Epistasis facilitates functional evolution in an ancient transcription factor

• DOI: 10.7554/elife.88737
• Publication Date: 2023-07-12T15:31:58Z
• Authors: Brian PH Metzger; Yeonwoo Park; Tyler N Starr; Joseph W Thornton
• Keywords: Epistasis; Genetic architecture

A protein's genetic architecture - the set of causal rules by which its sequence produces functions also determines possible evolutionary trajectories. Prior research has proposed that proteins is very complex, with pervasive epistatic interactions constrain evolution and make function difficult to predict from sequence. Most this work analyzed only direct paths between two interest excluding vast majority genotypes trajectories considered a single protein function, leaving unaddressed functional specificity impact on new functions. Here, we develop method based ordinal logistic regression directly characterize global determinants multiple 20-state combinatorial deep mutational scanning (DMS) experiments. We use it dissect transcription factor's for DNA, using data DMS an ancient steroid hormone receptor's capacity activate biologically relevant DNA elements. show recognition consists dense main pairwise effects involve virtually every amino acid state in protein-DNA interface, but higher-order epistasis plays tiny role. Pairwise enlarge sequences are primary different They massively expand number opportunities single-residue mutations switch one target another. By bringing variants close together space, therefore facilitates rather than constrains