Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins

TLDR

A beta‑lactamase allele with five point mutations confers roughly 100,000‑fold antibiotic resistance, and in principle 120 mutational trajectories could generate this allele. We demonstrate that 102 of these trajectories are inaccessible and most of the remaining ones have negligible probability because four of the five mutations are deleterious in some combinations, showing that biophysical pleiotropy constrains protein evolution and makes it largely reproducible and predictable.

Abstract

Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the beta-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.