Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis

DNA damage and mutations in hematopoietic stem cells (HSC) enable clonal hematopoiesis (CH). Such damage occurs throughout life, but its origins remain unknown. Here, we demonstrate that endogenous formaldehyde causes HSC attrition and subsequently CH. We generated conditional mouse models lacking formaldehyde detoxification and Fanconi anemia (FA) DNA repair in blood. Formaldehyde protection was crucial from embryonic HSC emergence and throughout life. Despite a severe deficiency in HSCs, these mice produce blood for many months. To determine what enables this, we employed a new unbiased method for detecting clones which exploits somatic variant data. This revealed initial polyclonal hematopoiesis which diminishes to monoclonal CH, devoid of known genetic selection. Furthermore, in FA children, we find the same transition to monoclonal hematopoiesis. Therefore, DNA damage-induced attrition down to a last functional cell can be a driving force for CH, representing an alternative route to CH other than purely by fitness-enhancing selection.