1. Evolutionary Biology
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Intermolecular epistasis shaped the function and evolution of an ancient transcription factor and its DNA binding sites

  1. Dave W Anderson
  2. Alesia N McKeown
  3. Joseph W Thornton  Is a corresponding author
  1. University of Oregon, United States
  2. University of Chicago, United States
Research Article
  • Cited 38
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Cite this article as: eLife 2015;4:e07864 doi: 10.7554/eLife.07864


Complexes of specifically interacting molecules, such as transcription factor proteins (TFs) and the DNA response elements (REs) they recognize, control most biological processes, but little is known concerning the functional and evolutionary effects of epistatic interactions across molecular interfaces. We experimentally characterized all combinations of genotypes in the joint protein-DNA sequence space defined by an historical transition in TF-RE specificity that occurred some 500 million years ago in the DNA-binding domain (DBD) of an ancient steroid hormone receptor. We found that rampant epistasis within and between the two molecules was essential to specific TF-RE recognition and to the evolution of a novel TF-RE complex with unique derived specificity. Permissive and restrictive epistatic mutations across the TF-RE interface opened and closed potential evolutionary paths accessible by the other, making the evolution of each molecule contingent on its partner's history and allowing a molecular complex with novel specificity to evolve.

Article and author information

Author details

  1. Dave W Anderson

    Institute of Ecology and Evolution, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alesia N McKeown

    Institute of Ecology and Evolution, University of Oregon, Eugene, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph W Thornton

    Department of Ecology and Evolution, University of Chicago, Chicago, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Detlef Weigel, Max Planck Institute for Developmental Biology, Germany

Publication history

  1. Received: April 2, 2015
  2. Accepted: June 13, 2015
  3. Accepted Manuscript published: June 15, 2015 (version 1)
  4. Version of Record published: July 14, 2015 (version 2)


© 2015, Anderson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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