Epistasis supports viability under extensive gene-dose insufficiency following chromosome loss

Abstract

The loss of a single chromosome in a diploid organism halves the dosage of many genes and is usually accompanied by a substantial decrease in fitness. We asked whether this decrease simply reflects the joint damage caused by individual gene dosage deficiencies. We measured the fitness effects of single heterozygous gene deletions in yeast and combined them for each chromosome. This predicted a negative growth rate, i.e. lethality, for multiple monosomies. However, monosomic strains remained alive and grew as if much (often most) of the damage caused by single mutations had disappeared, revealing an exceptionally large and positive epistatic component of fitness. We looked for functional explanations by analyzing the transcriptomes. There was no evidence of increased (compensatory) gene expression on the monosomic chromosomes. Nor were there signs of the cellular stress response that would be expected if monosomy led to protein destabilization and thus cytotoxicity. Instead, all monosomic strains showed extensive upregulation of genes encoding ribosomal proteins, but in an indiscriminate manner that did not correspond to their altered dosage. This response did not restore the stoichiometry required for efficient biosynthesis, which probably became growth limiting, making all other mutation-induced metabolic defects much less important. In general, the modular structure of the cell leads to an effective fragmentation of the total mutational load. Defects outside the module(s) currently defining fitness lose at least some of their relevance, producing the epiphenomenon of positive interactions between individually negative effects.