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

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Abstract

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.

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Dave W Anderson

Institute of Ecology and Evolution, University of Oregon, Eugene, United States

Competing interests
The authors declare that no competing interests exist.
Alesia N McKeown

Institute of Ecology and Evolution, University of Oregon, Eugene, United States

Competing interests
The authors declare that no competing interests exist.
Joseph W Thornton

Department of Ecology and Evolution, University of Chicago, Chicago, United States

For correspondence
joet1@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

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