Comparison of constitutional and replication stress-induced genome structural variation by SNP array and mate-pair sequencing

Genetics. 2011 Mar;187(3):675-83. doi: 10.1534/genetics.110.124776. Epub 2011 Jan 6.


Copy-number variants (CNVs) are a major source of genetic variation in human health and disease. Previous studies have implicated replication stress as a causative factor in CNV formation. However, existing data are technically limited in the quality of comparisons that can be made between human CNVs and experimentally induced variants. Here, we used two high-resolution strategies-single nucleotide polymorphism (SNP) arrays and mate-pair sequencing-to compare CNVs that occur constitutionally to those that arise following aphidicolin-induced DNA replication stress in the same human cells. Although the optimized methods provided complementary information, sequencing was more sensitive to small variants and provided superior structural descriptions. The majority of constitutional and all aphidicolin-induced CNVs appear to be formed via homology-independent mechanisms, while aphidicolin-induced CNVs were of a larger median size than constitutional events even when mate-pair data were considered. Aphidicolin thus appears to stimulate formation of CNVs that closely resemble human pathogenic CNVs and the subset of larger nonhomologous constitutional CNVs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aphidicolin / pharmacology
  • Cell Line
  • DNA Copy Number Variations / drug effects
  • DNA Copy Number Variations / genetics*
  • DNA Damage / genetics
  • DNA Replication*
  • Genome, Human
  • Humans
  • Oligonucleotide Array Sequence Analysis / methods*
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Analysis, DNA / methods*


  • Aphidicolin

Associated data

  • GEO/GSE26121