Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data Journal Article
| Authors: | Weiner, A. C.; Williams, M. J.; Shi, H.; Vázquez-García, I.; Salehi, S.; Rusk, N.; Aparicio, S.; Shah, S. P.; McPherson, A. |
| Article Title: | Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data |
| 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. © The Author(s) 2024. |
| Keywords: | controlled study; human tissue; gene mutation; human cell; genetics; mutation; cisplatin; nonhuman; dna replication; neoplasm; neoplasms; cell proliferation; mouse; animal; animals; mice; allele; animal tissue; cell cycle; cell cycle s phase; animal experiment; animal model; evolution; tumor xenograft; pathology; cell line, tumor; molecular cloning; statistical analysis; dna; molecular evolution; probability; genomic instability; quantitative analysis; tumor cell line; ovary carcinoma; genome; x chromosome inactivation; aneuploidy; s phase; sequence analysis, dna; dna copy number variations; copy number variation; cell dna; dna damage checkpoint; triple negative breast cancer; single cell analysis; single-cell analysis; procedures; dna replication timing; cell component; dna sequencing; humans; human; female; article; whole genome sequencing; cancer cell line; probabilistic estimation of single cell replication timing |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-10-01 |
| Start Page: | 8512 |
| Language: | English |
| DOI: | 10.1038/s41467-024-52544-7 |
| PUBMED: | 39353885 |
| PROVIDER: | scopus |
| PMCID: | PMC11445576 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK authors are Sohrab P. Shah and Andrew McPherson -- Source: Scopus |
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