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

Adam C. Weiner, Marc J. Williams, Hongyu Shi, Ignacio Vázquez-García, Sohrab Salehi, Nicole Rusk, Samuel Aparicio, Sohrab P. Shah () and Andrew McPherson ()
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Adam C. Weiner: Memorial Sloan Kettering Cancer Center
Marc J. Williams: Memorial Sloan Kettering Cancer Center
Hongyu Shi: 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
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center
Andrew McPherson: Memorial Sloan Kettering Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52544-7

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