Evolution of receptor functional diversity from an ancestral ER (AncSR1, circle). Present-day receptors are colored according to their transcriptional functions (blue, ligand-activated; green, constitutively active; red, inactive; estrogen-activated receptors are dark blue, and those activated by 3-ketosteroids are light blue). A, If AncSR1 was ligand dependent, two changes of function are required: one loss of transcriptional activity (red box) and one loss of ligand-dependence (green diamond). B, If AncSR1 was constitutively active, four independent gains of ligand dependence are required (blue ovals) plus loss of transcriptional activity (red box). The rescaled consistency index, a measure of how parsimoniously a phylogenetic scenario explains the distribution of character states among extant species, is 1.0 for the hypothesis in A (the maximum possible) and 0.0 for the hypothesis in B (the minimum possible).