Stability-mediated epistasis constrains the evolution of an influenza protein

By L. Gong, Marc A. Suchard, Jesse D. Bloom. 2013

336 citations recorded by the source corpus.

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

Subfields: Epidemiology, Genetics, Molecular Biology

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Citations in the corpus

Predicting evolution from the shape of genealogical trees (2014, background): “, 2011; Strelkowa and Lässig, 2012), for example compensatory or permissive mutations (Gong et al., 2013).”
Predicting evolution (2017, background): “The collateral damage of adaptation is subsequently repaired by compensatory mutations 55–57,59,61,81–87 (Fig.”
Evolutionary velocity with protein language models (2021, neutral): “These findings raise a number of interesting questions, including the degree to which the rules learned by language models are biologically interpretable, for example, in terms of thermostability or evolvability (Bloom et al., 2006; Gong et al., 2013).”
Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, neutral): “…implies ample evolutionary potential for compensation of deleterious mutations in the ACE2 interface in a manner reminiscent of multi-step escape pathways that have been described for other viruses (Bloom et al., 2010; Friedrich et al., 2004; Gong et al., 2013; Lynch et al., 2015; Wu et al., 2017).”
The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin (2014, background): “Instead, mutations in NP’s CTL epitopes are often deleterious and require secondary permissive or compensatory mutations to fix without a fitness cost (Rimmelzwaan et al., 2004; Berkhoff et al., 2005, 2006; Gong et al., 2013).”
Mega-scale experimental analysis of protein folding stability in biology and design (2023, background): “Even single point mutations that alter stability can have profound effects on health and disease 3,4 , pharmaceutical development 8–10 and protein evolution 5–7 .”
Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics (2014, background): “[85 ] reconstructed the evolutionary trajectory of the influenza nucleoprotein (NP) starting from the strain Aichi/1968 to Brisbane/ 2007.”
Mutational effects on stability are largely conserved during protein evolution (2013, methodology): “For instance, we have previously shown that three of the mutations characterized here are deleterious in some NP homologs because they are excessively destabilizing (11).”
Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality (2015, background): “In addition, it is known that most proteins are able to buffer a small destabilizing effect without becoming unfolded, and hence without attenuating the fitness [74, 75].”
Epistasis in protein evolution (2016, methodology): “For example, in the evolutionary trajectory of influenza nucleoprotein discussed above, each of the three cases of epistasis involves a destabilizing mutation that required a counterbalancing stabilizing mutation to be tolerated.(7) Any single stabilizing mutation can rescue any one of the individua”