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A MASCOT for mosaic analysis

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 that alone are insufficient to lead to the development of leukemia. However, patients with CH are significantly more likely to acquire subsequent cooperating mutations that produce acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasms (4, 5). Geneticists have investigated gene function by genetically engineering mosaic animals—typically worms, fruit flies, and mice. Mosaic analysis has become a widely used tool to study the behavior of mutant clones in a WT cellular environment. Distinct from conventional gene knockout, where a gene of interest is inactivated at the beginning of life throughout the organism or in all cells of a particular cell lineage, mosaic models are based on conditional gene knockout techniques that circumvent the lethality caused by global loss of gene function. Furthermore, mosaic analysis provides the opportunity to directly compare the phenotypes of mutant cells with their neighboring WT cells in the same animal. To facilitate the analysis of genetic mosaic animals and examine the mutant clones at high anatomical resolution, many contemporary mosaic systems couple gene knockout to simultaneous labeling with a fluorescent marker that enables one to distinguish and track the mutant and WT cells. Several methods have been employed to create such mosaic animal models. InDrosophila, the mosaic analysis with repressible cell marker system allows selective labeling of homozygous mutant cells following Flp recombinase-induced targeted mitotic recombination to analyze phenotypic changes resulting from gene inactivation in high resolution during Drosophila development and neurogenesis (6). In mice, a similar approach was used to engineer the MADM (mosaic analysis with double markers) system, which makes use of Cre/loxP-directed interchromosomal recombination during mitosis to generate uniquely labeled homozygous mutant or WT cells in a heterozygous background. As the null allele resides on the same chromosome as the engineered fluorescent reporter, MADM allows extremely tight coupling of the two events—gene knockout and fluorescent labeling of mutant clones (7). However, the MADM system has a number of limitations. Given that gene knockout is