Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model.

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains' growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.

Gene-by-environment interactions influence the fitness cost of gene copy-number variation in yeast.

Variation in gene copy number can alter gene expression and influence downstream phenotypes; thus copy-number variation provides a route for rapid evolution if the benefits outweigh the cost. We recently showed that genetic background significantly influences how yeast cells respond to gene overexpression, revealing that the fitness costs of copy-number variation can vary substantially with genetic background in a common-garden environment. But the interplay between copy-number variation tolerance and environment remains unexplored on a genomic scale. Here, we measured the tolerance to gene overexpression in four genetically distinct Saccharomyces cerevisiae strains grown under sodium chloride stress. Overexpressed genes that are commonly deleterious during sodium chloride stress recapitulated those commonly deleterious under standard conditions. However, sodium chloride stress uncovered novel differences in strain responses to gene overexpression. West African strain NCYC3290 and North American oak isolate YPS128 are more sensitive to sodium chloride stress than vineyard BC187 and laboratory strain BY4743. Consistently, NCYC3290 and YPS128 showed the greatest sensitivities to overexpression of specific genes. Although most genes were deleterious, hundreds were beneficial when overexpressed-remarkably, most of these effects were strain specific. Few beneficial genes were shared between the sodium chloride-sensitive isolates, implicating mechanistic differences behind their sodium chloride sensitivity. Transcriptomic analysis suggested underlying vulnerabilities and tolerances across strains, and pointed to natural copy-number variation of a sodium export pump that likely contributes to strain-specific responses to overexpression of other genes. Our results reveal extensive strain-by-environment interactions in the response to gene copy-number variation, raising important implications for the accessibility of copy-number variation-dependent evolutionary routes under times of stress.

Gene-by-environment interactions influence the fitness cost of gene copy-number variation in yeast.

Variation in gene copy number can alter gene expression and influence downstream phenotypes; thus copy-number variation (CNV) provides a route for rapid evolution if the benefits outweigh the cost. We recently showed that genetic background significantly influences how yeast cells respond to gene over-expression (OE), revealing that the fitness costs of CNV can vary substantially with genetic background in a common-garden environment. But the interplay between CNV tolerance and environment remains unexplored on a genomic scale. Here we measured the tolerance to gene OE in four genetically distinct Saccharomyces cerevisiae strains grown under sodium chloride (NaCl) stress. OE genes that are commonly deleterious during NaCl stress recapitulated those commonly deleterious under standard conditions. However, NaCl stress uncovered novel differences in strain responses to gene OE. West African strain NCYC3290 and North American oak isolate YPS128 are more sensitive to NaCl stress than vineyard BC187 and laboratory strain BY4743. Consistently, NCYC3290 and YPS128 showed the greatest sensitivities to gene OE. Although most genes were deleterious, hundreds were beneficial when overexpressed - remarkably, most of these effects were strain specific. Few beneficial genes were shared between the NaCl-sensitive isolates, implicating mechanistic differences behind their NaCl sensitivity. Transcriptomic analysis suggested underlying vulnerabilities and tolerances across strains, and pointed to natural CNV of a sodium export pump that likely contributes to strain-specific responses to OE of other genes. Our results reveal extensive strain-by-environment interaction in the response to gene CNV, raising important implications for the accessibility of CNV-dependent evolutionary routes under times of stress.