Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast

Abstract

Aneuploidy, referring here to genome contents characterized by abnormal numbers of chromosomes, has been associated with developmental defects, cancer, and adaptive evolution in experimental organisms1–9. However, it remains unresolved how aneuploidy impacts gene expression and whether aneuploidy could directly bring phenotypic variation and improved fitness over that of euploid counterparts. In this work, we designed a novel scheme to generate, through random meiotic segregation, 38 stable and fully isogenic aneuploid yeast strains with distinct karyotypes and genome contents between 1N and 3N without involving any genetic selection. Through phenotypic profiling under various growth conditions or in the presence of a panel of chemotherapeutic or antifungal drugs, we found that aneuploid strains exhibited diverse growth phenotypes, and some aneuploid strains grew better than euploid control strains under conditions suboptimal for the latter. Using quantitative mass spectrometry-based proteomics, we show that the levels of protein expression largely scale with chromosome copy numbers, following the same trend observed for the transcriptome. These results provide strong evidence that aneuploidy directly impacts gene expression at both the transcriptome and proteome levels and can generate significant phenotypic variation that could bring about fitness gains under diverse conditions. Our findings suggest that the fitness ranking between euploid and aneuploid cells is context- and karyotype-dependent, providing the basis for the notion that aneuploidy can directly underlie phenotypic evolution and cellular adaptation.

Killing cells by targeting mitosis

“…93,94 Other studies, however, suggest that aneuploidy facilitates phenotypic variation in yeast, providing proliferative advantages upon suboptimal conditions. 95 A recent study has shown that small molecules synergize with proteotoxic and energy stress efficiently and specifically antagonize the proliferation of aneuploid cells. 96 All together, these studies suggest that CIN or aneuploidy may be detrimental for cell proliferation and lead to a proliferative stress, resulting in cell cycle arrest or apoptosis (see figure).…”

Chromosomal duplication is a transient evolutionary solution to stress

“…In addition, structural rearrangements of the genome, and in particular chromosomal duplications, that lead to aneuploidy, may offer a simple means to boost expression level (1,2). Indeed, cancer cells often exercise massive genomic duplications, particularly of regions that harbor growth-promoting genes (3).…”

“…Whole genome duplications, too, can offer selective advantage under specific conditions (12), yet genome analysis has suggested that they also survive only under specific conditions (13). Indeed, whole genome and chromosomal duplication constitute crude solutions with significant overheads on the cell that are in part associated with increased copies of DNA, RNA, and proteins (1,2). Duplication of particular chromosomes (i.e., aneuploidy) creates, in addition, a stoichiometric imbalance between gene products (14,15) and promotes further genome destabilizing events (16,17).…”

Constitutive aneuploidy and genomic instability in the single‐celled eukaryote Giardia intestinalis

“…2006; Pavelka et al. 2010). The presence of originally four chromosome sets in Giardia cell can be on one hand a natural prerequisite enabling aneuploidy evolution – the tetraploid cells are generally considered an intermediate stage on route to aneuploidy and cancer (Storchova and Pellman 2004).…”