Epistatic interactions between residues determine a protein's adaptability
and shape its evolutionary trajectory. When a protein experiences a changed
environment, it is under strong selection to find a peak in the new fitness
landscape. It has been shown that strong selection increases epistatic
interactions as well as the ruggedness of the fitness landscape, but little is
known about how the epistatic interactions change under selection in the
long-term evolution of a protein. Here we analyze the evolution of epistasis in
the protease of the human immunodeficiency virus type 1 (HIV-1) using protease
sequences collected for almost a decade from both treated and untreated
patients, to understand how epistasis changes and how those changes impact the
long-term evolvability of a protein. We use an information-theoretic proxy for
epistasis that quantifies the co-variation between sites, and show that
positive information is a necessary (but not sufficient) condition that detects
epistasis in most cases. We analyze the "fossils" of the evolutionary
trajectories of the protein contained in the sequence data, and show that
epistasis continues to enrich under strong selection, but not for proteins
whose environment is unchanged. The increase in epistasis compensates for the
information loss due to sequence variability brought about by treatment, and
facilitates adaptation in the increasingly rugged fitness landscape of
treatment. While epistasis is thought to enhance evolvability via
valley-crossing early-on in adaptation, it can hinder adaptation later when the
landscape has turned rugged. However, we find no evidence that the HIV-1
protease has reached its potential for evolution after 9 years of adapting to a
drug environment that itself is constantly changing.Comment: 25 pages, 9 figures, plus Supplementary Material including
Supplementary Text S1-S7, Supplementary Tables S1-S2, and Supplementary
Figures S1-2. Version that appears in PLoS Genetic