REVIEW ARTICLE | FOCUS https://doi.org/10.1038/s41556-018-0243-8REVIEW ARTICLE | FOCUS https://doi.org/10.1038/s41556-018-0243-8 The diverse consequences of aneuploidy Narendra Kumar Chunduri and Zuzana Storchová * Aneuploidy, or imbalanced chromosome number, has profound effects on eukaryotic cells. In humans, aneuploidy is associated with various pathologies, including cancer, which suggests that it mediates a proliferative advantage under these conditions. Here, we discuss physiological changes triggered by aneuploidy, such as altered cell growth, transcriptional changes, proteo- toxic stress, genomic instability and response to interferons, and how cancer cells adapt to the changing aneuploid genome. ost eukaryotic organisms have their genome neatly orga- Mechanisms leading to aneuploidy have been thoroughly charac- nized in chromosomes, with characteristic number, size terized and there are several excellent reviews that summarize these Mand sequences that define the species. Yet, exceptions to discoveries30–32. Briefly, whole-chromosome aneuploidy is caused this so called euploidy (from ancient Greek eu—true, good) can by errors during chromosome segregation that result from incor- be found, such as aneuploidy that is characterized by copy num- rect attachments of the spindle microtubules to the kinetochore, a ber changes of whole chromosomes or chromosomal segments. proteinaceous complex that assembles at the centromeric region of Aneuploidy can be tolerated and occurs naturally in some uni- every chromosome33. The kinetochore enables the formation of a cellular eukaryotes, such as budding yeast, the pathogenic fungi stable attachment to the microtubules. Correct attachments create Candida albicans or parasites from genus Giardia, as well as in sev- tension between the spindle-generated forces and the forces gen- eral multicellular species1–6. In most contexts, whole-chromosome erated by sister chromatid cohesion that holds the sisters together aneuploidy has profound effects on cellular physiology. In humans, (Fig. 1a). Lack of attachments is recognized by the spindle assem- aneuploidy of autosomes is detrimental and only a few exceptions bly checkpoint (SAC) and corrected, while the activated checkpoint (trisomy of chromosomes 13, 18 and 21) are compatible with sur- delays anaphase onset until all chromosomes are properly attached34 vival, although accompanied with various pathologies. (Fig. 1b–d). Tension-less attachments are unstable and disassemble Aneuploidy is frequent in cancer, in which it is often associated to allow error correction35. Chromosome missegregation occurs due with a more complex phenotype called chromosomal instability to mutations or sporadic defects that impair mitotic spindle function, (CIN). CIN cells gain and lose chromosomes as they divide, thereby kinetochore structure, sister chromatid cohesion or SAC (Fig. 1e–g). creating progeny with variable aneuploid karyotypes. CIN and aneu- Mutations in genes regulating the chromosome segregation fidelity ploidy in cancer correlate with metastasis, resistance to drugs and in cancers are rather rare, but changes in their expression levels are disease progression7–14. Yet, exactly how aneuploidy affects eukary- frequently observed36,37. In addition, mutations in well-known onco- otic cells and how it contributes to tumorigenesis are only partially genes and tumour suppressor genes can trigger segregation errors. understood. Recent years have brought novel insights thanks to the Changes in transcriptional regulation of Rb-E2F and Ras affect the establishment of a wide palette of models of whole-chromosome fidelity of chromosome segregation by enhancing the expression aneuploidy. Moreover, next-generation sequencing and the broad of SAC genes or by causing sister chromatid cohesion defects38–41. use of -omics approaches have provided extensive data on chromo- Genes previously not linked to chromosome segregation may also some copy number changes and their consequences. In this Review, induce aneuploidy, as shown by two recent genetic screens42,43. we discuss recent insights into how aneuploidy affects cells and Furthermore, surrounding tissue may influence the occurrence organisms and relate these to findings from recent cancer analyses. of chromosome segregation defects, as a recent study demon- strated that epithelial tissue architecture promotes chromosome Occurrence and causes of aneuploidy segregation fidelity44. Whole-chromosomal aneuploidy arises from defects during chromo- Chromosome missegregation, particularly when coupled with some segregation in meiosis or mitosis. In particular, mammalian chromosome breakage, is often followed by irreversible cell cycle female meiosis is highly erroneous, resulting in aneuploid gametes