The Genetic Basis of Aneuploidy Tolerance in Wild Yeast
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE132425 | GEO | 2020/01/08
REPOSITORIES: GEO
Similar Datasets
Project description:Aneuploidy has a myriad of consequences for health and disease, yet models of aneuploidy toxicity are still widely debated. To distinguish the effects of specific genes from the generalized burden of chromosome amplification, we measured the effects of duplicating individual genes in euploid cells as well as in select aneuploids using a barcoded plasmid library. We analyzed the responses of cells with and without extra chromosomes, as well as those with and without RNA-binding protein Ssd1. Deletion of Ssd1 sensitizes cells to chromosome amplification, but the source of this vulnerability is not known. Results of this experiment were used to interrogate determinants of aneuploidy toxicity, test models of Ssd1 dependence, and identify vulnerabilities of sensitized (ssd1-) and wild-type aneuploids. We also used the fitness effects of gene duplication in euploid cells to model the cost associated with chromosome duplication.
2024-05-01 | GSE263221 | 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: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:Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated and natural aneuploid yeasts triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few, if any, fitness costs in nature. To address these discrepant findings, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples and applied it to natural isolates collected as part of the 1011 genomes project (Peter, J. et al, 2018). For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.
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Project description:Aneuploidy, a state of having uneven numbers of chromosomes, is a form of large-effect mutation able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stresses could in turn induce aneuploidy in budding yeast. Radicicol was shown to induce high level missegregation of an artificial chromosome (CF). This experiment examines possible aneuploidy of other (“natural”) chromosomes induced by radicicol. Red colonies (lost CF) were first screened by FACS. Possible aneuploids were then subjected to hybridization, with WT as the control.
2011-12-31 | E-GEOD-34086 | biostudies-arrayexpress
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: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: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: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