The Evolution of Polyclonal Competition in Aging Hematopoiesis

UNLABELLED: Clonal hematopoiesis (CH)-the expansion of genetic variants in blood-is a prime example of somatic evolution. Although it often precedes malignant transformation, many aspects of this process remain unknown. We show that a model of polyclonal competition, in which selectively advantaged clones continually occur and compete, explains observed CH dynamics throughout human life. We quantify the fitness distribution and occurrence rate of clonal expansions using either variant trajectories or hematopoietic stem cell (HSC) genetic heterogeneity. Inferences on both data converge. Approximately 3 fit clones enter the HSC pool per year, yet rarely more than 5 achieve >1.5% frequency throughout life. The fittest clones emerge predominantly later in life in accordance with a multistep evolutionary process. DNMT3A variants were enriched for single-hit clones, whereas TET2, ASXL1, JAK2, SF3B1, and SRSF2 showed enrichment for multihit evolution. These findings suggest that precursors of hematologic malignancies are identifiable prior to transformation and may facilitate early intervention strategies. SIGNIFICANCE: We study the evolution of CH through longitudinal variant trajectories and HSC genetic heterogeneity. Clonal interference and a multistep evolutionary process become evident. Clones further advanced on the path to malignant transformation are identifiable, and propensities for multiple hits differ among most commonly mutated CH variants.