Stochastic processes in cells are associated with fluctuations in mRNA1, protein production and degradation2,3, noisy partition of cellular components at division4, and other cell processes. Variability within a clonal population of cells originates from such stochastic processes, which may be amplified or reduced by deterministic factors5. 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 cells6. 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.
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We thank H. Miyoshi at the Riken Tsukuba for the Fucci markers, N. Barkai, N. Shoresh, J. Theiler, S. Kadener, L. Glass, G. Asher, A. W. Murray and J. Paulsson for discussions, and M. Gorfine and R. Heller for advice on statistical analysis. We thank Q. Yang and A. van Oudenaarden for the Cyanobacteria data sets, and the authors of ref. 24 for making their published data available online. This work was supported by the ISF (grants no. 592/10 (N.Q.B.); no. 567/10(I.S.); and no. 9/09, 302/14 (O.A.)) and the ERC Starting Grant no. 281306 (I.S.), no. 260871 (N.Q.B.), the Chief Scientist Office of the Israel Ministry of Health and the Weinkselbaum family medical research fund (I.S.). I.S. thanks the USAID’s ASHA Program for the upgrading of the FACS laboratory. S.P.M. is supported by the Clore Foundation.
Extended data figures
The video shows time lapse microscopy of dividing L1210 cells and their expression of the Fucci markers (clone 2). Cells were grown in PDMS chambers under the microscope and imaged with x20 magnification. Here a composite of phase-contrast, red fluorescence and green fluorescence is shown with time interval of 23 min. Phase contrast images were acquired at a faster rate.