Mutations often have different effects in genetically distinct individuals. Epistasis between mutations and segregating loci is known to be a major contributor to these background effects, but the architecture of these genetic interactions remains largely unknown. Here, we characterize how segregating loci in a cross of two Saccharomyces cerevisiae strains impact growth following the deletion of the histone deacetylase HOS3. The functions of HOS3 are not well understood and historically its

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... tion has shown little effect on reference strains. However, we map two loci that genetically interact with HOS3 and each other to produce a broad range of responses to the deletion, including near inviability. Although these interactions explain nearly all of the deletion's expressivity, their penetrance depends on a liability threshold involving at least 11 additional nuclear and mitochondrial loci. Multiple lines of evidence imply the deletion uncovers genetically complex changes in translation and genome stability in the mitochondria, suggesting a novel connection between Hos3-mediated deacetylation and the mitochondria. These results provide a valuable example of the complicated and unexpected mechanisms that can cause background effects in genetically diverse populations, and show how characterization of background effects can provide new insights into gene function.