Open Access funded by Wellcome Trust. Under a Creative Commons license.-- Understanding Society Scientific Group: et al. ; Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged 70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age. ; This project was funded by a Wellcome Trust Clinician Scientist Fellowship (100678/Z/12/Z; to T. McKerrell) and by the Wellcome Trust Sanger Institute (grant number WT098051). G.S.V. is funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA), and work in his laboratory is also funded by Leukaemia Lymphoma Research and the Kay Kendal Leukaemia Fund. I.V. is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal. C.S.G. is funded by a Leukaemia Lymphoma Research Clinical Research Training Fellowship. We thank Servicio Santander Supercomputación for their support. We acknowledge use of DNA from The UK Blood Services Collection of Common Controls (UKBS collection), funded by the Wellcome Trust grant 076113/C/04/Z, by the Juvenile Diabetes Research Foundation grant WT061858, and by the National Institute of Health Research of England. ; Peer Reviewed