Aneuploid genomes, characterized by unbalanced chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug-resistance of pathogenic fungi. The phenotypic diversity resulting from karyotypic diversity endows the cell population superior adaptability. We show here, using a combination of experimental data and a general statistical model, that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression. Such scaling likely explains the challenge of treating aneuploidy diseases with a single stress-inducing agent. Instead, we propose the design of an “evolutionary trap” (ET) targeting both karyotypic diversity and fitness. This strategy entails a selective condition “channeling” a karyotypically divergent population into one with a predominant and predictably-drugable karyotypic feature. We provide a proof-of-principle case in budding yeast and demonstrate the potential efficacy of this strategy toward aneuploidy-based azole resistance in Candida albicans. By analyzing existing pharmacogenomics data, we propose the potential design of an ET against glioblastoma.
Aneuploidy, the state of having a chromosome number different from a multiple of the haploid number, has been associated with diseases and developmental disorders. The role of aneuploidy in human disease pathology, especially in cancer, has been a subject of much attention and debate over the last century due to the intrinsic complexity of the phenomena and experimental challenges. Over the last decade, yeast has been an invaluable model for driving discoveries about the genetic and molecular aspects of aneuploidy. The understanding of aneuploidy has been significantly improved owing to the methods for selectively generating aneuploid yeast strains without causing other genetic changes, techniques for detecting aneuploidy, and cutting-edge genetics and ‘omics’ approaches. In this review, we discuss the contribution of studies in yeast to current knowledge about aneuploidy. Special emphasis is placed on experimental features which make yeast a simpler and efficient model to investigate the complex questions in the field of aneuploidy.
Errors in mitosis are a primary cause of chromosome instability (CIN), generating aneuploid progeny cells. Whereas a variety of factors can influence CIN, under most conditions mitotic errors are rare events that have been difficult to measure accurately. Here we report a green fluorescent protein−based quantitative chromosome transmission fidelity (qCTF) assay in budding yeast that allows sensitive and quantitative detection of CIN and can be easily adapted to high-throughput analysis. Using the qCTF assay, we performed genome-wide quantitative profiling of genes that affect CIN in a dosage-dependent manner and identified genes that elevate CIN when either increased (icCIN) or decreased in copy number (dcCIN). Unexpectedly, qCTF screening also revealed genes whose change in copy number quantitatively suppress CIN, suggesting that the basal error rate of the wild-type genome is not minimized, but rather, may have evolved toward an optimal level that balances both stability and low-level karyotype variation for evolutionary adaptation.
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