|Fig 1 from Harms and Thornton|
a, Evolution of hormone specificity in vertebrate GRs6. Icons indicate
taxa (tetrapods, teleosts, elasmobranchs); circles show sensitivity to cortisol
(purple) or 11-deoxycorticosterone (orange). Transparent box represents
evolution of new function. b, Seven historical substitutions recapitulate the
shift in specificity. Two permissive mutations (P), which have no effect on
specificity when introduced alone, allow AncGR1 to tolerate five function-
switching mutations (F)6. Spheres are coloured by primary ligand (orange,
11-deoxycorticosterone; purple, cortisol), or no activation (grey). Thick bars
connect functional proteins; thin bars lead to non-functional proteins. Arrows
represent evolutionary paths that pass only through functional intermediates.
c, Historical (P) or alternative permissive (P′) mutations rescue AncGR1+F
and are tolerated in the ancestral background. Non-permissive pathways pass
through non-functional intermediates (A and B, grey spheres) or fail to rescue
F (C). Inset: screening conditions in yeast that identify AncGR1+F variants
that confer growth in 1 μM cortisol, compared with vehicle-only control.
By looking at genes in ancestral organisms they demonstrate that two permissive mutations were necessary to allow the ancestral GR1 gene to tolerate five function-switching mutations. These permissive mutations cannot directly have been the result of selection pressure becasue they had no function on their own.
Then (and this seems to me to be the really clever bit) they show that alternative mutations which could have permitted such tolerance are extremely rare in the set of genotypes that are accessible to the ancestral GRs. They do this both by screening and by elucidating the complex physical requirements that such mutations would have to satisfy - three simultaneously.
They therefore conclude that the evolution of this vital and largely ubiquitous mechanism is extremely unlikely.
Of course it's impossible to say how many other ways such a mechanism might have evolved overall, and also how many parallel attempts would have been being made. Since the GR is so important, these accidental improvements might have mattered a great deal and even a tiny chance of a successful series of mutations would have been enough. It would be great to see one of Martin Nowak's team give some calculations. But it is a sober reminder that, however much convergent evolution there may be, life is full of contingencies and what we think of as inevitable just isn't.