title: Genome-wide copy number profiling of single cells in S-phase reveals DNA-replication domains.
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.
authors.affiliation: Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, 3000, Belgium.
authors.forename: Niels
authors.initials: N
authors.lastname: Van der Aa
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Cheng
authors.forename: Ligia
authors.initials: L
authors.lastname: Mateiu
authors.forename: Masoud
authors.initials: M
authors.lastname: Zamani Esteki
authors.forename: Parveen
authors.initials: P
authors.lastname: Kumar
authors.forename: Eftychia
authors.initials: E
authors.lastname: Dimitriadou
authors.forename: Evelyne
authors.initials: E
authors.lastname: Vanneste
authors.forename: Yves
authors.initials: Y
authors.lastname: Moreau
authors.forename: Joris Robert
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
mesh_terms: D016477:Artifacts; D001482:Base Composition; D002461:Cell Line, Transformed; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000737:chemistry; D056915:DNA Copy Number Variations; D004261:DNA Replication; D042522:DNA Replication Timing; D056426:Genetic Loci; D023281:Genomics / Q000379:methods; D006801:Humans; D016196:S Phase / Q000235:genetics*; D059010:Single-Cell Analysis
chemical_list: D004247:DNA