Aneuploidy as the large adaptive mutation: Mechanism and theory


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Rong Li1
1Johns Hopkins University School of Medicine

Abstract

Aneuploidy, the state of having unequal number of chromosomes, is a hallmark of cancer and pathogenic eukaryotic microbes. As a result of the altered chromosome stoichiometry, the expression of hundreds to thousands of genes is altered in any given aneuploid genome compared to the euploid genome, producing drastic changes in cellular phenotypes under diverse growth conditions. Under stressful conditions, elevated mitotic error rates result in aneuploid cell populations with diverse chromosome stoichiometry. The karyotypic heterogeneity gives rise to phenotypic variability, the degree of which increases with overall fitness decline of the population. The combination of phenotypic variation and selection fuels the rapid emergence of stress-resistant variants. Evidence suggests that this chromosome-based adaptive mechanism is prevalent in cancer and eukaryotic microbes for their pathogenesis and drug resistance. Therapies against these diseases must therefore not only target the fitness of disease-causing cells but also effectively manage these cells’ evolutionary potential due to chromosome instability and aneuploidy.