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bioRxiv · 10.1101/2025.06.14.659605

Mapping genetic modifiers of epimutation rates reveals a punctuated-equilibrium model of CG methylome evolution

Zhang, Z.·Wanney, W.·Xu, Y.·Zicola, J.·Hancock, A. M.·Schmitz, R. J.·Johannes, F.
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Abstract

Spontaneous epimutations--stochastic changes in cytosine methylation--can persist across generations in plants and are thought to contribute to phenotypic variation. Although epimutations are increasingly studied for their potential long-term effects, it remains unclear why their accumulation varies across genotypes. Here, we tracked DNA methylation across ten generations in [~]400 mutation accumulation lineages derived from [~]70 Arabidopsis Ler x Cvi recombinant inbred lines. Treating epimutation rates as quantitative molecular traits, we mapped a major QTL to a Cvi-derived deletion near VIM2 and VIM4, two genes involved in CG methylation (mCG) maintenance. We show that this deletion rapidly reduces genome-wide methylation to a lower steady-state and compromises mCG maintenance fidelity across generations, resulting in a [~]1.5-fold increase in epimutation rates. Genotypes with elevated rates exhibited accelerated epigenetic drift and phenotypic divergence. Our findings support a punctuated-equilibrium model of mCG evolution, in which sudden disruptions to methylation homeostasis can destabilize epigenetic inheritance over longer time-scales.

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Zhang, Z., Wanney, W., Xu, Y., Zicola, J., Hancock, A. M., Schmitz, R. J., Johannes, F.. 2025-06-16. Mapping genetic modifiers of epimutation rates reveals a punctuated-equilibrium model of CG methylome evolution. https://doi.org/10.1101/2025.06.14.659605

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