Using somatic mutations to understand historic HSC clonal relationships. (A) Simplified phylogenetic tree of HSC relatedness. Based on the mutations detected in each stem cell by WGS, we can build a “family tree” of HSCs using unique and shared somatic mutations. The shapes within the circles represent unique somatic mutations that are inherited by a cell’s progeny. (B) Hypothetical phylogenetic tree. The terminal point of each line represents the stem cell that was sampled. Traveling up these lines, any point of convergence (termed a “coalescence”) indicates an ancestral HSC where 2 progeny stem cells and their subsequent progeny can be traced. The uppermost branch points represent the stem cell divisions that are likely to occur during embryogenesis. The dotted box highlights how the structure in (A) would appear within a phylogenetic tree. The presence and distribution of coalescence are related to both aging and disease states. Example tree structures representing HSC relatedness in 3 different contexts are shown in (C-F). (C) Phylogenies from younger healthy adults appear highly polyclonal with many HSCs contributing to the overall structure,⁶⁷ as indicated by the back of the branch points beyond early development. (D) By the time individuals reach their seventh decade of life, tree structures begin to show evidence of decreased clonal diversity,⁶⁷ with a greater number of sampled HSCs being part of the large clones. These expansions are often (but not always) associated with nonpathogenic mutations that provide HSCs with a survival advantage. (E) The skewed clonal structure is even more exaggerated in the case of myeloid malignancy. In this context, pathogenic mutations, such as JAK2V617F, cause large expansions of specific HSCs. (F) The phylogenetic trees of patients with SDS show evidence of clonal expansions more characteristic of older adults. Colored branches indicate which clones carry driver mutations (trees adapted from Machado et al⁵⁶).