Jin Zhu

Rong Li Laboratory

The Yin and Yang of Aneuploidy

Our DNA is packaged into structures called chromosomes. Sophisticated surveillance mechanisms ensure that most cells inside our body have exactly 46 of them. Yet, when things go wrong during the cell division process despite the stringent control measures some cells still can end up with a chromosome number that is not an exact multiple of 23. This condition is defined as aneuploidy and generally considered to be detrimental at a cellular and organismal level. For example, aneuploid yeasts grow slower than their euploid counterparts under standard lab conditions. And people with Down syndrome, which is caused by the presence of an additional copy of chromosome 21, have severe defects in cognitive ability and physical growth. On the other hand, recent studies have shown that part of our brain and liver consist of aneuploid cells. Most interestingly, it has long been known that most solid tumors are aneuploid. Besides, aneuploidy is frequently observed in natural populations of the protozoan parasite Leishmania and the plant-pathogenic fungus Mycosphaerella graminicola. And aneuploidy is also found to be associated with drug resistance in human fungal pathogen Candida albicans.

Taoist philosophy tells us that there are two sides—yin and yang—to everything and that they are interconnected. Is it possible that aneuploidy could be beneficial to a cell that is struggling to survive?

To answer this question, we designed a new isolation method to generate a large collection of relatively stable and fully isogenic aneuploid yeast strains with distinct karyotypes and genome contents falling between that of a haploid and that of a triploid cell.  We subjected this collection to phenotypic profiling under various growth conditions representing either environmental or chemical perturbations. We found that, while under conditions optimized for wild-type cells, the euploid strains grew better than the aneuploid ones, under adverse conditions many aneuploid strains grew far better than the euploid ones.  Interestingly, karyotypic similarity correlated with phenotypic similarity, suggesting that the fitness of any given aneuploid strain under different conditions is mostly determined by its specific set of chromosome copy numbers. Using microarrays and quantitative mass spectrometry-based proteomics, we showed that gene expression levels and protein abundances directly scale with chromosome copy numbers. Taken together, these results indicate that aneuploidy, by directly affecting gene expression at both the transcriptome and the proteome level can generate significant phenotypic variation and bring about fitness gains under conditions suboptimal for euploid cells.These findings provide evidence that aneuploidy as a result of genome instability can drive phenotypic evolution and cellular adaptation.