Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants

Am J Hum Genet. 2009 Mar;84(3):339-50. doi: 10.1016/j.ajhg.2009.01.024. Epub 2009 Feb 19.


Copy number variants (CNVs) are an important component of genomic variation in humans and other mammals. Similar de novo deletions and duplications, or copy number changes (CNCs), are now known to be a major cause of genetic and developmental disorders and to arise somatically in many cancers. A major mechanism leading to both CNVs and disease-associated CNCs is meiotic unequal crossing over, or nonallelic homologous recombination (NAHR), mediated by flanking repeated sequences or segmental duplications. Others appear to involve nonhomologous end joining (NHEJ) or aberrant replication suggesting a mitotic cell origin. Here we show that aphidicolin-induced replication stress in normal human cells leads to a high frequency of CNCs of tens to thousands of kilobases across the human genome that closely resemble CNVs and disease-associated CNCs. Most deletion and duplication breakpoint junctions were characterized by short (<6 bp) microhomologies, consistent with the hypothesis that these rearrangements were formed by NHEJ or a replication-coupled process, such as template switching. This is a previously unrecognized consequence of replication stress and suggests that replication fork stalling and subsequent error-prone repair are important mechanisms in the formation of CNVs and pathogenic CNCs in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aphidicolin / pharmacology
  • Cells, Cultured
  • DNA Replication / drug effects
  • DNA Replication / genetics*
  • DNA Replication / physiology
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Gene Dosage*
  • Genetic Variation*
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Recombination, Genetic


  • Aphidicolin