DNA sequence sets the destination of spontaneous epimutations in plants

Abstract

Plant genomes gain and lose cytosine methylation spontaneously, far faster than DNA mutates, and these epimutations are inherited. The genome is thought to set a steady state around which methylation fluctuates. Here we show that this steady state, the set point, is written in the DNA of each CG site: REED, a deep-learning model trained on one methylome, reads it. In pedigrees of seven Arabidopsis thaliana accessions, gains concentrated at high set points and losses at low ones, and the equilibrium implied by their rates matched the set point, tracking it within genes. Stress sped epimutation but barely shifted its destination. The set point predicted germline epimutations in rice and changes accumulated in the wild and in a 330-year-old tree. Its rules, cooperation between nearby CG sites and transcription-factor motifs that lower methylation, are shared across flowering plants, so a genome and one methylome reveal where epigenetic variation is heading.