Genome-wide copy number profiling of single cells in S-phase reveals DNA-replication domains |
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Authors: | Niels Van der Aa Jiqiu Cheng Ligia Mateiu Masoud Zamani Esteki Parveen Kumar Eftychia Dimitriadou Evelyne Vanneste Yves Moreau Joris Robert Vermeesch Thierry Voet |
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Institution: | 1Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, 3000, Belgium, 2ESAT-SCD, Department of Electrical Engineering, KU Leuven, Heverlee, 3001, Belgium, 3SISTA, IBBT-KULeuven Future Health Department, KU Leuven, Heverlee, 3001, Belgium and 4Laboratory for Cytogenetics and Genome Research, Department of Human Genetics, KU Leuven, Leuven, 3000, Belgium |
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Abstract: | Single-cell genomics is revolutionizing basic genome research and clinical genetic diagnosis. However, none of the current research or clinical methods for single-cell analysis distinguishes between the analysis of a cell in G1-, S- or G2/M-phase of the cell cycle. Here, we demonstrate by means of array comparative genomic hybridization that charting the DNA copy number landscape of a cell in S-phase requires conceptually different approaches to that of a cell in G1- or G2/M-phase. Remarkably, despite single-cell whole-genome amplification artifacts, the log2 intensity ratios of single S-phase cells oscillate according to early and late replication domains, which in turn leads to the detection of significantly more DNA imbalances when compared with a cell in G1- or G2/M-phase. Although these DNA imbalances may, on the one hand, be falsely interpreted as genuine structural aberrations in the S-phase cell’s copy number profile and hence lead to misdiagnosis, on the other hand, the ability to detect replication domains genome wide in one cell has important applications in DNA-replication research. Genome-wide cell-type-specific early and late replicating domains have been identified by analyses of DNA from populations of cells, but cell-to-cell differences in DNA replication may be important in genome stability, disease aetiology and various other cellular processes. |
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