Aneuploidy Causes Non-genetic Individuality

Abstract

SUMMARY Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down Syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

“…Chromosome copy number alterations have been proposed to drive disease by modulating the dosage of cancer driver genes (Davoli et al, 2013). Aneuploidy also endows cells with phenotypic variability (Beach et al, 2017; Chen et al, 2015; Rutledge et al, 2016), which could help facilitate metastasis or resistance to therapeutic interventions. Indeed aneuploidy has been shown to be associated with metastatic behavior, resistance to chemotherapy and poor patient outcome (Bakhoum et al, 2011; Heilig et al, 2009; Lee et al, 2011; Walther et al, 2008).…”

Aneuploidy in yeast: Segregation error or adaptation mechanism?

“…For instance, several experimental evolution studies using yeast (Chen, Bradford, Seidel, & Li, ; Gorter et al, ; Pavelka et al, ; Selmecki et al, ; Selmecki, Dulmage, Cowen, Anderson, & Berman, ; Yona et al, ) and other pathogenic fungi such as Candida albicans (Selmecki, Forche, & Berman, ) and Cryptococcus neoformans (Gerstein et al, ) suggest that aneuploidy can confer increased stress and drug resistance. This is likely due to the variation in gene dosage caused by the loss or gain of chromosomes causing higher phenotypic diversity or pathogenic potential in aneuploid microbial populations (Bader et al, ; Beach et al, ; Gerstein et al, ; Hirakawa, Chyou, Huang, Slan, & Bennett, ; Hu et al, ; Ni et al, ).…”

Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers

“…Excessive centrosomes in cancer cells lead to multipolar spindle assembly, causing asymmetric chromosome segregation and aneuploidy in daughter cells after multipolar cell division (4,11–13). This contributes to tumor initiation or evolution (14–19) by increasing the proliferative advantage of some cellular populations through the loss of a chromosome domain that contains tumor suppressor genes or by gain of a region containing oncogenes (8,20–23). The appearance of supernumerary centrosomes is associated with tumor progression and an unfavorable clinical outcome (7,11).…”