Investigating determinants of aneuploidy toxicity using gene duplication in Saccharomyces cerevisiae
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE263221 | GEO | 2024/05/01
REPOSITORIES: GEO
Similar Datasets
Project description:Aneuploidy, in which cells carry an abnormal chromosome count, is detrimental during development yet common in human cancers; why cells differ in tolerance remains unclear. We mapped the genetic basis of aneuploidy tolerance in wild Saccharomyces cerevisiae versus the sensitive lab strain to Ssd1, an RNA-binding protein involved in translation whose loss recapitulates aneuploidy signatures in laboratory yeast. We find Ssd1 localizes to mitochondria, influences localization of nuclear-encoded mitochondrial mRNAs and/or abundance of the encoded proteins, influences mitochondrial function, and minimizes protein aggregates upon chromosome amplification. Recapitulating ssd1D defects with combinatorial drug treatment selectively targets wild-type aneuploids in multiple strains, suggesting therapeutic approaches. Our work adds to elegant studies done in the sensitized laboratory strain to present a mechanistic understanding of aneuploidy tolerance in eukaryotes.
2020-01-08 | GSE132425 | GEO
Project description:Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions, and allows assessment of the generalizability of laboratory findings. One notable discovery made in Saccharomyces cerevisiae natural isolates is frequent (~20%) aneuploidy – an imbalance in chromosome copy numbers – that appears to contradict the significant fitness costs and transient nature reported for lab-engineered aneuploids. Here, we generated a proteomic resource and merged it with genomic and transcriptomic data for 796 euploid and aneuploid natural isolates. We found that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins, especially protein complex subunits, show reduced expression, yet the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage-compensated, with average protein levels being shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and demonstrates the utility of exploiting the natural diversity of species to reach generalizable molecular insights into complex biological processes. This resource provides the SILAC dataset from this work.
2024-03-13 | PXD048219 | Pride
Project description:Aneuploidy has profound effects on an organism, typically more so than polyploidy, and the basis of this contrast is not fully understood. A dosage series of maize chromosome arm 1L was used to compare relative global gene expression in different types and degrees of aneuploidy to gain insight into how the magnitude of genomic imbalance as well as hypoploidy affect global gene expression. While previously available methods required a selective examination of specific genes, RNA sequencing provides a whole-genome view of gene expression in aneuploids. Most studies of global aneuploid effects have concentrated on trisomics because other types of aneuploids are difficult to produce in most model genetic organisms. The genetic toolkit of maize allows the examination of multiple ploidies and 1-4 doses of chromosome arms. Thus, a detailed examination of expression changes both on the varied chromosome arm and elsewhere in the genome is possible, in both hypoploids and hyperploids, compared with euploid controls. Previous studies observed the inverse trans effect, in which genes not varied in DNA dosage are expressed in a negative relationship to the varied chromosomal region. This response was also the major type of change found globally in this study. It was also found that the effects of aneuploidy are progressive, with more severe aneuploids producing effects of greater magnitude.
2020-02-17 | GSE134936 | GEO
Project description:Recent advancements in genome sequencing have facilitated accessing the natural genetic diversity of species, unveiling hidden genetic traits, clarifying gene functions, and the degree to which laboratory studies can be generalized. One notable discovery is the frequent (~20%) aneuploidy - an imbalance in chromosome copy numbers - in natural Saccharomyces cerevisiae (Sc) isolates, despite the significant fitness costs and transient nature reported for lab-engineered yeast aneuploids. To examine this discrepancy, we adapted a high-throughput proteomic platform to analyze the proteome of 800 diverse yeast isolates. Matching these proteomes to the natural isolates’ genomes, transcriptomes, as well as generating ubiquitinome and protein turnover data for selected isolates, we report that natural and lab-generated aneuploids differ specifically at the proteome. While lab-generated aneuploids attenuate specific proteins – mostly protein complex subunits – and do not alter the average gene dosage provided by chromosome duplications, in natural strains, 70% of proteins encoded on aneuploid chromosomes are attenuated, and protein levels are shifted towards the euploid state chromosome-wide. Our data links chromosome-wide dosage compensation in natural strains to i) genome-wide buffering of gene expression changes manifesting in trans on euploid chromosomes, ii) increased expression of structural components of the ubiquitin proteasome system, and iii) increased global rates of protein turnover. Our results encourage the exploitation of natural diversity of species to understand complex biological processes at the molecular level. This submission contains the raw files for the disomics lab engineered strains, the library used for the analysis and the corresponding DIA-NN report and associated files.
