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Elife. 2013 May 14;2:e00631. doi: 10.7554/eLife.00631.

Stability-mediated epistasis constrains the evolution of an influenza protein.

Author information

1
Division of Basic Sciences , Fred Hutchinson Cancer Research Center , Seattle , United States.

Abstract

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.

KEYWORDS:

Viruses; epistasis; influenza; protein evolution; protein stability

PMID:
23682315
PMCID:
PMC3654441
DOI:
10.7554/eLife.00631
[Indexed for MEDLINE]
Free PMC Article

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