No evidence for whole-chromosome dosage compensation or global transcriptomic expression differences in spontaneously-aneuploid mutation accumulation lines ofSaccharomyces cerevisiae

Abstract

Aneuploidy, the state in which an organism's genome contains one or more missing or additional chromosomes, often causes widespread genotypic and phenotypic effects. Most often, aneuploidies are deleterious; the most common examples in humans being Down's syndrome (Trisomy 21) and Turner's syndrome (monosomy X). However, aneuploidy is surprisingly common in wild yeast populations. In recent years, there has been debate as to whether yeast contain an innate dosage compensation response that operates at the gene, chromosome, or the whole-genome level, or if natural isolates are robust to aneuploidy without such a mechanism. In this study, we tested for differential gene expression in 20 aneuploid and 16 euploid lines of yeast from two previous mutation accumulation experiments, where selection was minimized and therefore aneuploidies arose spontaneously. We found no evidence for whole-chromosome dosage compensation in aneuploid yeast but did find some evidence for attenuation of expression on a gene-by-gene basis. We additionally found that aneuploidy has no effect on the expression of the rest of the genome (i.e. 'trans' genes), and that very few mutually exclusive aneuploid lines shared differentially expressed genes. However, we found there was a small set of genes that exhibited a shared expression response in the euploid lines, suggesting an effect of mutation accumulation on gene expression. Our findings contribute to our understanding of aneuploidy in yeast and support the hypothesis that there is no innate dosage compensation mechanism at the whole-chromosome level.

The natural diversity of the yeast proteome reveals chromosome-wide dosage compensation in aneuploids

“…Compensation for the burden of aneuploidy could occur by multiple molecular mechanisms. Our results show, in agreement with previous studies [1][2][3][4][5][6][7] , that mRNA levels are not buffered chromosome-wide, and thus any dosage-compensation must occur post-transcriptionally. Consistent with this hypothesis of post-transcriptional mediation of the burden of aneuploidy, a recent study that analyzed ribosomal footprints in the induced-meiosis aneuploid collection also found no evidence for co-translational buffering of aneuploidy 5 .…”

“…We explored this large multi-omic dataset for a systematic assessment of the pervasiveness of aneuploidy from genome to the mRNA and protein level in natural isolates. Our data confirms that, on the chromosome-wide level, aneuploidy is transmitted unbuffered to the transcriptome [1][2][3][4][5]8 . However, in sharp contrast to prior studies, we discovered a significant degree of dosage compensation at the chromosome-wide level, and report that proteins that are encoded on the aneuploid chromosomes are systematically buffered.…”

“…First, we assessed how aneuploidy impacted mRNA and protein expression levels by visualizing mRNA and protein levels per chromosome with a heatmap that highlights changes in medians of normalized log 2 gene expression relative to the change in karyotype (Fig 2a). From the graphical analysis, it is evident that aneuploidy in the genome is transmitted to the transcriptome, as described previously for lab-engineered strains 1,4,5 , selected wild isolates [6][7][8] , and even a collection of aneuploid strains that evolved spontaneously and under minimal selection during mutation accumulation experiments 3 . Since we studied chromosome-and species-wide mRNA expression distributions instead of performing gene-by-gene comparisons, this result should not be confused, and is compatible, with the situation that the expression of specific individual genes is dosage-compensated at the transcriptome level 6 .…”

“…The natural strain dataset complements previous studies using laboratory-generated aneuploid strains by providing general answers to questions that are too complex to be fully answered by relying on individual laboratory strains. Indeed, we discovered a high degree of chromosome-wide buffering of protein levels of genes encoded on aneuploid chromosomes -a feature that had not been observed in aneuploid laboratory strains [1][2][3][4][5] , or selected wild isolates that had been primarily investigated at the transcriptome level [6][7][8] .…”

“…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 [1][2][3][4][5] and natural aneuploid yeasts [6][7][8] 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 9 .…”