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

Abstract

AbstractChromosome loss results in halving the dose of multiple genes. We reasoned that yeast monosomic strains would constitute a relatively simple model suited to address the complex question of how extant diploid organisms can stay relatively fit despite harboring numerous function-canceling (mostly heterozygous) mutations. We started by re-examining diploid yeast strains with a single heterozygous gene deletion and ascertained that many of them produced small but measurable growth defects. Mapped to individual chromosomes, they often combined into burdens sufficient to turn the growth rate negative, that is, inflict lethality. However, the subsequently derived monosomics did experience such loads yet continued to proliferate as if much (often most) of the harm introduced by single mutations disappeared. This constitutes an outstanding example of positive epistasis for fitness. We then sought its functional explanation by analyzing transcriptomes. There was no evidence for widespread gene-dose compensation or cellular stress response. Alterations were abundant but not parallel. A notable exception was the general upregulation of genes coding for ribosomal proteins and the concomitant downregulation of those coding for the proteasome. It indicates that the (irreparably) distorted stoichiometry of ribosomal proteins was the most common and critical impediment to growth and eclipsed the impact of other metabolic insufficiencies. In general terms, the modular structure of the cell leads to effective fragmentation of the total burden of mutations. Those located outside the module(s) currently defining fitness lose at least some of their relevance which produces the epiphenomenon of positive epistasis between individually negative effects.