2013/05/14 by Lizhi Ian Gong, Marc A. Suchard, Jesse D. Bloom · 2 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Influenza Virus Research Studies #RNA and protein synthesis mechanisms #Evolution and Genetic Dynamics
paper · doi:10.7554/elife.00631
openalex publication_date 2013/05/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
John Maynard Smith compared protein evolution to the game where one word is converted into another a single letter at a time, with the constraint that all intermediates are words: WORD→WORE→GORE→GONE→GENE. In this analogy, epistasis constrains evolution, with some mutations tolerated only after the occurrence of others. To test whether epistasis similarly constrains actual protein evolution, we created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and also introduced each mutation individually into the parent. Several mutations were deleterious to the parent despite becoming fixed during evolution without negative impact. These mutations were destabilizing, and were preceded or accompanied by stabilizing mutations that alleviated their adverse effects. The constrained mutations occurred at sites enriched in T-cell epitopes, suggesting they promote viral immune escape. Our results paint a coherent portrait of epistasis during nucleoprotein evolution, with stabilizing mutations permitting otherwise inaccessible destabilizing mutations which are sometimes of adaptive value. DOI:http://dx.doi.org/10.7554/eLife.00631.001.