Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer

Abstract

When cells in our body change their genome and develop into cancer, we blame it on genome instability. When novel species conquer inhospitable environments, we credit it to genome evolution. From a cellular perspective, however, both processes are outcomes of the same fundamental biological properties-genome and pathway plasticity and the natural selection of cells that escape death and acquire growth advantages. Unraveling the consequences of genome plasticity at a cellular level is not only central to the understanding of species evolution but also crucial to deciphering important cell biological problems, such as how cancer cells emerge and how pathogens develop drug resistance. Aside from the well-known role of DNA sequence mutations, recent evidence suggests that changes in DNA copy numbers in the form of segmental or whole-chromosome aneuploidy can bring about large phenotypic variation. Although usually detrimental under conditions suitable for normal proliferation of euploid cells, aneuploidization may be a frequently occurring genetic change that enables pathogens or cancer cells to escape physiological or pharmacological roadblocks.

Figure 1. Effects of aneuploidy on gene expression and phenotype

Schematic representation of several possible mechanisms by which aneuploidy can affect gene expression and give rise to adaptive phenotypes. (A) Direct effect of gene copy number change due to aneuploidy on gene expression level, which in some cases might be sufficient to bring about an adaptive phenotype. (B) Some of the genes directly affected by aneuploidy can have trans-acting effects on the expression of target genes not necessarily residing on the aneuploid chromosomes. In some cases, adaptive phenotypic changes are brought about by such indirect effects. (C) When aneuploidy increases the copy number of more than one gene at a time, changes in the expression of each of the genes can independently and additively converge to influence a cellular phenotype. (D) Changes in the expression of multiple genes on aneuploid chromosomes can synergistically cause large changes in the expression of target genes that are not necessarily carried on aneuploid chromosomes. In some cases, such synergistically-induced changes could give rise to adaptive phenotypes. Chromosomes are represented as grey bars, genes as colored rectangles, gene products as colored circles, trans-acting effects as black arrows and phenotypic effects as green arrows. The hypothetical two-chromosome haploid genome is depicted on the left; the corresponding aneuploid genome (carrying an extra copy of the first chromosome) is shown on the right.

Figure 2. Phenotypic leaps produced by aneuploidy during adaptive walks on a fitness landscape

(A) When a cell (represented by a hiker) is atop or very close to a fitness peak, point mutations with small effects on fitness normally allow the cell to stay in the vicinity of the peak, while large-effect mutations such as aneuploidy typically push the cells towards regions of lower fitness. (B) When a cell is situated in a fitness valley far away from a peak (because of either a physiological growth control mechanism or a strong genetic or environmental perturbation), small-effect mutations rarely bring significant fitness gain in a single step, whereas the large phenotypic leaps brought about by aneuploidy can in some cases bring the cell much closer toward a nearby fitness peak, enabling immediate fitness advantage.