00-00
Pages
1502
Language
English
Region
England
NLM ID
101528555
PMCID
PMC3633418
Subset
IM
Grants
NIGMS NIH HHS · R01 GM096190 · United States
NCI NIH HHS · U54 CA143798 · United States
NCI NIH HHS · U54CA143798 · United States
External Links
PubMed source DOI: 10.1038/ncomms2502 PMC Full Text View journal details
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