New insights into the troubles of aneuploidy

Abstract

Deviation from a balanced genome by either gain or loss of entire chromosomes is generally tolerated poorly in all eukaryotic systems studied to date. Errors in mitotic or meiotic cell division lead to aneuploidy, which places a burden of additional or insufficient gene products from the missegregated chromosomes on the daughter cells. The burden of aneuploidy often manifests itself as impaired fitness of individual cells and whole organisms, in which abnormal development is also characteristic. However, most human cancers, noted for their rapid growth, also display various levels of aneuploidy. Here we discuss the detrimental, potentially beneficial, and sometimes puzzling effects of aneuploidy on cellular and organismal fitness and tissue function as well as its role in diseases such as cancer and neurodegeneration.

Figure 1

Cell division errors that result in aneuploidy. Mitotic cells mis-segregate one or multiple chromosomes by (a) mutations to the spindle assembly checkpoint pathway, where aberrantly attached chromosomes do not trigger a cell cycle arrest, (b) premature loss of chromatid cohesion, where single chromatids attach to microtubules and are randomly segregated, (c) merotelic attachment, where kinetochores attach to microtubules emanating from both centrosomes, or by (d) transition through a multi-polar spindle. Kinetochores are attached to several centrosomes, which eventually cluster, resulting in merotelic and syntelic attachments. (e) Aneuloidy can also result form mis-segregation of homologous chromosomes during meiosis I (bottom) or sister chromatids in meiosis II (top). “x” denotes any number of mis-segregated chromosomes.

Figure 2

Examples of the effects of aneuploidy on organisms. (a) Aneuploid Arabidopsis thaliana rosettes (right, trisomic for chromosomes 3 and 5) show thinner, distorted leaves in comparison with diploid rosettes (left), from Henry et al. 2010. Tetrasomy IV Drosophila melanogaster wings (b, right) are smaller and more pointed than wild type (left), from Grell 1961. Trisomy 16 (Ts16) mouse embryos (c, right) show a smaller size compared to diploid littermates (left), as well as a variety of developmental abnormalities including nuchal edema, from Williams et al. 2008. “Ts” indicates trisomy and “Tet” indicates tetrasomy.

Figure 3

Laboratory models of aneuploidy. Several methods have been used to create aneuploid yeast strains and mammalian cells. (a) Yeast strains with uneven ploidy produce highly aneuploid meiotic products (spores). (b) Karyogamy defective yeast strains (kar1Δ15) can be used to produce rare chromosome transfers between nuclei during abortive matings by simultaneously selecting for two different markers present on homologous chromosomes. (c) Aneuploid mouse embryos can be generated by relying on meiotic non-disjunctions during gamete formation in male mice with two heterozygous Robertsonian fusion chromosomes (for example the fusions of 11/13 and 13/16 can create sperm with two copies of chromosome 13). When such males are crossed to wild-type females, trisomic embryos are generated. (d) Chromosome transfer by fusion of micro-cell encapsulated chromosomes to recipient cells (Saxon & Stanbridge 1987) can be used to create aneuploid cell lines. “x” denotes any number of mis-segregated chromosomes.

Figure 4

Cellular systems of aneuploidy display growth defects and proteotoxic stress phenotypes. (a) Micro-array DNA content analysis, micro-array gene expression data, and SILAC protein profiling of a haploid budding yeast strain disomic for chromosome V shows transcript and protein levels of chromosome V-encoded genes to be increased by approximately 1.8 fold over wild-type (data from Torres et al. 2007 & Torres et al. 2010a). (b) Growth of aneuploid budding yeast shows a proliferation defect in most aneuploid strains (data from Torres et al. 2007). (c) Increased basal expression of the inducible protein chaperone Hsp72 in trisomic (Ts) MEFs (data from Tang et al. 2011).

Figure 5

Observed characteristics of aneuploidy in (a) yeast and (b) mammalian cells. Purple boxes indicate conditional changes resulting from aneuploidy, while blue boxes indicate observed physiological stresses. See text for details.

Figure 6

Aneuploidy can be beneficial under certain circumstances and could be a useful therapeutic target in the treatment of cancer. (a) An additional copy of the left arm of chromosome 5 confers increased resistance to fluconazole in C. albicans, (data from Selmecki et al. 2009). (b) Some aneuploid budding yeast strains show increased resistance to the microtubule poison benomyl, while others show increased sensitivity (data from Torres et al. 2007). (c) Xenografts of highly aneuploid human colon cancer cells (Aneuploid, SW620 cells) were reduced in size compared to xenografts of near diploid colon cancer cells (Near Diploid, HCT15 cells) after treatment with AICAR and 17-AAG, drugs that preferentially target aneuploid cells (data from Tang et al. 2011). (d) Spectral Karyotype Analysis of the pancreatic cell line Capan-2, (left) (data from Sirivatanauksorn et al. 2001) and aligned chromosomes (right) of same cell (data from http://www.path.cam.ac.uk/~pawefish/index.html).