Trans-acting mutations reveal non-nuclear modulators of both intrinsic and extrinsic gene expression noise in a eukaryote.

Gene expression regulation is a stochastic process that can be modified by mutations not only in a deterministic manner but also in a probabilistic way, for example by changing the extent of cell-to-cell variability in gene expression (also called "gene expression noise") without necessarily changing the expected (mean) expression level. Such mutations can act either in cis (perturbing expression noise at their own locus) or in trans (perturbing expression noise of a gene located elsewhere in the genome). Although systematic studies have successfully analyzed the properties of cis-acting mutations modulating gene expression noise, less is known about the type of genetic changes that may alter expression noise in trans. Here, we applied genetic mapping on yeast strains (Saccharomyces cerevisiae) generated by random mutagenesis and identified three mutations (in chs1, yme2 and msh1 genes) that changed the expression noise of a reporter gene in the nuclear genome regulated by the yeast TDH3 promoter. Each of these mutations affected either extrinsic noise (variability due to cell-specific factors), intrinsic noise (inherent variability within each cell), or both. Surprisingly, all three mutations targeted proteins located outside of the nucleus: Yme2 and Msh1 being involved in the maintenance of mitochondrial genome integrity, and Chs1 being necessary for the repair of cell-wall defects in freshly-born daughter cells. Our results reveal that mitochondrial state can modulate the extent of intrinsic expression noise of eukaryotic nuclear genes.