2024-03-11 | PXD044526 | Pride
Project description:Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21; but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results raise major implications for other aneuploidy disorders including Down syndrome.
2024-07-31 | GSE269238 | GEO
Project description:Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21; but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results raise major implications for other aneuploidy disorders including Down syndrome.
2024-07-31 | GSE269237 | GEO
Project description:Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21; but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results raise major implications for other aneuploidy disorders including Down syndrome.
2024-07-31 | GSE269236 | GEO
Project description:Segmental aneuploidy refers to the relative excess or deficiency of specific chromosome regions. This condition results in gene dosage imbalance and often causes severe phenotypic alterations in plants and animals. The mechanisms by which gene dosage imbalance effects gene expression and phenotype are not completely clear. The effects of aneuploidy on the transcriptome may depend on the types of cells analyzed and on the developmental stage. We performed global gene expression profiling to determine the effects of segmental aneuploidy on gene expression levels in two different maize tissues and a detailed analysis of expression of 30 genes affected by aneuploidy in multiple maize tissues. Multiple genes demonstrated qualitative changes in gene expression due to aneuploidy, when the gene became ectopically expressed or erroneously transcriptionally silenced in aneuploids relative to wild type plants. Our data strongly suggested that quantitative changes in gene expression at developmental transition points caused by variation in gene copy number progressed through tissue development and resulted in stable qualitative changes in gene expression patterns. Thus, aneuploidy in maize results in alterations of gene expression patterns that differ between tissues and developmental stages of maize seedlings. RNA was extracted from meristem tissues of 14 day-old maize seedlings segregating for segmental trisome of a short arm of chromosome 5. There are three biological replicates of pooled wild-type siblings and three biological replicates of pooled DpDf plants. The DpDf plants are segmental aneuploids that contain three copies of the short arm of chromosome 5. These plants are all in the B73 inbred genetic background.
2010-01-01 | E-GEOD-19212 | biostudies-arrayexpress
Project description:Genomic imbalance caused by varying the dosage of individual chromosomes or chromosomal segments (aneuploidy) has more detrimental effects than altering the dosage of complete chromosome sets (ploidy). Previous analysis on RNA-sequencing data of varied dosage of various chromosomal regions in maize (Zea mays) revealed global modulation of gene expression both on the varied chromosome (cis) and the remainder of the genome (trans). Dysregulation of microRNA (miRNA) dosage has been reported to have profound deleterious effects in many species. miRNAs are preferentially retained as duplicates following whole-genome duplication in grass species and are postulated to be dosage-sensitive. However, little is known regarding the role of miRNAs under genomic imbalance. We examined the impact of increased and/or decreased dosage of 1 interstitial and 19 distal chromosomal regions in concert with a whole-genome ploidy series of haploid, diploid, triploid, and tetraploid via small RNA-sequencing of diploid and haploid maize mature leaf tissue to investigate the impact of aneuploidy and polyploidy on expression of miRNAs. In general, cis miRNAs in aneuploids present a predominant gene-dosage effect, whereas trans miRNAs trend toward the inverse level, although other types of responses including dosage compensation, increased effect, and decreased effect also occur. Significant correlations between expression levels of miRNAs and their targets were identified in aneuploids, indicating the regulatory role of miRNAs on gene expression triggered by genomic imbalance. The findings provide novel insights into understanding of gene balance from the aspect of the function of miRNAs.
2022-05-12 | GSE189317 | GEO
Project description:We show that aneuploidy is common in wild isolates of yeast, which are inherently tolerant to chromosome amplification and down-regulate expression at 40% of amplified genes. To dissect the mechanism of this dosage response, we generated isogenic strain panels in which diploid cells carried either two, three, or four copies of the affected chromosomes. Using a mixture of linear regression (MLR) model to classify genes, we find that expression is actively down regulated in proportion to increased gene copy at up to 30% of genes. Genes subject to dosage control are under higher expression constraint – but show elevated rates of gene amplification – in wild populations, suggesting that dosage compensation buffers copy number variation (CNV) at toxic genes RNA-seq and transcriptome analysis of S. cerevisiae natural isolates having aneuploidy. Technical triplicate was performed for isogenic diploid strains having 2, 3 and 4 copies of a given chromosome (strain panels), while technical duplicate or singulate was performed on all other aneuploids.
2015-05-08 | E-GEOD-61532 | biostudies-arrayexpress