The genetic landscape of a physical interaction. synthetic construct

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 we provide the first comprehensive view of how point mutations in two genes combine to alter a molecular phenotype. Using a new sequencing-based protein interaction assay – deepPCA – we quantified the effects of >100,000 pairs of point mutations on the formation of the AP-1 transcription factor complex between the products of the FOS and JUN proto-oncogenes. We then compared how mutations interact in cis (within one protein) and in trans (between the two molecules). Genetic interactions are abundant and consist of two classes –interactions driven by thermodynamics and captured by a global model that explains ~90% of the double mutant data in both cis and trans, and structural interactions that are enriched between proximally located residues. There are more structural interactions between mutations within one gene than between the two genes. These results reveal how physical interactions generate abundant and quantitatively predictable genetic interactions, even in the absence of complex regulatory dynamics. Overall design: Epistasis between mutations in two interacting proteins