@article{TEXTUAL,
      recid = {12089},
      author = {Metzger, Brian P. H. and Park, Yeonwoo and Starr, Tyler N.  and Thornton, Joseph W.},
      title = {Epistasis facilitates functional evolution in an ancient  transcription factor},
      journal = {eLife},
      address = {2024-05-20},
      number = {TEXTUAL},
      abstract = {A protein’s genetic architecture – the set of causal rules  by which its sequence produces its functions – also  determines its possible evolutionary trajectories. Prior  research has proposed that the genetic architecture of  proteins is very complex, with pervasive epistatic  interactions that constrain evolution and make function  difficult to predict from sequence. Most of this work has  analyzed only the direct paths between two proteins of  interest – excluding the vast majority of possible  genotypes and evolutionary trajectories – and has  considered only a single protein function, leaving  unaddressed the genetic architecture of functional  specificity and its impact on the evolution of new  functions. Here, we develop a new method based on ordinal  logistic regression to directly characterize the global  genetic determinants of multiple protein functions from  20-state combinatorial deep mutational scanning (DMS)  experiments. We use it to dissect the genetic architecture  and evolution of a transcription factor’s specificity for  DNA, using data from a combinatorial DMS of an ancient  steroid hormone receptor’s capacity to activate  transcription from two biologically relevant DNA elements.  We show that the genetic architecture of DNA recognition  consists of a dense set of main and pairwise effects that  involve virtually every possible amino acid state in the  protein-DNA interface, but higher-order epistasis plays  only a tiny role. Pairwise interactions enlarge the set of  functional sequences and are the primary determinants of  specificity for different DNA elements. They also massively  expand the number of opportunities for single-residue  mutations to switch specificity from one DNA target to  another. By bringing variants with different functions  close together in sequence space, pairwise epistasis  therefore facilitates rather than constrains the evolution  of new functions.},
      url = {http://knowledge.uchicago.edu/record/12089},
}