AlphaBeta: Computational inference of epimutation rates and spectra from high-throughput DNA methylation data in plants

Introduction: Heritable changes in cytosine methylation can arise stochastically in plant genomes independently of DNA sequence alterations. These so-called "spontaneous epimutations" appear to be a byproduct of imperfect DNA methylation maintenance during mitotic or meitotic cell divisions. Accurate estimates of the rate and spectrum of these stochastic events are necessary to be able to quantify how epimutational processes shape methylome diversity in the context of plant evolution, development and aging. Method: Here we describe AlphaBeta, a computational method for estimating epimutation rates and spectra from pedigree-based high-throughput DNA methylation data. The approach requires that the topology of the pedigree is known, which is typically the case in the experimental construction of mutation accumulation lines (MA-lines) in sexually or clonally reproducing species. However, this method also works for inferring somatic epimutation rates in long-lived perennials, such as trees, using leaf methylomes and coring data as input. In this case, we treat the tree branching structure as an intra-organismal phylogeny of somatic lineages and leverage information about the epimutational history of each branch. Results: To illustrate the method, we applied AlphaBeta to multi-generational data from selfing- and asexually-derived MA-lines in Arabidopsis and dandelion, as well as to intragenerational leaf methylome data of a single poplar tree. Our results show that the epimutation landscape in plants is deeply conserved across angiosperm species, and that heritable epimutations originate mainly during somatic development, rather than from DNA methylation reinforcement errors during sexual reproduction. Finally, we also provide the first evidence that DNA methylation data, in conjunction with statistical epimutation models, can be used as a molecular clock for age-dating trees. Conclusion: AlphaBeta faciliates unprecedented quantitative insights into epimutational processes in a wide range of plant systems. Software implementing our method is available as a Bioconductor R package at http://bioconductor.org/packages/3.10/bioc/html/AlphaBeta.html Keywords: epimutation; DNA methylation; plants; trees; epigenetics; epimutation rate; evolution