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Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data

Author

Listed:
  • Adam C. Weiner

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Marc J. Williams

    (Memorial Sloan Kettering Cancer Center)

  • Hongyu Shi

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Ignacio Vázquez-García

    (Memorial Sloan Kettering Cancer Center)

  • Sohrab Salehi

    (Memorial Sloan Kettering Cancer Center)

  • Nicole Rusk

    (Memorial Sloan Kettering Cancer Center)

  • Samuel Aparicio

    (British Columbia Cancer
    University of British Columbia)

  • Sohrab P. Shah

    (Memorial Sloan Kettering Cancer Center)

  • Andrew McPherson

    (Memorial Sloan Kettering Cancer Center)

Abstract

Dysregulated DNA replication is a cause and a consequence of aneuploidy in cancer, yet the interplay between copy number alterations (CNAs), replication timing (RT) and cell cycle dynamics remain understudied in aneuploid tumors. We developed a probabilistic method, PERT, for simultaneous inference of cell-specific replication and copy number states from single-cell whole genome sequencing (scWGS) data. We used PERT to investigate clone-specific RT and proliferation dynamics in >50,000 cells obtained from aneuploid and clonally heterogeneous cell lines, xenografts and primary cancers. We observed bidirectional relationships between RT and CNAs, with CNAs affecting X-inactivation producing the largest RT shifts. Additionally, we found that clone-specific S-phase enrichment positively correlated with ground-truth proliferation rates in genomically stable but not unstable cells. Together, these results demonstrate robust computational identification of S-phase cells from scWGS data, and highlight the importance of RT and cell cycle properties in studying the genomic evolution of aneuploid tumors.

Suggested Citation

  • Adam C. Weiner & Marc J. Williams & Hongyu Shi & Ignacio Vázquez-García & Sohrab Salehi & Nicole Rusk & Samuel Aparicio & Sohrab P. Shah & Andrew McPherson, 2024. "Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52544-7
    DOI: 10.1038/s41467-024-52544-7
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