TY - JOUR TI - Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes AU - Baier, Florian AU - Hong, Nansook AU - Yang, Gloria AU - Pabis, Anna AU - Miton, Charlotte M AU - Barrozo, Alexandre AU - Carr, Paul D AU - Kamerlin, Shina CL AU - Jackson, Colin J AU - Tokuriki, Nobuhiko A2 - Lupas, Andrei N A2 - Wittkopp, Patricia J A2 - Lupas, Andrei N VL - 8 PY - 2019 DA - 2019/02/05 SP - e40789 C1 - eLife 2019;8:e40789 DO - 10.7554/eLife.40789 UR - https://doi.org/10.7554/eLife.40789 AB - Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution. KW - protein evolution KW - evolvability KW - molecular mechanisms of evolution KW - enzyme KW - enzyme promiscuity JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -