Proulx-Giraldeau, F. | bioRxiv Science

bioRxiv2025

Division Asymmetry Drives Cell Size Variability in Budding Yeast

Cell size variability within proliferating populations reflects the interdependent regulation of cell growth and division as well as intrinsically stochastic effects. In budding yeast, the G1/S transition exerts strong size control in daughter cells, which manifests as the inverse correlation between how big a cell is when it is born and how much it grows in G1. However, mutations affecting this size control checkpoint only modestly influence population-wide size variability, often altering the coefficient of variation (CV) only by [~]10%. To resolve this paradox, we combine computational modeling and live-cell imaging to identify the principal determinants of cell size variability. Using an experimentally validated stochastic model of the yeast cell cycle, we perform parameter sensitivity analysis and find that division asymmetry between mothers and daughters is the dominant driver of CV, outweighing the effects of G1/S size control. Experimental measurements across genetic perturbations and growth conditions confirm a strong correlation between mother-daughter size asymmetry and population CV. These findings reconcile previous observations and show how asymmetric division operates in concert with G1/S size control to govern cell size heterogeneity.

cell biology↗

bioRxiv2022

Evolution of cell size control is canalized towards adders or sizers by cell cycle structure and selective pressures

Cell size is controlled to be within a specific range to support physiological function. To control their size, cells use diverse mechanisms ranging from sizers, in which differences in cell size are compensated for in a single cell division cycle, to adders, in which a constant amount of cell growth occurs in each cell cycle. This diversity raises the question why a particular cell would implement one rather than another mechanism? To address this question, we performed a series of simulations evolving cell size control networks. The size control mechanism that evolved was influenced by both cell cycle structure and specific selection pressures. Moreover, evolved networks recapitulated known size control properties of naturally occurring networks. If the mechanism is based on a G1 size control and an S/G2/M timer, as found for budding yeast and some human cells, adders likely evolve. But, if the G1 phase is significantly longer than the S/G2/M phase, as is often the case in mammalian cells in vivo, sizers become more likely. Sizers also evolve when the cell cycle structure is inverted so that G1 is a timer, while S/G2/M performs size control, as is the case for the fission yeast S. pombe. For some size control networks, cell size consistently decreases in each cycle until a burst of cell cycle inhibitor drives an extended G1 phase much like the cell division cycle of the green algae Chlamydomonas. That these size control networks evolved such self-organized criticality shows how the evolution of complex systems can drive the emergence of critical processes.

systems biology↗