Karyotypic Determinants of Chromosome Instability in Aneuploid Budding Yeast

Zhu, Jin; Pavelka, Norman; Bradford, W. David; Rancati, Giulia; Li, Rong

doi:10.1371/journal.pgen.1002719

Cited by 129 publications

(146 citation statements)

References 40 publications

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“…Chromosomes also vary in stability when in aneuploid states (31). With our limited number of observed events, the distribution of whole-chromosomal copy number gains appeared random across chromosomes (Poisson distribution, P = 0.17, G test).…”

Section: Resultsmentioning

confidence: 82%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

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

397

444

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Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae.neighbor-dependent mutation rate | strongly deleterious mutation S pontaneous mutations are the source of all genetic variation in nature. The rate of emergence of new mutations and the relative proportions of advantageous, neutral, and deleterious mutations are key determinants in how species evolve and adapt to new selective challenges. Unfortunately, our knowledge of the properties of spontaneous mutations remains incomplete primarily due to the difficulty of observing large enough numbers of mutational events in an unbiased way.Analyzing patterns of divergence in nonfunctional sequences is a statistically powerful method used to study relative rates of different mutation classes. This method is applicable to most organisms and now can generally be carried out on a genomewide scale. However, this approach relies crucially on the assumption that mutations in certain regions, such as pseudogenes or fourfold degenerate codon positions, are not affected by selection and are thus reliable approximations of true mutation rate. It is now becoming apparent that selection or selectionlike processes, such as biased gene conversion, are acting even at these sequences and can substantially bias the observed patterns (1-5).Studies focusing on mutations in reporter genes use a more restrictive method that can be applied only in model organisms. In some cases, such reporter genes can be placed genome-wide and thus provide estimates of genomic variation in mutation rates. However, this approach is limited by the inability to detect mutations without a visible phenotype and thus ...

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Section: Resultsmentioning

confidence: 82%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

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

397

444

View full text Add to dashboard Cite

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“…Triploid cells induced to undergo meiosis produce highly aneuploid progeny with karyotypes ranging from diploid to highly aneuploid (St Charles et al 2010). The majority of the aneuploid progeny is inviable (Parry and Cox 1970), but some genetically unstable aneuploid strains can be obtained (Sheltzer et al 2011;Zhu et al 2012). As colony formation is a prerequisite for the analysis, we were only able to analyze those aneuploids that were healthy enough to form colonies.…”

Section: Disomic Yeast Strains Harbor a Higher Load Of Endogenous Promentioning

confidence: 99%

Aneuploidy causes proteotoxic stress in yeast

2012

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Gains or losses of entire chromosomes lead to aneuploidy, a condition tolerated poorly in all eukaryotes analyzed to date. How aneuploidy affects organismal and cellular physiology is poorly understood. We found that aneuploid budding yeast cells are under proteotoxic stress. Aneuploid strains are prone to aggregation of endogenous proteins as well as of ectopically expressed hard-to-fold proteins such as those containing polyglutamine (polyQ) stretches. Protein aggregate formation in aneuploid yeast strains is likely due to limiting protein quality-control systems, since the proteasome and at least one chaperone family, Hsp90, are compromised in many aneuploid strains. The link between aneuploidy and the formation and persistence of protein aggregates could have important implications for diseases such as cancer and neurodegeneration.

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“…Gross changes in chromosome number including polyploidy have been shown to deregulate the genome in yeast (Storchova et al 2006) and mammalian (Li et al 1997) systems. In addition, studies in yeast (Sheltzer et al 2011, Zhu et al 2012) and more recently in human cells (Nicholson et al 2015, Passerini et al 2016 have shown that the presence of a single extra chromosome appears to be sufficient to initiate further chromosome missegregation events, with mechanisms underlying this beginning to be elucidated. In some cases, aneuploidydriven CIN appears to depend upon deregulated gene expression of specific genes (Nicholson et al 2015), and as such may depend upon the identity of the chromosome in aneuploidy.…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

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Karyotypic Determinants of Chromosome Instability in Aneuploid Budding Yeast

Cited by 129 publications

References 40 publications

Precise estimates of mutation rate and spectrum in yeast

Precise estimates of mutation rate and spectrum in yeast

Aneuploidy causes proteotoxic stress in yeast

Role of chromosomal instability in cancer progression

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