The aneuploidy paradox: costs and benefits of an incorrect karyotype

Abstract

Aneuploidy has a paradoxical effect on cell proliferation. In all normal cells analyzed to date, aneuploidy has been found to decrease the rate of cell proliferation. Yet, aneuploidy is also a hallmark of cancer, a disease of enhanced proliferative capacity, and aneuploid cells are frequently recovered following the experimental evolution of microorganisms. Thus, in certain contexts, aneuploidy might also have growth-advantageous properties. New models of aneuploidy and chromosomal instability have shed light on the diverse effects that karyotypic imbalances have on cellular phenotypes, and suggest novel ways of understanding the role of aneuploidy in development and disease.

Figure 1. Cellular and organismal fitness vary according to the deviation from euploidy

A. A model of the effect of ploidy on cell fitness. Cells with balanced sets of all chromosomes are generally healthy, though haploid and polyploid cells are moderately less fit than diploid cells. As cells move away from euploidy, fitness decreases, and greater karyotypic imbalances typically cause more severe phenotypes. Note that transformed cells are able to tolerate a high degree of aneuploidy via mechanisms which are largely unknown. B. The survival in utero of trisomic mouse embryos correlates with the number of genes encoded by the additional chromosome. A linear correlation is plotted against the data (figure adapted from [45]). C. The cell cycle delay in aneuploid yeast strains correlates with the number of open reading frames encoded by the additional chromosome. A linear correlation is plotted against the data (figure adapted from [32]).

Figure 2. Consequences of changes in gene copy number

A. An increased dosage of a single gene, such as a rate-limiting enzyme, can increase a cellular pathway’s output or function. B. Altered gene dosage can interfere with the function of stoichiometry-sensitive complexes. C. Protein-protein interactions depend on the concentration of each binding partner. Altered expression of some proteins, such as signal-transduction kinases, may cause promiscuous molecular interactions which alter cellular phenotypes. D. Many proteins require chaperones to fold correctly. If aneuploidy overwhelms cellular chaperones, then misfolded proteins which escape chaperone-dependent folding may form insoluble and potentially cytotoxic aggregates. It is also possible that other essential clients of these chaperones remain unfolded. E. Quality-control mechanisms, including the ubiquitin-proteasome pathway, ensure that misfolded or improperly expressed proteins are rapidly turned over. Regulated protein degradation is also utilized to trigger various cellular programs, including cell cycle progression. The overabundance of certain proteins may interfere with the folding or turnover of other client proteins.