Contingency and entrenchment in protein evolution under purifying selection

“…There is a borderline trend for the significantly shifted sites to be more likely to have substituted between BG505 and BF520 ( Figure 7—source data 1 ), but most shifted sites have not substituted (only 8 of the 30 shifted sites differ in amino acid identity between the two Envs). The lack of strong enrichment in shifts at substituted sites contrasts with previous protein-wide experimental ( Doud et al, 2015 ) and simulation-based ( Pollock et al, 2012 ; Shah et al, 2015 ) studies of shifting amino acid preferences, which found that shifts were dramatically more pronounced at sites of substitutions. The difference may arise because these earlier studies examined proteins that are fairly conformationally static (absolutely so in the case of the simulations).…”

“…There is a borderline trend for the significantly shifted sites to be more likely to have substituted between BG505 and BF520 (Figure 7-Figure supplement 1), but most shifted sites have not substituted (only 8 of the 30 shifted sites differ in amino-acid identity between the two Envs). The lack of strong enrichment in shifts at substituted sites contrasts with previous protein-wide experimental ( Doud et al, 2015 ) and simulation-based ( Pollock et al, 2012; Shah et al, 2015 ) studies of shifting amino-acid preferences, which found that shifts were dramatically more pronounced at sites of substitutions. The difference may arise because these earlier studies examined proteins that are fairly conformationally static (absolutely so in the case of the simulations).…”

“…In extreme cases, sign epistasis can cause a single substitution to have opposing functional or fitness consequences in different genetic backgrounds Harms and Thornton 2013;Shah et al 2015;Storz 2016;Ono et al 2017). Unlike our results, Natarajan et al (2015Natarajan et al ( , 2016 found that convergence in hemoglobin-oxygen affinity in high-altitude avian species did not evolve through a repeated order of mutations to hemoglobin.…”