A key question in human genetics and evolutionary biology is how mutations in different genes combine to alter phenotypes. Efforts to systematically map genetic interactions have mostly made use of gene deletions. However, most genetic variation consists of point mutations of diverse and difficult to predict effects. Here, by developing a new sequencing-based protein interaction assay - deepPCA - we quantified the effects of >120,000 pairs of point mutations on the formation of the AP-1 transcription factor complex between the products of the FOS and JUN proto-oncogenes. Genetic interactions are abundant both in cis (within one protein) and trans (between the two molecules) and consist of two classes - interactions driven by thermodynamics that can be predicted using a three-parameter global model, and structural interactions between proximally located residues. These results reveal how physical interactions generate quantitatively predictable genetic interactions.
Submitter: Shu-Ching Ou
Submission Date: March 12, 2019, 4:58 p.m.
Scripts and original data can be found in: https://github.com/lehner-lab/FOS_JUN_trans_epistasis
|Number of data points||1127396|
|Proteins||P55-C-Fos Proto-Oncogene Protein,C-Jun Proto-Oncogene Protein|
|Assays/Quantities/Protocols||Experimental Assay: Mean Protein-Protein Interactions (PPI) Score ; Derived Quantity: Mean Epistasis Score ; Derived Quantity: p-value of Epistasis score ; Derived Quantity: FDR associated with p-value ; Derived Quantity: SD of FDR associated with p-value ; Derived Quantity: Mean Epistasis Score (Thermodynamic Model) ; Derived Quantity: p-value of Epistasis score (Thermodynamic Model) ; Derived Quantity: FDR associated with p-value (Thermodynamic Model) ; Derived Quantity: SD of FDR associated with p-value (Thermodynamic Model)|
|Libraries||trans Library: mutations on both Fos and Jun ; cis library: all mutations on Fos|