DOI: 10.1126/science.1123348 , 97 (2006); 312Science et al.Jamie T. Bridgham,Molecular ExploitationEvolution of Hormone-Receptor Complexity by www.sciencemag.org (this information is current as of December 11, 2007 ):The following resources related to this article are available online at http://www.sciencemag.org/cgi/content/full/312/5770/97version of this article at: including high-resolution figures, can be found in the onlineUpdated information and services, http://www.sciencemag.org/cgi/content/full/312/5770/97/DC1 can be found at: Supporting Online Materialfound at: can berelated to this articleA list of selected additional articles on the Science Web sites http://www.sciencemag.org/cgi/content/full/312/5770/97#related-content http://www.sciencemag.org/cgi/content/full/312/5770/97#otherarticles, 10 of which can be accessed for free: cites 25 articlesThis article 32 article(s) on the ISI Web of Science. cited byThis article has been http://www.sciencemag.org/cgi/content/full/312/5770/97#otherarticles 13 articles hosted by HighWire Press; see: cited byThis article has been http://www.sciencemag.org/cgi/collection/evolutionEvolution : subject collectionsThis article appears in the following http://www.sciencemag.org/about/permissions.dtl in whole or in part can be found at: this articlepermission to reproduce of this article or about obtaining reprintsInformation about obtaining registered trademark of AAAS. is aScience2006 by the American Association for the Advancement of Science; all rights reserved. The title CopyrightAmerican Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by theScience on December 11, 2007 www.sciencemag.orgDownloaded fromReferences and Notes1. P. J. Webster, G. J. Holland, J. A. Curry, H.-R. Chang,Science 309, 1844 (2005).2. K. E. Trenberth, Science 308, 1753 (2005).3. K. Emanuel, Nature 436, 686 (2005).4. C. W. Landsea, Nature 438, E11 (2005).5. K. Emanuel, Nature 438, E13 (2005).6. J. A. Curry, P. J. Webster, G. J. Holland, in preparation.7. R. A. Pielke Jr., C. Landsea, M. Mayfield, J. Laver, R. Pasch,Bull. Am. Meteorol. Soc. 86, 1571 (2005).8. L. J. Shapiro, S. B. Goldenberg, J. Clim. 11, 578 (1998).9. P. J. Webster, G. J. Holland, R. A. Houze Jr., paperpresented at the 85th American Meteorological SocietyAnnual Meeting, the Ed Lorenz Symposium, San Diego, CA,13 January 2005 (http://ams.confex.com/ams/Annual2005/techprogram/paper_87148.htm).10. T. M. Smith, R. W. Reynolds, J. Clim. 17, 2466 (2004).11. E. M. Kalnay et al., Bull. Am. Meteorol. Soc. 77, 437 (1996).12. R. M. Hirsch, J. R. Slack, R. Smith, Water Resour. Res. 18,107 (1982).13. C. E. Shannon, Bell System Tech. J. 27, 379 (1948).14. Information on the statistical method is available assupporting material on Science Online.15. J. Lighthill et al., Bull. Am. Meteorol. Soc. 75,2147(1994).16. W. M. Gray, Mon. Weather Rev. 96, 669 (1968).17. Values of MI vary from 0 (total independence) to 2.8(total dependence), corresponding to the entropy ofNCAT45 (minimum among all variables).18. SST correlations for the remaining three basins are asfollows (using the same notation as in Table 2): WPAC0.44* (0.13), NIO 0.28 (–0.10), SIO 0.54* (0.02).19. This research was supported by the Climate DynamicsDivision of NSF under award NSF-ATM 0328842.Supporting Online Materialwww.sciencemag.org/cgi/content/full/1123560/DC1SOM TextFigs. S1 to S5Reference7 December 2005; accepted 7 March 2006Published online 16 March 2006;10.1126/science.1123560Include this information when citing this paper.Evolution of Hormone-ReceptorComplexity by Molecular ExploitationJamie T. Bridgham, Sean M. Carroll, Joseph W. Thornton*According to Darwinian theory, complexity evolves by a stepwise process of elaboration andoptimization under natural selection. Biological systems composed of tightly integrated parts seemto challenge this view, because it is not obvious how any element’s function can be selected forunless the partners with which it interacts are already present. Here we demonstrate how anintegrated molecular system—the specific functional interaction between the steroid hormonealdosterone and its partner the mineralocorticoid receptor—evolved by a stepwise Darwinianprocess. Using ancestral gene resurrection, we show that, long before the hormone evolved, thereceptor’s affinity for aldosterone was present as a structural by-product of its partnership withchemically similar, more ancient ligands. Introducing two amino acid changes into the ancestralsequence recapitulates the evolution of present-day receptor specificity. Our results indicate thattight interactions can evolve by molecular exploitation—recruitment of an older molecule,previously constrained for a different role, into a new functional complex.The ability of mutation, selection, and driftto generate elaborate, well-adapted phe-notypes has been demonstrated theoreti-cally (1, 2), by computer simulation (3, 4), inthe laboratory (5, 6),andinthefield(7). Howevolutionary processes assemble complex sys-tems that depend on specific interactions amongthe parts is less clear, however. Simultaneousemergence of more than one element by muta-tional processes is unlikely, so it is not apparenthow selection can drive the evolution of anypart or the system as a whole. Most molecularprocesses are regulated by specific interactions,so the lack of exemplars for the emergence ofsuch systems represents an important gap inevolutionary knowledge. As Darwin stated, BIf itcould be demonstrated that any complex organexisted which could not possibly have beenformed by numerous, successive, slight mod-ifications, my theory would absolutely breakdown[ (8).The functional interaction between thesteroid hormone aldosterone and its specificpartner the mineralocorticoid receptor (MR)—a ligand-activated transcriptional regulator(9, 10)—illustrates this evolutionary puzzle.MR and the glucocorticoid receptor (GR) de-scend from a gene duplication deep in thevertebrate lineage (11) and now have distinctsignaling functions. In most vertebrates, GR isspecifically activated by the stress hormonecortisol to regulate metabolism, inflammation,and immunity (9). MR is activated by aldoster-one to control electrolyte homeostasis and otherprocesses (9, 12). MR can also be activated bycortisol, although the presence of a cortisol-Fig. 4.
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