arrest, impaired proliferation or cell death45–50. Thus, accumula- and subsequently in whole-organismal aneuploidy15,16. Early embryos tion of aneuploid cells in a tissue is affected not only by mutations often accumulate aneuploid cells due to mitotic errors, thus creat- that increase mitotic errors but also by those that facilitate survival ing a mosaic of euploid and aneuploid cells17,18. Later, the aneuploid immediately after abnormal mitosis47,51,52 and those that increase cells are removed from embryonic tissues by senescence or apoptosis, tolerance to stresses induced by aneuploidy53–55. Although these or become outgrown by euploid cells that proliferate better19,20. The types of mutation might be difficult to find experimentally, their frequency of aneuploid cells in mammalian tissue is difficult to esti- identification will help to understand how aneuploid cells arise and mate: whereas single-cell sequencing reveals less than 1% of aneuploid propagate in cancer. neurons and fibroblasts, the same tissues show frequent abnormal chromosome counts when evaluated by fluorescence in situ hybrid- Models of whole-chromosome aneuploidy ization21–24. For example, fluorescence in situ hybridization analysis of There are two main approaches to study aneuploidy and its cellular hepatocytes shows aneuploidy in as many as 50% of the cells, whereas consequences. First, acute aneuploidy can be induced by mutating single-cell sequencing indicates 4%21,25. Tissue-specific differences in genes involved in chromosome segregation or by impairing mito- aneuploidy were found also in other species, but the causes remain sis by adding inhibitors to cell cultures, specific tissues or even the unclear26. Importantly, aneuploidy is found in most malignant neopla- whole organism49,56–60 (Fig. 2a). This approach generates heteroge- sia, with occurrence depending on the cancer type and ranging up to neous aneuploid populations and allows the study of the immediate 90% in solid tumours and 35–60% in haematopoietic cancers27–29. cellular response to chromosome missegregation, that is, the acute Department of Molecular Genetics, TU Kaiserslautern, Kaiserslautern, Germany. *e-mail: [email protected] 54 NATURE CELL BIOLOGY | VOL 21 | JANUARY 2019 | 54–62 | www.nature.com/naturecellbiology FOCUS | REVIEW ARTICLE NATURE CELL BIOLOGY FOCUShttps://doi.org/10.1038/s41556-018-0243-8 | REVIEW ARTICLE a Metaphase Prometaphase Amphitelic attachment Anaphase SAC SAC b c d Absence of attachment Monotelic attachment Syntelic attachment SAC SAC SAC ef g Merotelic attachment Premature loss of sister Multipolar spindle chromatid cohesion SAC Kinetochore Microtubule Centrosome Cohesin SAC Engaged SAC SAC Satisfied SAC Fig. 1 | Routes to whole-chromosome aneuploidy. a, The newly replicated sister chromatids that are held together by sister chromatid cohesion attach to microtubules via their respective kinetochores. During metaphase, each kinetochore has to attach to microtubules emanating from one spindle pole (centrosome); this amphitelic bipolar attachment results in a tension between sisters held together by sister chromatid cohesion and the pulling forces of the microtubules. Bipolar attachments of all chromatid pairs silence the checkpoint. In anaphase, the sister chromatid cohesion is dissolved and the chromosomes segregate to the opposite spindle poles. b, Lack of microtubule–kinetochore attachment. c, Monotelic attachment—that is, lack of attachment by one of the sister chromatids. Unattached kinetochores in b and c are recognized by the SAC and the progress to anaphase is halted until the error is corrected. d, Syntelic attachment—that is, when both sisters are attached to the same pole. This type of attachment is highly unstable and disassembles; the empty kinetochore is then recognized by the SAC. The events described in b–d lead to chromosome missegregation if uncorrected, for instance, due to a SAC defect. e, Merotelic attachment—that is, when one sister kinetochore attaches to microtubules emanating from both centrosomes. This attachment usually generates enough tension to remain stable and therefore escapes the SAC. Merotelically attached chromatids often lag during anaphase and may become missegregated. f, Lack of sister chromatid cohesion interferes with the establishment of bipolar attachment. g, Multipolar spindles owing to supernumerary centrosome lead to defective attachments and frequent merotely, particularly when the extra centrosomes cluster (depicted by connected arrows). Defects in the SAC interfere with error recognition and increase the frequency of missegregation. The arrows depict the direction in which chromosomes are pulled. consequences of aneuploidy. On the downside, the identities and Although the models of acute cellular