Multilevel gene expression changes in lineages containing adaptive copy number variants

Abstract

Copy-number variants (CNVs) are large-scale amplifications or deletions of DNA that can drive rapid adaptive evolution and result in large-scale changes in gene expression. Whereas alterations in the copy number of one or more genes within a CNV can confer a selective advantage, other genes within a CNV can decrease fitness when their dosage is changed. Dosage compensation - in which the gene expression output from multiple gene copies is less than expected - is one means by which an organism can mitigate the fitness costs of deleterious gene amplification. Previous research has shown evidence for dosage compensation at both the transcriptional level and at the level of protein expression; however, the extent of compensation differs substantially between genes, strains, and studies. Here, we investigated sources of dosage compensation at multiple levels of gene expression regulation by defining the transcriptome, translatome and proteome of experimentally evolved yeast (Saccharomyces cerevisiae) strains containing adaptive CNVs. We quantified the gene expression output at each step and found evidence of widespread dosage compensation at the protein abundance (~47%) level. By contrast we find only limited evidence for dosage compensation at the transcriptional (~8%) and translational (~3%) level. We also find substantial divergence in the expression of unamplified genes in evolved strains that could be due to either the presence of a CNV or adaptation to the environment. Detailed analysis of 82 amplified and 411 unamplified genes with significantly discrepant relationships between RNA and protein abundances identified enrichment for upstream open reading frames (uORFs). These uORFs are enriched for binding site motifs for SSD1, a RNA binding protein that has previously been associated with tolerance of aneuploidy. Our findings suggest that, in the presence of CNVs, SSD1 may act to alter the expression of specific genes by potentiating uORF mediated translational regulation.

The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast

“…For instance, Aviner et al (72) demonstrated that the ribosome collisions on mutant Huntington transcript produce a cycle of dysfunction that sequesters eIF5a, thereby depleting it from other transcripts and altering translation of stress-responsive transcripts, in part by misregulating their upstream open reading frames (uORFs). Interestingly, a recent preprint linked yeast gene copy number variation, Ssd1, and uORFs by suggesting that genes whose encoded mRNA abundance is substantially discordant with its protein abundance were more likely to contain uORFs, and that those reading frames were enriched for Ssd1 binding motifs (73). While we were unable to find enrichment of known uORFs among the 218 genes, these findings highlight how the altered regulation of Ssd1 targets could render a specific group of gene duplicates toxic, through direct or indirect effects.…”