An epistatic ratchet constrains the direction of glucocorticoid receptor evolution Export

@article{citeulike:5836151, abstract = {The extent to which evolution is reversible has long fascinated biologists1, 2, 3, 4, 5, 6, 7, 8. Most previous work on the reversibility of morphological and life-history evolution9, 10, 11, 12, 13 has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters14, 15. Further, despite theoretical work on the factors that could contribute to irreversibility1, 8, 16, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available3, 8, 17. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.}, author = {Bridgham, Jamie T. and Ortlund, Eric A. and Thornton, Joseph W.}, citeulike-article-id = {5836151}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nature08249}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature08249}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19779450}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19779450}, day = {24}, doi = {10.1038/nature08249}, issn = {0028-0836}, journal = {Nature}, keywords = {epistasis, pleiotropy, ref\_molecular\_sociobiology}, month = {September}, number = {7263}, pages = {515--519}, posted-at = {2009-09-24 17:07:02}, priority = {2}, publisher = {Nature Publishing Group}, title = {An epistatic ratchet constrains the direction of glucocorticoid receptor evolution}, url = {http://dx.doi.org/10.1038/nature08249}, volume = {461}, year = {2009} }

TY - JOUR ID - citeulike:5836151 L3 - citeulike-article-id:5836151 N2 - The extent to which evolution is reversible has long fascinated biologists1, 2, 3, 4, 5, 6, 7, 8. Most previous work on the reversibility of morphological and life-history evolution9, 10, 11, 12, 13 has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters14, 15. Further, despite theoretical work on the factors that could contribute to irreversibility1, 8, 16, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available3, 8, 17. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution. IS - 7263 JF - Nature SN - 0028-0836 EP - 519 TI - An epistatic ratchet constrains the direction of glucocorticoid receptor evolution PB - Nature Publishing Group VL - 461 SP - 515 KW - epistasis KW - pleiotropy KW - ref_molecular_sociobiology AU - Bridgham, Jamie AU - Ortlund, Eric AU - Thornton, Joseph PY - 2009/09/24/ UR - http://dx.doi.org/10.1038/nature08249 ER -