Positive Selection or Free to Vary? Assessing the Functional Significance of Sequence Change Using Molecular Dynamics.

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dc.contributor.author Allison, Jane R
dc.contributor.author Lechner, Marcus
dc.contributor.author Hoeppner, Marc P
dc.contributor.author Poole, Anthony M
dc.coverage.spatial United States
dc.date.accessioned 2022-05-11T04:32:59Z
dc.date.available 2022-05-11T04:32:59Z
dc.date.issued 2016-01
dc.identifier.citation (2016). PLoS One, 11(2), e0147619-.
dc.identifier.issn 1932-6203
dc.identifier.uri https://hdl.handle.net/2292/59182
dc.description.abstract Evolutionary arms races between pathogens and their hosts may be manifested as selection for rapid evolutionary change of key genes, and are sometimes detectable through sequence-level analyses. In the case of protein-coding genes, such analyses frequently predict that specific codons are under positive selection. However, detecting positive selection can be non-trivial, and false positive predictions are a common concern in such analyses. It is therefore helpful to place such predictions within a structural and functional context. Here, we focus on the p19 protein from tombusviruses. P19 is a homodimer that sequesters siRNAs, thereby preventing the host RNAi machinery from shutting down viral infection. Sequence analysis of the p19 gene is complicated by the fact that it is constrained at the sequence level by overprinting of a viral movement protein gene. Using homology modeling, in silico mutation and molecular dynamics simulations, we assess how non-synonymous changes to two residues involved in forming the dimer interface-one invariant, and one predicted to be under positive selection-impact molecular function. Interestingly, we find that both observed variation and potential variation (where a non-synonymous change to p19 would be synonymous for the overprinted movement protein) does not significantly impact protein structure or RNA binding. Consequently, while several methods identify residues at the dimer interface as being under positive selection, MD results suggest they are functionally indistinguishable from a site that is free to vary. Our analyses serve as a caveat to using sequence-level analyses in isolation to detect and assess positive selection, and emphasize the importance of also accounting for how non-synonymous changes impact structure and function.
dc.format.medium Electronic-eCollection
dc.language eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartofseries PloS one
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Tombusvirus
dc.subject Lycopersicon esculentum
dc.subject Viral Proteins
dc.subject RNA
dc.subject Crystallography, X-Ray
dc.subject Sequence Alignment
dc.subject Phylogeny
dc.subject Plant Diseases
dc.subject Gene Expression
dc.subject Binding Sites
dc.subject Amino Acid Sequence
dc.subject Protein Structure, Secondary
dc.subject Protein Binding
dc.subject Sequence Homology, Amino Acid
dc.subject Mutation
dc.subject Molecular Sequence Data
dc.subject Protein Interaction Domains and Motifs
dc.subject Protein Multimerization
dc.subject Selection, Genetic
dc.subject Molecular Dynamics Simulation
dc.subject Immune Evasion
dc.subject Genetics
dc.subject Prevention
dc.subject 1.1 Normal biological development and functioning
dc.subject Generic health relevance
dc.subject Infection
dc.subject Science & Technology
dc.subject Multidisciplinary Sciences
dc.subject Science & Technology - Other Topics
dc.subject BRANCH-SITE
dc.subject VIRUS
dc.subject EVOLUTION
dc.subject GENES
dc.subject DROSOPHILA
dc.subject RECOGNITION
dc.subject 0604 Genetics
dc.title Positive Selection or Free to Vary? Assessing the Functional Significance of Sequence Change Using Molecular Dynamics.
dc.type Journal Article
dc.identifier.doi 10.1371/journal.pone.0147619
pubs.issue 2
pubs.begin-page e0147619
pubs.volume 11
dc.date.updated 2022-04-28T03:02:21Z
dc.rights.holder Copyright: The author en
dc.identifier.pmid 26871901 (pubmed)
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/26871901
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Research Support, Non-U.S. Gov't
pubs.subtype research-article
pubs.subtype Journal Article
pubs.elements-id 630167
pubs.org-id Science
pubs.org-id Biological Sciences
dc.identifier.eissn 1932-6203
dc.identifier.pii PONE-D-15-31446
pubs.number ARTN e0147619
pubs.record-created-at-source-date 2022-04-28
pubs.online-publication-date 2016-02-12

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