Aneuploidy underlies a multicellular phenotypic switch

Tan, Zhihao; Hays, Michelle; Cromie, Gareth A.; Jeffery, Eric; Scott, Adrian C.; Ahyong, Vida; Sirr, Amy; Skupin, Alexander; Dudley, Andrew T.

doi:10.1073/pnas.1301047110

Cited by 78 publications

(115 citation statements)

References 49 publications

(56 reference statements)

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“…Other recent studies reveal that unisexual reproduction can generate phenotypic and genotypic diversity de novo, and that much of this diversity is attributable to aneuploidy (Ni et al 2013). Although a prevailing view is that aneuploidy is uniformly deleterious, in fungi, a large number of studies have revealed that aneuploidy promotes adaptive evolutionary trajectories and underlies morphogenic switches (Yona et al 2012;Tan et al 2013). Similar pathways may operate in animals as well, such as the frequent changes in ploidy and aneuploidy observed in hepatocytes (Duncan et al 2010).…”

Section: Monokaryotic Fruiting Resembles Hyphal Sexual Developmentmentioning

confidence: 99%

Sexual Reproduction of Human Fungal Pathogens

Heitman

Carter

Dyer

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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We review here recent advances in our understanding of sexual reproduction in fungal pathogens that commonly infect humans, including Candida albicans, Cryptococcus neoformans/gattii, and Aspergillus fumigatus. Where appropriate or relevant, we introduce findings on other species associated with human infections. In particular, we focus on rapid advances involving genetic, genomic, and population genetic approaches that have reshaped our view of how fungal pathogens evolve. Rather than being asexual, mitotic, and largely clonal, as was thought to be prevalent as recently as a decade ago, we now appreciate that the vast majority of pathogenic fungi have retained extant sexual, or parasexual, cycles. In some examples, sexual and parasexual unions of pathogenic fungi involve closely related individuals, generating diversity in the population but with more restricted recombination than expected from fertile, sexual, outcrossing and recombining populations. In other cases, species and isolates participate in global outcrossing populations with the capacity for considerable levels of gene flow. These findings illustrate general principles of eukaryotic pathogen emergence with relevance for other fungi, parasitic eukaryotic pathogens, and both unicellular and multicellular eukaryotic organisms.

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Section: Monokaryotic Fruiting Resembles Hyphal Sexual Developmentmentioning

confidence: 99%

Sexual Reproduction of Human Fungal Pathogens

Heitman

Carter

Dyer

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…Recently it was suggested that in yeast, aneuploidy may be a "quick fix" to tolerate stress during adaptive evolution since an aneuploidy state was shown to be transient while more "refined" mutations take over the culture (Yona et al 2012). Moreover, changes in aneuploidy can be an "on-off switch" for colony morphological changes (Tan et al 2013).…”

mentioning

confidence: 99%

The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification

et al. 2014

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Gain or loss of chromosomes resulting in aneuploidy can be important factors in cancer and adaptive evolution. Although chromosome gain is a frequent event in eukaryotes, there is limited information on its genetic control. Here we measured the rates of chromosome gain in wild-type yeast and sister chromatid cohesion (SCC) compromised strains. SCC tethers the newly replicated chromatids until anaphase via the cohesin complex. Chromosome gain was measured by selecting and characterizing copper-resistant colonies that emerged due to increased copies of the metallothionein gene CUP1. Although all defective SCC diploid strains exhibited increased rates of chromosome gain, there were 15-fold differences between them. Of all mutants examined, a hypomorphic mutation at the cohesin complex caused the highest rate of chromosome gain while disruption of WPL1, an important regulator of SCC and chromosome condensation, resulted in the smallest increase in chromosome gain. In addition to defects in SCC, yeast cell type contributed significantly to chromosome gain, with the greatest rates observed for homozygous mating-type diploids, followed by heterozygous mating type, and smallest in haploids. In fact, wpl1-deficient haploids did not show any difference in chromosome gain rates compared to wild-type haploids. Genomic analysis of copper-resistant colonies revealed that the "driver" chromosome for which selection was applied could be amplified to over five copies per diploid cell. In addition, an increase in the expected driver chromosome was often accompanied by a gain of a small number of other chromosomes. We suggest that while chromosome gain due to SCC malfunction can have negative effects through gene imbalance, it could also facilitate opportunities for adaptive changes. In multicellular organisms, both factors could lead to somatic diseases including cancer.

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“…In addition, some of the colonies had scalloped edges, a property observed in some colonies derived from aneuploid strains (Jung et al 2011;Tan et al 2013). The possibility of aneuploidy is also suggested by the high frequency of nondisjunction observed for cXII ( Figure 1B).…”

Section: Gross Chromosomal Rearrangements and Ploidy Changes In The Gmentioning

confidence: 75%

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

et al. 2015

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Genomic instability is a common feature found in cancer cells . Accordingly, many tumor suppressor genes identified in familiar cancer syndromes are involved in the maintenance of the stability of the genome during every cell division and are commonly referred to as caretakers. Inactivating mutations and epigenetic silencing of caretakers are thought to be the most important mechanisms that explain cancer-related genome instability. However, little is known of whether transient inactivation of caretaker proteins could trigger genome instability and, if so, what types of instability would occur. In this work, we show that a brief and reversible inactivation, during just one cell cycle, of the key phosphatase Cdc14 in the model organism Saccharomyces cerevisiae is enough to result in diploid cells with multiple gross chromosomal rearrangements and changes in ploidy. Interestingly, we observed that such transient loss yields a characteristic fingerprint whereby trisomies are often found in small-sized chromosomes, and gross chromosome rearrangements, often associated with concomitant loss of heterozygosity, are detected mainly on the ribosomal DNAbearing chromosome XII. Taking into account the key role of Cdc14 in preventing anaphase bridges, resetting replication origins, and controlling spindle dynamics in a well-defined window within anaphase, we speculate that the transient loss of Cdc14 activity causes cells to go through a single mitotic catastrophe with irreversible consequences for the genome stability of the progeny. KEYWORDS Cdc14; Saccharomyces cerevisiae; gross chromosomal rearrangements; aneuploidy; caretaker genes G ENOMIC instability is one of the hallmarks of cancer cells. Many genomic alterations result in gene dose variation including deletions/duplication, gross chromosomal rearrangements (GCRs), and aneuploidy; loss of heterozygosity (LOH) associated with mitotic recombination is also observed (Hanahan and Weinberg 2011). In wild-type cells, specialized mechanisms exist, such as cell cycle checkpoints and DNA repair activities, which suppress genome instability. Genes encoding for proteins that protect cells from cancer-related genomic instability are referred to as caretakers. Many of the tumor suppressor genes identified in familiar cancer-prone syndromes are caretakers. Although caretakers are not directly responsible for the decision of a cell to divide, their loss leads cells to rapidly accumulate genomic aberrations and mutations that potentially result in disorganization of cell division and their subsequent transformation into cancer cells (Kinzler and Vogelstein 1997;van Heemst et al. 2007). For example, mutations in genes involved in DNA repair pathways such as nonhomologous end joining, homologous recombination, mismatch repair, base excision repair, and nucleotide excision repair have been shown to lead to the accumulation of mutations within the genome that significantly increase the risk of carcinogenesis (Negrini et al. 2010; Aguilera and García-Muse 2013 protein (BLM) ac...

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Aneuploidy underlies a multicellular phenotypic switch

Cited by 78 publications

References 49 publications

Sexual Reproduction of Human Fungal Pathogens

Sexual Reproduction of Human Fungal Pathogens

The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces cerevisiae

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