A strategy for constructing aneuploid yeast strains by transient nondisjunction of a target chromosome

Anders, Kirk R.; Kudrna, Julie R; Keller, Kirstie E; Kinghorn, BreAnna; Miller, Elizabeth M.; Pauw, Daniel; Peck, Anders T; Shellooe, Christopher E; Strong, I

doi:10.1186/1471-2156-10-36

Cited by 46 publications

(52 citation statements)

References 41 publications

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“…Last, although many aneuploidy-induced phenotypes appear to be independent of the identity of the extra chromosome, copy number changes of a few particularly dosage-sensitive genes may have direct consequences. For instance, budding yeast cells are exquisitely sensitive to tubulin levels, and a single extra copy of beta-tubulin causes the lethality of disome VI (13,36,37). We posit that these factors contribute to limit the proliferative capacity of aneuploid cells, thereby resulting in the common downregulation of cell cycle and ribosomal genes.…”

Section: Discussionmentioning

confidence: 94%

Transcriptional consequences of aneuploidy

Sheltzer

Torres

Dunham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

261

265

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Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a metaanalysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, and genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical antiproliferative response that must be overcome before transformation.stress response | trisomy | chromosomal instability E ukaryotic organisms have evolved elaborate mechanisms that ensure that chromosomes are partitioned equally during cell division (1). Aberrant segregation events can result in aneuploidy, a condition in which cells acquire a karyotype that is not a whole-number multiple of the haploid complement. In humans, aneuploidy is the leading cause of spontaneous abortions and developmental disabilities, and aneuploid karyotypes are observed in greater than 90% of solid tumors (2-4). Thus, understanding the consequences of aneuploidy has broad relevance for the study of mammalian development and cancer.The cause of aneuploidy-induced syndromes remains an open question. For instance, it has been hypothesized that the phenotypes associated with Down syndrome (trisomy 21) are caused by the triplication of a small set of genes that lie within a 5.4-Mb "Down syndrome critical region" on chromosome 21 (5, 6). However, evidence from mouse models suggest that this region is not sufficient to recapitulate Down syndrome-like phenotypes, and genetic mapping of partially trisomic individuals has revealed that numerous regions of chromosome 21 affect clinical presentation (7-9). Alternately, changes in gene dosage across an entire chromosome might have additive effects on organismal development (10). It has been observed that the three human trisomies that survive until birth (trisomy 13, 18, and 21) have the fewest proteincoding genes on them, implying that these karyotypes can be tolerated in utero because they have the lowest net dosage imbalances (11). However, the consequences of copy number variation range from benign to extremely deleterious, demonstrating that different genes exhibit varying levels of dosage sensitivity (12).To examine the consequences of aneuploidy, we have previously constructed and analyzed a series of haploid budding yeast strains and mouse embryonic fibroblasts (MEFs) that carry single extra chromosomes (13-17). These aneuploid cells...

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Section: Discussionmentioning

confidence: 94%

Transcriptional consequences of aneuploidy

Sheltzer

Torres

Dunham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

261

265

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“…Strains with conditional centromeres were constructed using a PCR-based method (Anders et al, 2009; Longtine et al, 1998). Briefly, the conditional centromere construct was amplified from plasmid p1888 (see Table S5) using primers designed to target the conditional centromere construct to a particular chromosome (see Table S4).…”

Section: Star Methodsmentioning

confidence: 99%

“…Studies of aneuploidy to date have largely been confined to cell lines with chromosome gains (Stingele et al, 2012; Torres et al, 2007; Williams et al, 2008) because cell lines with chromosome losses are difficult to maintain (Alvaro et al, 2006; Anders et al, 2009). Thus, it is not known how chromosome loss impacts cell physiology or whether monosomic cells exhibit the same aneuploidy-associated stresses that are widespread among cells with chromosome gains.…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy Causes Non-genetic Individuality

Beach

Ricci-Tam

Brennan

et al. 2017

Cell

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SUMMARY Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down Syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.

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“…Replacement of the native centromeres of chromosomes with a conditional centromere was adapted from a protocol using a well-characterized construct (33) that has been modified further (32). Briefly, galactose induction was performed by first growing the strains in YP-Raffinose for 48 h at 30°C to saturation and diluting 1:2,000 for growth overnight at 30°C.…”

Section: Isolation Of Smooth Colony Strainsmentioning

confidence: 99%

Aneuploidy underlies a multicellular phenotypic switch

Tan

Hays

Cromie

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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Although microorganisms are traditionally used to investigate unicellular processes, the yeast Saccharomyces cerevisiae has the ability to form colonies with highly complex, multicellular structures. Colonies with the "fluffy" morphology have properties reminiscent of bacterial biofilms and are easily distinguished from the "smooth" colonies typically formed by laboratory strains. We have identified strains that are able to reversibly toggle between the fluffy and smooth colony-forming states. Using a combination of flow cytometry and high-throughput restriction-site associated DNA tag sequencing, we show that this switch is correlated with a change in chromosomal copy number. Furthermore, the gain of a single chromosome is sufficient to switch a strain from the fluffy to the smooth state, and its subsequent loss to revert the strain back to the fluffy state. Because copy number imbalance of six of the 16 S. cerevisiae chromosomes and even a single gene can modulate the switch, our results support the hypothesis that the state switch is produced by dosage-sensitive genes, rather than a general response to altered DNA content. These findings add a complex, multicellular phenotype to the list of molecular and cellular traits known to be altered by aneuploidy and suggest that chromosome missegregation can provide a quick, heritable, and reversible mechanism by which organisms can toggle between phenotypes. colony morphology | copy number variation | phenotypic switching | bet-hedging

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A strategy for constructing aneuploid yeast strains by transient nondisjunction of a target chromosome

Cited by 46 publications

References 41 publications

Transcriptional consequences of aneuploidy

Transcriptional consequences of aneuploidy

Aneuploidy Causes Non-genetic Individuality

Aneuploidy underlies a multicellular phenotypic switch

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