Hidden long-range memories of growth and cycle speed correlate cell cycles in lineage trees

Abstract

Cell heterogeneity may be caused by stochastic or deterministic effects. The inheritance of regulators through cell division is a key deterministic force, but identifying inheritance effects in a systematic manner has been challenging. Here, we measure and analyze cell cycles in deep lineage trees of human cancer cells and mouse embryonic stem cells and develop a statistical framework to infer underlying rules of inheritance. The observed long-range intra-generational correlations in cell-cycle duration, up to second cousins, seem paradoxical because ancestral correlations decay rapidly. However, this correlation pattern is naturally explained by the inheritance of both cell size and cell-cycle speed over several generations, provided that cell growth and division are coupled through a minimum-size checkpoint. This model correctly predicts the effects of inhibiting cell growth or cycle progression. In sum, we show how fluctuations of cell cycles across lineage trees help in understanding the coordination of cell growth and division.

Intrinsic growth heterogeneity of mouse leukemia cells underlies differential susceptibility to a growth-inhibiting anticancer drug

“…We also calculated the correlation between the generation times of mother and daughter cells and found a relatively strong positive correlation (Pearson's correlation coefficient, r = 0.62 ± 0.01; Spearman's correlation coefficient, ⇢ = 0.62 ± 0.01, Fig 2C). The positive correlation between the generation times of mother and daughter cells observed here is one of the strongest reported to date for eukaryotic and prokaryotic cells [27][28][29][30][31][32][33]. The correlation monotonically decayed across generations, but we still found a positive correlation of r = 0.20 ± 0.02 even after ten generations ( Fig 2D).…”

Automated deep lineage tree analysis using a Bayesian single cell tracking approach

“…We observed moderate correlations (Pearson and Spearman rank coefficients of 0.43 and 0.51, respectively) between 11,696 reference and mother cell pairs (Figure 4D), which represents an order of magnitude higher, yet still relatively low, mother-daughter correlation compared to previously shown trends 4,7,8 . The correlations continued to decrease with increasing ancestor distance all the way to a cell's great-great-grandmother (0.24, 0.10, 0.17 for Pearson and 0.25, 0.07, 0.14 for Spearman rank coefficients).…”

“…For example, the observed distribution of cell cycle durations in a population of cells is governed either by stochastic processes, inherited in a deterministic fashion, or some combination of both [3][4][5][6] (Figure 1A). Previous studies have shown poor correlations within lineages when observing direct ancestral relationships, but remain correlated with immediate relatives 4,7,8 . However, these studies have been performed using manually annotated data, which is laborious to acquire and limits the depth and statistical power to study more distant relationships amid noisy data.…”

“…generational depth compared to the reference cell ( Figure 4A). In doing so, we were able to analyse orders of magnitude greater numbers and significantly greater depth of lineage trees then in previous studies 4,7,8 . Our ancestral analysis comprised 11,696 mother, 4,667 grandmother, 1,002 great-grandmother, 109 great-great-grandmother and 10 great-great-greatgrandmother comparisons (Figure 4).…”

“…Previous studies suggested that cell cycle durations within lineages show poor correlation when observing the direct ancestral cell pairs (mother-daughter and grandmother-granddaughter), but remain highly correlated when examining intra-generational relationships (sister and cousin cells) 4,7,8 . However, due to lack of deep datasets, the analysis has traditionally focussed on immediate cell relatives, including mother, grandmother, sister and first cousin relationships 4,7 and less frequently on more remote family members, such as greatgrandmothers or second cousins 8 . We have extended previous studies using the enhanced depth (up to eight generations), breadth (up to fourth cousin distance from reference cell), and number of lineages (5,032 trees) from our automatically reconstructed lineage tree pool ( Figure 4A).…”