mutation pathway
Salverda MLM, Dellus E, Gorter FA, Debets AJM, van der Oost J, Hoekstra RF, Tawfik DS & de Visser JAGM 2011 Initial mutations direct alternative pathways of protein evolution. PLoS Genet 7:e1001321.
- epistasis can constrain the type and order of selected mutations
- it can also make adaptive trajectories contingent upon the first random substitution
- this effect is particularly strong under sign epistasis
- we examine how epistatic interactions between mutations determine alternative evolutionary pathways
- using in vitro evolution of the antibiotic resistance enzyme TEM-1 β-lactamase
- consistent with the prediction of epistatic constraints, most lines increased resistance by acquiring three mutations in a fixed order
- a few lines deviated from this pattern
- to test whether negative interactions between alternative initial substitutions drive this divergence, alleles containing initial substitutions from the deviating lines were evolved under identical conditions
- these alternative initial substitutions consistently led to lower adaptive peaks, involving more and other substitutions than those observed in the common pathway
- a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines (Gly238Ser and Arg164Ser, respectively)
- epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations
