Schematic of development of CH. At birth, the HSC pool is relatively uniform. Over time, somatic mutations accumulate at a rate of ∼10 per year such that all HSCs are slightly different in early adults. These differences manifest in disadvantages and advantages for survival and contribution to peripheral blood production, resulting in some HSCs that “win” with advanced age (red cells at the far right). While expanded clones can be detected in middle age with sensitive sequencing techniques, the current accepted definition is when a clone reaches a proportion of ∼4% of cells measured in the peripheral blood. This equates to a variant allele frequency (VAF) of 2% when the variants (mutations) are heterozygous.