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How to Count Chromosomes in a Cell: an Overview of Current and Novel Technologies

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How to Count Chromosomes in a Cell: an Overview of Current and Novel Technologies Prospects & Overviews How to count chromosomes in a cell: An overview of current and novel technologies Bjorn Bakker, Hilda van den Bos, Peter M. Lansdorp and Floris Foijerà Aneuploidy, an aberrant number of chromosomes in a cell, Introduction is a feature of several syndromes associated with cognitive and developmental defects. In addition, aneuploidy is A brief history of aneuploidy considered a hallmark of cancer cells and has been During each cell division, all chromosomes are duplicated and Methods, Models & Techniques suggested to play a role in neurodegenerative disease. To distributed equally over the two emerging daughter cells. better understand the relationship between aneuploidy Various checkpoints help to ensure that chromosome segrega- and disease, various methods to measure the chromo- tion occurs accurately during the cell cycle. When errors occur during mitosis, cells can end up with an abnormal number of some numbers in cells have been developed, each with chromosomes, a state called aneuploidy. The relationship their own advantages and limitations. While some methods between aneuploidy and disease was first proposed early in the rely on dividing cells and thus bias aneuploidy rates to that 20th century by Theodor Boveri. By injecting multiple sperm population, other, more unbiased methods can only detect cells into sea urchin embryos, he showed that an increased the average aneuploidy rates in a cell population, cloaking chromosome content can result in abnormal development or death [1–3]. From the mid-20th century on, a large number of cell-to-cell heterogeneity. Furthermore, some techniques assays have been developed to quantify aneuploidy, which are more prone to technical artefacts, which can result in allowed linking various human syndromes and diseases to over- or underestimation of aneuploidy rates. In this aneuploidy. review, we provide an overview of several ‘‘traditional’’ Most systemic aneuploidies for human autosomes are karyotyping methods as well as the latest high throughput incompatible with embryonic development, and those that next generation sequencing karyotyping protocols with are viable (trisomies for chromosomes 13, 18, and 21) all result in a wide range of developmental and cognitive defects. The most their respective advantages and disadvantages. well-known aneuploidy-related syndrome is Down’s syndrome, which was first linked to a trisomy for chromosome 21 in 1959 [4]. Keywords: One year later, Edward’s syndrome (trisomy 18) and Patau’s .aneuploidy; chromosomal instability; karyotyping; next syndrome (trisomy 13) were uncovered as congenital syndromes generation sequencing caused by chromosomal copy number changes [5, 6]. Collec- tively, these syndromes demonstrate the severe consequences of DOI 10.1002/bies.201400218 an additional chromosome at the organismal level. European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Aneuploidy accelerates cancer *Corresponding author: Cancer cells frequently exhibit errors in chromosome segrega- Floris Foijer E-mail: [email protected] tion, resulting in chromosomal imbalances [7]. In fact, roughly two out of three human tumors display aneuploidy [8, 9], and Abbreviations: genomic instability is considered to be a major enabling CGH, comparative genomic hybridization; CNV, copy number variation; FISH, characteristic of malignant transformation [10]. Paradoxically, fluorescence in situ hybridization; MCB, multicolor banding; M-FISH, multiplex FISH; SAC, spindle assembly checkpoint; SKY, spectral studies in aneuploid yeast strains and mouse embryonic karyotyping. fibroblasts have shown that aneuploidy reduces cell fitness 570 www.bioessays-journal.com Bioessays 37: 570–577, ß 2015 WILEY Periodicals, Inc. ....Prospects & Overviews B. Bakker et al. and leads to growth defects, as well as metabolic and aggregates and thus neurodegeneration. However, most of proteotoxic stresses [11–13]. It is therefore remarkable that these studies relied on noisy techniques to quantify aneuploidy aneuploid cancer cells can proliferate in vivo despite aneu- in post-mitotic cells (e.g. in situ interphase FISH), which might Methods, Models & Techniques ploidy-induced stress [14], and this suggests that aneuploid have resulted in over- or underestimation of the actual cancer cells somehow adjust their physiology to cope with the aneuploidy in neurons. Therefore, improved methods to detrimental consequences of aneuploidy. measure the number of chromosomes in non-dividing cells While structural genomic rearrangements (local amplifi- are a necessity to further substantiate the role of aneuploidy in cations/deletions