Genetic mosaicism is a phenomenon that occurs naturally in multicellular organisms, by which genetically diverse cell populations arise through the process of somatic mutation within the organism. Somatic mutations that underlie genetic mosaicism result from intrinsic errors in DNA replication and/or exposure to exogenous genotoxic agents, such as radiation, ultraviolet light, or cigarette smoke. Genetic mosaicism is one of several mechanisms that promote cellular heterogeneity in tissues. Whereas most of the mosaicism that progressively emerges during life is inconsequential, i.e., unable to lead to pathological effects at the cellular and organismal level, a small proportion may produce deleterious effects and lead to pathologies such as cancer (1). In PNAS, Wang et al. (2) report an elegant mosaic system, MASCOT (mosaic analysis system with Cre or Tomato), enabling the temporally controlled introduction of mosaicism and fluorescent markers to a tissue of interest.

Cancer pathogenesis involves a succession of genetic alterations. A small fraction of randomly occurring genetic alterations that increase proliferative capacity, such as oncogenic mutations, confer a growth advantage, resulting in the expansion of the mutant cell clone within its cellular lineage (Fig. 1A). Subsequently, subclones within the pool of mutant cells can acquire additional advantageous alterations, resulting in subclonal expansion (3). As such, each round of clonal expansion generates a cell population with increasingly neoplastic and malignant phenotypes, eventually producing clinically manifest tumors that often harbor remarkable heterogeneity. This process is a textbook example of Darwinian natural selection, with each round of somatic mutation leading to the expansion of the fittest clones embedded in a pool of cells that are “wild type” (WT) with respect to the newly acquired mutation (Fig. 1A). Clonal hematopoiesis (CH) is a fascinating example of such genetic mosaicism, whereby hematopoietic stem cells acquire somatic mutations that confer the mutant cells a growth advantage, but …

↵¹To whom correspondence may be addressed. Email: tammelat{at}mskcc.org.