Before revision:  Information can also be encoded in the interaction between residues in a single protein as well as across proteins, leading to a change in the epistatic patterns that can affect how the virus can change in the future. Measuring epistasis usually requires fitness measurements that are difficult to obtain in high-throughput .
After revision:  Information can also be encoded in the interaction between residues in a protein determine its adaptability as well the shape of its evolutionary trajectory. While several studies have shown that strong selection pressures enrich epistatic interactions in an evolving protein, little is known about how epistatic interactions themselves change over time when selection pressures are not constant. Obtaining fitness data to measure epistasis in a protein over significant and evolutionarily relevant time scales is a daunting task, rendering a study of the long-term evolution of epistasis in a protein currently infeasible .