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Experimental evolution of cellular miniaturization reveals a putative mechanism for cell size evolution

Garoña Ana, Lemos Victoria Morgane, Giometto Andrea, Fumasoni Marco

Posted on: 5 May 2026

Preprint posted on 9 April 2026

The incredible shrinking cells: a guide to efficient downsizing

Selected by Anastasia Moraiti

Categories: cell biology

The cost of scaling (may not be that high)

Ask your entrepreneurial friends: scaling up or downsizing while maintaining smooth operations is tricky business. Cells face a similar challenge – grow too big and you risk a diluted cytoplasm and, eventually, senescence. Being too small is associated with impaired biosynthetic processes, which is no better. While cells are generally pretty good at maintaining their characteristic size, if we were to take a step back and look at the array of cell sizes across the tree of life, then the question comes up: How did evolution give rise to cell sizes spanning many an order of magnitude (think 0.2 μm in the small prokaryotes to the whooping 15 cm of the ostrich egg), when changes in cell size are met with detrimental consequences?

Garoña and colleagues came up with a clever approach to address this in the preprint highlighted here. They set up a regimen for experimental evolution of smaller budding yeast S. cerevisiae and explored the accompanying adaptations that enabled the size change. The process involved selecting for smaller cells (FAC-sorting them based on their forward scatter) and then letting the sorted cells grow to favour small cells that maintained a high proliferation potential. By iterating this process for 1,500 generations they eventually obtained cells with a four-fold reduced volume compared to the ancestor, the so-called S cells (preprint Figure 1A). This new size did not majorly affect fitness and was robust, reflecting a newly established cell-size homeostasis. But the question remains: how do these newly tiny cells make it? Through a description of physiological adaptations and by probing the molecular mechanisms behind them, this work reveals the unexpected plasticity of cell size and hints at how this may have been established during evolution.

 

Growing small

How cells regulate their size remains an open and fascinating question. Our general understanding is that this happens before DNA synthesis, where a cell will commit to division after having reached a critical volume, or after having added a predetermined volume to the one it had at birth.

The authors of this preprint find an impressive adaptation in cell cycle dynamics occurring along their experimental evolution regimen. The final S cells spend markedly less time in G1, where cell growth primarily occurs, without majorly affecting total cell cycle time. The authors also observed adaptations in intracellular organisation, with organelles becoming smaller (albeit not proportionally), and in the utilisation of energy resources, which is also a key determinant of cell growth.

Specifically, the authors suggest that nutrient utilisation in S cells resembles the response to poor nutrient availability, irrespective of the energy source, thus uncoupling nutrient sensing from cell size control. Indeed, small cell size was not associated with slower growth or reduced biosynthetic activity. Compared to cells bearing a mutation in the TOR pathway, which is critical for cell size control, S cells showed a relative fitness (a measure of reproductive success) 7.9% lower than the control (Figure 1B), a modest decrease compared to TOR mutants at 24% lower fitness, despite having decreased their volume only by 2.5 fold.

Figure 1: Experimental evolution of cellular miniaturisation and the effect of size decrease on fitness.

A. Selection regimen to obtain small cells with a four-fold volume increase via FAC-sorting of the smallest cell fraction followed by culture in a rich medium, iterated for 1500 generations. B. Relative fitness decreased by a modest 7% in small cells (compared to ~24% in TOR mutants). Fitness initially dropped sharply before recovering and eventually stabilising, reflected also in sustained biosynthetic activity.

 

Going through changes

The authors then turned to exploring the mechanisms behind smaller cell size. In the absence of selection, S cells did not revert back to their ancestral size. Even more, S cells returned to their newly characteristic size after transient perturbations, indicating a newly evolved homeostatic state that was actively controlled.

Having excluded a diffusible or secreted factor and/or changes in ploidy as causative factors, the next step was to explore a genetic basis for the observed change in size and associated adaptations. Whole genome sequencing across distinct time points in the evolutionary process revealed that, as expected, it’s complicated.

The next challenge was to disentangle the causative mutations from the ones representing compensatory adaptations to the smaller size. The authors focused on two attractive candidates, CLN3, encoding a G1 cyclin, and SCH9, encoding a TOR pathway effector.

