Shifting Fitness and Epistatic Landscapes Reflect Trade-offs along an Evolutionary Pathway

J Mol Biol. 2016 Jul 3;428(13):2730-43. doi: 10.1016/j.jmb.2016.04.033. Epub 2016 May 10.


Nature repurposes proteins via evolutionary processes. Such adaptation can come at the expense of the original protein's function, which is a trade-off of adaptation. We sought to examine other potential adaptive trade-offs. We measured the effect on ampicillin resistance of ~12,500 unique single amino acid mutants of the TEM-1, TEM-17, TEM-19, and TEM-15 β-lactamase alleles, which constitute an adaptive path in the evolution of cefotaxime resistance. These protein fitness landscapes were compared and used to calculate epistatic interactions between these mutations and the two mutations in the pathway (E104K and G238S). This series of protein fitness landscapes provides a systematic, quantitative description of pairwise/tertiary intragenic epistasis involving adaptive mutations. We find that the frequency of mutations exhibiting epistasis increases along the evolutionary pathway. Adaptation moves the protein to a region in the fitness landscape characterized by decreased mutational robustness and increased ruggedness, as measured by fitness effects of mutations and epistatic interactions for TEM-1's original function. This movement to such a "fitness territory" has evolutionary consequences and is an important adaptive trade-off and cost of adaptation. Our systematic study provides detailed insight into the relationships between mutation, protein structure, protein stability, and epistasis and quantitatively depicts the different costs inherent in the evolution of new functions.

Keywords: beta-lactamase; epistasis; fitness landscape; protein evolution.

MeSH terms

  • Adaptation, Physiological / genetics*
  • Alleles
  • Amino Acids / genetics
  • Ampicillin Resistance / genetics
  • Biological Evolution
  • Epistasis, Genetic / genetics*
  • Models, Genetic
  • Mutation / genetics
  • Protein Stability
  • Proteins / genetics
  • Signal Transduction / genetics*
  • beta-Lactamases / genetics


  • Amino Acids
  • Proteins
  • beta-Lactamases