Evolutionary dynamics of mutations in hematopoietic stem cells and beyond

Mutations are a natural consequence of the interactions of our genome with genotoxic agents and imperfections in the DNA replication machinery. Every cell is at risk of mutations and therefore the probability of acquiring mutations is increasing with population size. However, the impact of a mutation depends on the type of cell where it occurs and the average lifetime of that cell. Tissue architecture is organized in such a way that many mutations will have no consequence, although the cell harboring them may expand into a detectable clone. We will use the known architecture and dynamics of hematopoiesis to describe the evolution of mutant clones in age structured populations and show why the appearance of well recognized mutations is inevitable even if usually of no consequence. Most mutant populations merely cause transient ripples in a tissue. However, whenever mutations occur in stem cells or other primitive cells, the associated clones can have long lasting consequences and may lead to disease.