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Chromosomal duplications increase gene dosage and mRNA level in C. elegans

ABSTRACT: Isolation of copy number variations and chromosomal duplications at high frequency in Caenorhabditis elegans suggested that this organism tolerates dosage problems. Here we addressed if this tolerance is due to a genome-wide compensation mechanism acting at the level of mRNA expression. We characterized several chromosomal duplication strains using DNA-seq and analyzed gene expression in two duplication and a fosmid integration strain using mRNA-seq. Our results show that on average, increased gene dosage leads to increased mRNA expression, pointing to a lack of genome-wide dosage compensation. Different genes within the same duplicated region show variable changes in mRNA expression, suggesting feedback regulation of individual genes. Transcriptional repression by somatic dosage compensation and germline silencing contribute to the level of mRNA increase from a large X chromosomal duplication. In sum, our results show a lack of genome-wide dosage compensation mechanism acting at the mRNA level in C. elegans and highlight the role of epigenetic and individual gene regulation contributing to the varied consequences of increased gene dosage.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE198682 | GEO | 2022/03/22

REPOSITORIES: GEO

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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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Chromosomal duplications increase gene dosage and mRNA level in C. elegans

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