Whole genome doubling (WGD) generates genetically unstable tetraploid cells that fuel tumorigenesis. Cells that undergo WGD must acquire adaptive characteristics to accommodate their tetraploid state, and these adaptations may confer unique vulnerabilities that can be exploited therapeutically. We analyzed the genomes of ~9,700 primary human cancer samples to uncover genetic alterations that are specifically enriched in WGD+ cancer cells. Through integrating our genetic analysis with gene essentiality data acquired from Project Achilles, we identified gene dependencies in WGD+ cells. Moreover, we identified genes that are essential for the viability of WGD+ cancer cells, but non-essential to non-transformed diploid cells. We demonstrated that the gene encoding for the mitotic kinesin KIF18A is dispensable for mitosis in diploid cells, but becomes critical for accurate chromosome segregation and viability in WGD+ cells, making it an attractive drug target. Collectively, this work revealed new strategies to specifically target WGD+ cancer cells, namely targeting the gene KIF18A, while sparing the normal diploid cells from which they arise. / 2022-06-04T00:00:00Z

The breadth of genetic diversity in the mammalian immune response stands out amongst the ubiquity of variation seen in the genome, evidence that microbial infections have been a major driver of evolution. As technology has facilitated an understanding of the etiology of immunological diversity, so too has it enabled the assessment of its varied functions. Functional genomics, with its ability to assess both cause and effect, has revolutionized our understanding of fundamental biological phenomena and recalibrated our hypotheses. We build upon the model of host immunity established by rare genetic variants that are causative of immunodeficiencies, but that incompletely consider the complexities of the genome. To expand our understanding, we performed a series of forward genetic screens to identify regulators of distinct functions of the innate immune system. Our studies discovered genes with novel functions in antigen presentation and immunoregulation, including several involved in central metabolism. Studies in macrophages and dendritic cells identified mitochondrial respiration as a positive regulator of the interferon-gamma response, and cells incapable of respiration failed to activate T cells. Notably, human mutations in several of these genes are responsible for immune dysfunction. In summary, this work uses new methods in genetic engineering to systematically assess the regulation of innate immunity. Our results suggest that variation in these regulatory pathways is likely to alter immunity in states of health and disease. Thus, our work validates a new approach to identify candidate genes relevant to immune dysfunction.

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