and translocations) in cancer have been neurodegenerative disease. studied in great detail, we only begin to understand the precise role of whole-chromosome aberrations [15]. One disease that links cancer to aneuploidy is the mosaic Accurate karyotyping tools are needed variegated aneuploidy syndrome (MVA). MVA is caused by mutations in the spindle assembly checkpoint (SAC) gene As argued above, accurate karyotyping is a crucial tool to BUB1B. The SAC monitors kinetochore–microtubule attach- better understand the role of aneuploidy in disease. While ment during metaphase, and blocks anaphase onset until all various karyotyping methods have been developed since the chromosomes are properly aligned and attached to micro- late 1950s, their accuracy and reliability differ. Importantly, tubules, thus preventing chromosome missegregation and each karyotyping method is limited as to which cytogenetic consequent aneuploidy [16]. MVA patients are indeed abnormalities can be detected, and in which cell type (e.g. characterized by random aneuploidies, suffer from devel- proliferating vs. post-mitotic). Furthermore, each method is opmental and cognitive defects [17, 18], and are significantly prone to its own technical and biological artefacts that need to more likely to develop pediatric cancers, including rhabdo- be considered. Importantly, few platforms exist that allow for myosarcoma, Wilms tumor, and leukemia [17]. quantifying full karyotypes of non-dividing cells, a type of Mouse models, in which chromosomal instability (CIN) measurement that is becoming increasingly more important in was provoked in vivo by inactivation of SAC genes (reviewed studying the relationship between chromosomal instability extensively elsewhere [19–21]), have been instrumental in and disease. In this review we provide an overview of the most better understanding the link between aneuploidy and cancer. common cytogenetic techniques, along with a number of new Briefly summarized, CIN results in four major phenotypes: (i) methods, and their associated applications and limitations. embryonic lethality when the SAC is fully alleviated in the The first important consideration when selecting a whole organism; (ii) weak tumor predisposition when SAC protocol for karyotyping is the type of cells to be assessed: genes are heterozygously inactivated; (iii) tumor suppression dividing cells or non-dividing cells. While essentially all in some tumor predisposed backgrounds (e.g. knockout of cytogenetic methods can be used to quantify chromosome tumor suppressor genes or exposure to carcinogens); and (iv) copy numbers, some are either restricted to detection of only a premature aging [19–21]. These phenotypes even differ few chromosomes per cell, reducing the resolution of the between in vivo cell lineages: for instance, the basal layer analysis, or fail to detect some types of karyotypic abnormal- in mouse epidermis copes much better with CIN than the hair ities (e.g. balanced translocations), which we will further follicle stem cells that reside in the same tissue [22]. While, discuss below. The detection limits of all of the addressed these data indicate that CIN is an important accelerating factor methods are summarized in Figure 1. in cancer, the next challenge will be to understand how CIN contributes to malignant transformation. For this, we need to faithfully quantify the dynamics of chromosome missegrega- Tools to detect chromosome copy tion in individual tumors, analyses that will heavily depend numbers in dividing cells on improved cytogenetic tools, the topic of this review. Traditional karyotyping and fluorescence in situ hybridization (FISH) Aneuploidy might lead to neurodegeneration Traditional metaphase spread-based karyotyping requires Various studies have suggested that aneuploidy is not unique to cycling cells [33]. For this, cells are arrested in metaphase, cancer cells. For instance, a large fraction of normal mouse [23] using spindle assembly checkpoint poisons such as colcemid, and human [24–26] neurons appear to be aneuploid. Strikingly, to simplify chromosome counting. Cells are then incubated in these aneuploid neurons seem to be fully functional, because a hypotonic solution followed by fixation. The fixed cells they are integrated into the brain circuitry and can be are then dropped onto a microscope slide to spread the activated [27]. While the levels of aneuploidy in healthy brain chromosomes, and stained with Giemsa or DAPI to visualize are still under debate [28–30], aneuploidy in the brain could the chromosomes. This protocol allows for the detection of play a role in neurodegeneration [31]. For instance, patients whole chromosome copy number gains and losses, large suffering from Alzheimer’s Disease (AD) exhibit frequent copy amplifications, insertions, deletions, inversions, transloca-
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