Changes in gene expression shift and switch genetic interactions

Summary An important goal in disease genetics and evolutionary biology is to understand how mutations combine to alter phenotypes and fitness. Non-additive interactions between mutations occur extensively and change across conditions, cell types, and species, making genetic prediction a difficult challenge. To understand the reasons for this, we reduced the problem to a minimal system where we combined mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, a change in gene expression altered both the strength and type of genetic interactions. These seemingly complicated changes could, however, be predicted by a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. We show that similar changes will be observed for many genes. These results provide fundamental insights into genotype-phenotype maps and illustrate how changes in genetic interactions can be predicted using hierarchical mechanistic models. One sentence Summary Deep mutagenesis of the lambda repressor reveals that changes in gene expression will alter the strength and direction of genetic interactions between mutations in many genes. Highlights Deep mutagenesis of the lambda repressor at two expression levels reveals extensive changes in mutational effects and genetic interactions Genetic interactions can switch from positive (suppressive) to negative (enhancing) as the expression of a gene changes A mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype accurately predicts changes in mutational effects and interactions Changes in expression will alter mutational effects and interactions for many genes For some genes, perfect mechanistic models will never be able to predict how mutations of known effect combine without measurements of intermediate phenotypes