Abstract
We lack an understanding of how the full range of genetic variants that occur in individuals can interact. To address this shortcoming, here we combine diverse mutations between genes in a model regulatory network, the galactose (GAL) switch of budding yeast. The effects of thousands of pairs of mutations fall into a limited number of phenotypic classes. While these effects are mostly predictable using simple rules that capture the ‘stereotypical’ genetic interactions of the network, some double mutants have unexpected outcomes including constituting alternative functional switches. Each of these ‘harmonious’ genetic combinations exhibits altered dependency on other regulatory genes. These cases illustrate how both pairwise and higher epistasis determines gene essentiality and how combinations of mutations rewire regulatory networks. Together, our results provide an overview of how broad spectra of mutations interact, how these interactions can be predicted, and how diverse genetic solutions can achieve ‘wild-type’ phenotypic behavior.
Highlights
Human genomes contain millions of genetic variants
A more complete understanding of how mutations combine in individuals will require functionally diverse mutations in individual genes to be combined in large numbers
-4 double mutants were Constitutive, a significant enrichment (p = 1.5 * 10, Chi-squared test and Fig 2D and Supplementary Fig 4). These results suggest that gene expression in the GAL system changes in a largely stereotypical manner when combining mutations in the GAL The regulatory (GALR) genes, especially for loss-of-function mutations
Summary
Human genomes contain millions of genetic variants. Each of these variants can have diverse effects, for example quantitatively increasing, decreasing or changing the activity of individual genes. Understanding and predicting how the particular combination of variants present in each individual affects molecular processes and phenotypic traits is a fundamental challenge for human genetics and evolutionary biology. Systematic analyses of how mutations in different genes combine to influence phenotypes have used only one or a few. 3,4 mutations in each gene, most often an inactivating null allele. . A more complete understanding of how mutations combine in individuals will require functionally diverse mutations in individual genes to be combined in large numbers. GAL The regulatory (GALR) system from yeast is a promising model to begin such studies because it is mechanistically well-understood, has relatively few molecular players, and is an important model of gene network
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