Title: Methylation as a causal driver in cancer and ageing.

Abstract: With age, organisms are subjected to internal and external stresses. Some of these stresses, along with stochastic drift, will affect methylation, but we have a limited understanding to what extent are methylation states heritable over cell division or longer periods of time. In this project, we sequenced genomes and methylomes of hundreds of single hematopoietic stem cells (HSCs) from normal individuals and cancer patients. We constructed a phylogeny for each donor and overlaid methylation states to infer how methylation changed from the zygote onwards at each CpG in the genome. We found that methylation states are remarkably heritable, often over several decades, stochastic and usually affect one chromosomal copy. Methylation changes often affect clusters of adjacent CpGs in regulatory regions of the genome, which can result in cancer decades later, and we present compelling evidence for a methylation driver in breast cancer.