Model of HSC divisions that can result in CH. (A) There is a balance between regeneration of stem cells (blue) and differentiated cells (orange). This schematic does not necessarily imply an asymmetric division, but depicts the net result of the stem cell decisions (dashed box). (B) A stem cell divides faster, but each decision has the same net outcome as in panel A. Therefore, the net, after more cell divisions, does not increase the stem cell pool and does not outcompete normal HSCs. (C) The HSC has a slight bias toward self-renewal. Every few divisions (red arrows), it generates an imbalance such that the net, over time, is generation of more stem cells. The speed with which it results in truly biased outputs will depend on the frequency of imbalanced decisions. For most CH genes, this is probably a very subtle bias initially, explaining the very long time lag for CH to become apparent.