In the case of CLN3, the observed mutations conferred a gain of function, stabilising the protein via C-terminal truncations. This stable, overactive Cln3, has previously been associated with smaller cell size, through shortening of the G1 phase. The case of SCH9, which accumulated loss-of-function mutations, was a bit more puzzling as its well-known role in controlling ribosome biosynthesis was not supported by the sustained biosynthetic activity of S cells. This suggested an alternative function of identified Sch9 allele in the control of cell size and to explore this, the authors turned to the Sch9 effect on the pathway that controls cell cycle progression in yeast, the Greatwall kinase pathway. Sch9 is known to inhibit the Greatwall kinase Rim15, an inhibition that is proposed to be relieved in the SCH9 mutant S cells. This, along with further gain-of-function mutations identified along the Greatwall pathway, suggests that Rim15 derepression leads to size decrease. Indeed, using an inducible system to tune RIM15 expression, the authors revealed a dosage-dependent effect on cell size decrease, where an overexpressed RIM15 leads to smaller size. This effect was even more pronounced when RIM15 overexpression occurred in an SCH9/CLN3 mutant background, hinting at the synergistic effect of these genetic changes.

The authors thus propose a mechanism where cell size reduction is mediated by a hyperactive G1 cyclin and increased Greatwall pathway activity. How exactly this is facilitated merits further exploration, but Garoña and colleagues speculate that the combination of these two events leads to a fast phosphorylation of Whi5, thus quickly driving it outside the nucleus (preprint Figure 2). Interestingly, they also show a further size decrease when SWE1 was deleted in CLN3 cells, revealing that the limits of cell size may have not yet been reached in the duration of this regimen. Onwards and downwards!

Figure 2: Proposed model of the cell cycle adaptations facilitating decreased cell size while maintaining fitness. An increase of Cln3 activity, combined with increased Rim15 activity (via Sch9 derepression) allows for faster progression through G1/S and G2/M, allowing for smaller cell size without an effect on biomass production.

 

Small cell, big world

Overall, Garoña and colleagues show striking adaptations in cell cycle dynamics and its control by nutrients that can lead to an impressive decrease in cell size without compromising on growth and fitness. While it remains to be uncovered whether these adaptations may serve as more generalisable principles for cell size change across evolution, the powerful system set up here pushes the limits of minimal cell size and of cell cycle rewiring. Furthermore, given the complex genetic changes observed, there is potentially more to learn from how these little cells navigate the great big world, both in terms of the facilitating mechanisms and the accompanying remodelling.

 

 

Tags: cell cycle, cell size, saccharomyces cerevisiae, size evolution, yeast

Read preprint (No Ratings Yet)

My questions to the authors

Fumasoni Marco shared

I found the trajectory of relative fitness and G1 duration as measured through the evolved generations very interesting. Have you looked at how these associated with the decoupling of growth to nutritional conditions and do you think there is more to be learnt from these intermediate stages of adaptation (and presumably mutation accumulation)?

That’s a great point! We haven’t yet fully exploited the “fossil record” generated during the evolution experiment. Systematically tracking phenotypes such as the cell size response under poor carbon conditions across evolutionary time could allow us to correlate their emergence with the spread of specific mutations in the population. This approach should help disentangle causative variants from later compensatory adaptations, and it’s definitely an experiment we’re excited to pursue.

 

You describe that scaling was not proportionate between organelles -I was curious about any interesting observations regarding mitochondria and the nucleus specifically?

At this stage, our EM data are not sufficiently quantitative to draw firm conclusions. That said, preliminary observations point to allometric scaling of both organelles: the nucleus appears to shrink less than expected, whereas the mitochondrial network may shrink more. To resolve this more rigorously, we are now moving toward high-resolution live-cell imaging, which should allow us to quantify these scaling relationships with much greater precision.

 

Would you think that the unimodal volume distribution of S cells at the entry to stationary phase reflects a different size control mechanism to the ancestral lines?

The bimodal volume distribution in wild-type cells at stationary phase is generally attributed to asymmetric division, which produces larger mother cells and smaller daughter cells. Our working hypothesis is that this asymmetry may have been altered during the evolution experiment, contributing to the unimodal distribution observed in S cells. We are currently planning live-cell imaging experiments to directly test whether and how division asymmetry, and the underlying size control mechanisms have changed.

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