Control of Caenorhabditis elegans germ-line stem-cell cycling speed meets requirements of design to minimize mutation accumulation

Background: Stem cells are thought to play a critical role in minimizing the accumulation of mutations, but it is not
clear which strategies they follow to fulfill that performance objective. Slow cycling of stem cells provides a simple
strategy that can minimize cell pedigree depth and thereby minimize the accumulation of replication-dependent
mutations. Although the power of this strategy was recognized early on, a quantitative assessment of whether and
how it is employed by biological systems is missing.

Results: Here we address this problem using a simple self-renewing organ – the C. elegans gonad – whose overall
organization is shared with many self-renewing organs. Computational simulations of mutation accumulation
characterize a tradeoff between fast development and low mutation accumulation, and show that slow-cycling stem
cells allow for an advantageous compromise to be reached. This compromise is such that worm germ-line stem cells
should cycle more slowly than their differentiating counterparts, but only by a modest amount. Experimental
measurements of cell cycle lengths derived using a new, quantitative technique are consistent with these predictions.

Conclusions: Our findings shed light both on design principles that underlie the role of stem cells in delaying aging
and on evolutionary forces that shape stem-cell gene regulatory networks.