Changes in gene expression predictably shift and switch genetic interactions

Xianghua Li, Jasna Lalić, Pablo Baeza-Centurion, Riddhiman Dhar and Ben Lehner ()
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Xianghua Li: The Barcelona Institute of Science and Technology
Jasna Lalić: The Barcelona Institute of Science and Technology
Pablo Baeza-Centurion: The Barcelona Institute of Science and Technology
Riddhiman Dhar: The Barcelona Institute of Science and Technology
Ben Lehner: The Barcelona Institute of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. More generally, changes in gene expression should be expected to alter the effects of mutations and how they interact whenever the relationship between expression and a phenotype is nonlinear, which is the case for most genes. These results have important implications for understanding genotype-phenotype maps and illustrate how changes in genetic interactions can often—but not always—be predicted by hierarchical mechanistic models.

Date: 2019
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DOI: 10.1038/s41467-019-11735-3

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