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Reversal by a direct path that restores the key residues in group X became exceedingly unlikely, because features that once enabled the ancestral conformation of helix 7 had been modified. To restore the ancestral conformation by reversing group X, the restrictive effect of the substitutions in group W must first be reversed, as must group y ובסיכומם: but it became far more difficult to access just 40million years later because of intervening epistatic mutations. Selection is an extraordinarily powerful evolutionary force;28 nevertheless, our observations suggest that, because of the complexity of glucocorticoid receptor architecture, low-probability permissive substitutions were required to open some mutational trajectories to exploration under selection24,29, whereas restrictive substitutions closed other potential paths. Under selection, some kind of adaptation will always occur30, but the specific adaptive forms that are realized depend on the historical trajectory that precedes them. The conditions that once facilitated evolution of the glucocorticoid receptor’s ancestors were destroyed during the realization of its present form2,4,7,16,18. The past is difficult to recover because it was built on the foundation of its אבל כפי שאמרתי, גם אם נסתמך על *אמונתם* שזה אפשרי. הרי דוגמאות למוטציות ניטרליות שלכאורה נדרשו לפונקציות חדשות יש בשפע. מדוע להתעלם מהן?