title: Lineage correlations of single cell division time as a probe of cell-cycle dynamics.
abstract: Stochastic processes in cells are associated with fluctuations in mRNA, protein production and degradation, noisy partition of cellular components at division, and other cell processes. Variability within a clonal population of cells originates from such stochastic processes, which may be amplified or reduced by deterministic factors. Cell-to-cell variability, such as that seen in the heterogeneous response of bacteria to antibiotics, or of cancer cells to treatment, is understood as the inevitable consequence of stochasticity. Variability in cell-cycle duration was observed long ago; however, its sources are still unknown. A central question is whether the variance of the observed distribution originates from stochastic processes, or whether it arises mostly from a deterministic process that only appears to be random. A surprising feature of cell-cycle-duration inheritance is that it seems to be lost within one generation but to be still present in the next generation, generating poor correlation between mother and daughter cells but high correlation between cousin cells. This observation suggests the existence of underlying deterministic factors that determine the main part of cell-to-cell variability. We developed an experimental system that precisely measures the cell-cycle duration of thousands of mammalian cells along several generations and a mathematical framework that allows discrimination between stochastic and deterministic processes in lineages of cells. We show that the inter- and intra-generation correlations reveal complex inheritance of the cell-cycle duration. Finally, we build a deterministic nonlinear toy model for cell-cycle inheritance that reproduces the main features of our data. Our approach constitutes a general method to identify deterministic variability in lineages of cells or organisms, which may help to predict and, eventually, reduce cell-to-cell heterogeneity in various systems, such as cancer cells under treatment.
authors.affiliation: Department of Microbiology and Molecular Genetics, IMRIC, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Sandler
authors.affiliation: 1] Department of Microbiology and Molecular Genetics, IMRIC, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel [2] Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Sivan Pearl
authors.initials: SP
authors.lastname: Mizrahi
authors.affiliation: Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Noga
authors.initials: N
authors.lastname: Weiss
authors.affiliation: Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Agam
authors.affiliation: Department of Microbiology and Molecular Genetics, IMRIC, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Simon
authors.affiliation: Racah Institute of Physics, Edmond J. Safra Campus, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Nathalie Q
authors.initials: NQ
authors.lastname: Balaban
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage; D008322:Mammals; D008954:Models, Biological; D013269:Stochastic Processes; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents