Complex modifier landscape underlying genetic background effects.

Abstract

The phenotypic consequence of a given mutation can be influenced by the genetic background. For example, conditional gene essentiality occurs when the loss of function of a gene causes lethality in one genetic background but not another. Between two individual <i>Saccharomyces cerevisiae</i> strains, S288c and Σ1278b, ∼1% of yeast genes were previously identified as "conditional essential." Here, in addition to confirming that some conditional essential genes are modified by a nonchromosomal element, we show that most cases involve a complex set of genomic modifiers. From tetrad analysis of S288C/Σ1278b hybrid strains and whole-genome sequencing of viable hybrid spore progeny, we identified complex sets of multiple genomic regions underlying conditional essentiality. For a smaller subset of genes, including <i>CYS3</i> and <i>CYS4</i>, each of which encodes components of the cysteine biosynthesis pathway, we observed a segregation pattern consistent with a single modifier associated with conditional essentiality. In natural yeast isolates, we found that the <i>CYS3</i>/<i>CYS4</i> conditional essentiality can be caused by variation in two independent modifiers, <i>MET1</i> and <i>OPT1</i>, each with roles associated with cellular cysteine physiology. Interestingly, the <i>OPT1</i> allelic variation appears to have arisen independently from separate lineages, with rare allele frequencies below 0.5%. Thus, while conditional gene essentiality is usually driven by genetic interactions associated with complex modifier architectures, our analysis also highlights the role of functionally related, genetically independent, and rare variants.