The genetic basis of aneuploidy tolerance in wild yeast.

James Hose,Venera Bouriakov,Audrey P Gasch,Katie J Clowers,H Auguste Dutcher,Leah E Escalante,Evgenia Shishkova,Deelegant Robinson,Joshua J Coon

doi:10.7554/elife.52063

Abstract

Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory strain W303. Loss of SSD1 recapitulates myriad aneuploidy signatures previously taken as eukaryotic responses. We show that aneuploidy tolerance is enabled via a role for Ssd1 in mitochondrial physiology, including binding and regulating nuclear-encoded mitochondrial mRNAs, coupled with a role in mitigating proteostasis stress. Recapitulating ssd1Δ defects with combinatorial drug treatment selectively blocked proliferation of wild-type aneuploids compared to euploids. Our work adds to elegant studies in the sensitized laboratory strain to present a mechanistic understanding of eukaryotic aneuploidy tolerance.

Highlights

Aneuploidy, in which cells carry an abnormal number of one or more chromosomes, is highly detrimental during mammalian development, since amplification of most human chromosomes is inviable during embryogenesis
To identify the genetic basis of differential aneuploidy tolerance, we crossed a haploid derivative of oak-soil strain YPS1009 disomic for chromosome 12 (YPS1009_Chr12) to W303 disomic for the same chromosome (W303_Chr12, Figure 1A)
We realized during tetrad dissection that W303-inherited auxotrophies, especially adenine auxotrophy, influenced aneuploidy tolerance (Figure 1—figure supplement 2A-B)

Summary

Introduction

Aneuploidy, in which cells carry an abnormal number of one or more chromosomes, is highly detrimental during mammalian development, since amplification of most human chromosomes is inviable during embryogenesis. Despite the deleterious effects reported in lab strains, chromosome amplification is beneficial in the right environment and provides a rapid route to phenotypic evolution (Rancati et al, 2008; Pavelka et al, 2010; Yona et al, 2012; Filteau et al, 2015; Fontanillas et al, 2010). This is consistent with the prevalence of chromosome amplification in fungal pathogens emerging after drugtreatment regimens (Ni et al, 2013; Selmecki et al, 2009; Selmecki, 2006). Integrating our results with past yeast and mammalian studies presents a holistic view of eukaryotic responses to chromosome amplification

Results

Discussion

Materials and methods