Genetic instability from a single S phase after whole-genome duplication

Nature. 2022 Apr;604(7904):146-151. doi: 10.1038/s41586-022-04578-4. Epub 2022 Mar 30.


Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers1-3. It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis4-8; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis9. Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.

MeSH terms

  • Chromosomal Instability* / genetics
  • DNA Damage*
  • DNA Replication
  • Gene Duplication*
  • Humans
  • Karyotype
  • Mitosis
  • S Phase* / genetics
  • Tetraploidy*