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Home / Equine Research Bank / Mol Biol Evol / Site-Specific Amino Acid Preferences Are Mostly Conserved in...
Molecular biology and evolution2015; 32(11); 2944-2960; doi: 10.1093/molbev/msv167

Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs.

Abstract: Evolution drives changes in a protein's sequence over time. The extent to which these changes in sequence lead to shifts in the underlying preference for each amino acid at each site is an important question with implications for comparative sequence-analysis methods, such as molecular phylogenetics. To quantify the extent that site-specific amino acid preferences shift during evolution, we performed deep mutational scanning on two homologs of human influenza nucleoprotein with 94% amino acid identity. We found that only a modest fraction of sites exhibited shifts in amino acid preferences that exceeded the noise in our experiments. Furthermore, even among sites that did exhibit detectable shifts, the magnitude tended to be small relative to differences between nonhomologous proteins. Given the limited change in amino acid preferences between these close homologs, we tested whether our measurements could inform site-specific substitution models that describe the evolution of nucleoproteins from more diverse influenza viruses. We found that site-specific evolutionary models informed by our experiments greatly outperformed nonsite-specific alternatives in fitting phylogenies of nucleoproteins from human, swine, equine, and avian influenza. Combining the experimental data from both homologs improved phylogenetic fit, partly because measurements in multiple genetic contexts better captured the evolutionary average of the amino acid preferences for sites with shifting preferences. Our results show that site-specific amino acid preferences are sufficiently conserved that measuring mutational effects in one protein provides information that can improve quantitative evolutionary modeling of nearby homologs.
© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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Publication Date: 2015-07-29 PubMed ID: 26226986PubMed Central: PMC4626756DOI: 10.1093/molbev/msv167Google Scholar: Lookup
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  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research analyzes the impact of evolution on protein sequences and determines that the site-specific preferences for each amino acid in the sequences are largely conserved, even between two closely related protein homologs. Evolution does not significantly change these preferences, and this insight can improve quantitative evolutionary modeling of nearby proteins.

Research Background and Purpose

  • The researchers set out to understand the degree to which evolution influences changes in the sequence of proteins, specifically the preference for each amino acid at each site.
  • The study aims at contributing to comparative sequence-analysis methods such as molecular phylogenetics, which is the study of evolutionary relationships by comparing proteins or DNA sequences.

Methodology

  • The team performed deep mutational scanning on two homologs of the human influenza nucleoprotein that share 94% amino acid identity.
  • Deep mutational scanning is a method that helps determine the effects of all possible mutations on a protein’s function.

Findings

  • The findings show that only a small fraction of sites in the protein’s sequence display changes in amino acid preferences exceeding the noise level of their experiments.
  • Even among sites that showed detectable shifts, the extent of these shifts was small when compared to the differences between nonhomologous proteins.

Implications for Evolutionary Models

  • The researchers concluded that considering the limited variations in amino acid preferences among these closely related homologs, this knowledge can be used to inform site-specific substitution models.
  • These models describe the evolution of nucleoproteins from diverse influenza viruses.
  • It was also found that these site-specific evolutionary models, informed by experimental data, were far more effective in fitting phylogenies of nucleoproteins from various sources of influenza, such as human, swine, equine, and avian influenza.

Significance of the Research

  • The research demonstrated that site-specific amino acid preferences are mostly preserved during evolution, implying that measurements of mutational effects in one protein could provide information beneficial to the quantitative evolutionary modeling of similar proteins.
  • This is significant because it opens up avenues for improving the accuracy of evolutionary models related to protein functions and structures, which can assist in the study, prediction, and perhaps manipulation of protein evolution.

Cite This Article

APA
Doud MB, Ashenberg O, Bloom JD. (2015). Site-Specific Amino Acid Preferences Are Mostly Conserved in Two Closely Related Protein Homologs. Mol Biol Evol, 32(11), 2944-2960. https://doi.org/10.1093/molbev/msv167

Publication

Molecular biology and evolution
ISSN: 1537-1719
NlmUniqueID: 8501455
Country: United States
Language: English
Volume: 32
Issue: 11
Pages: 2944-2960

Researcher Affiliations

Doud, Michael B
  • Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA Department of Genome Sciences, University of Washington Medical Scientist Training Program, University of Washington School of Medicine.
Ashenberg, Orr
  • Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
Bloom, Jesse D
  • Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA Department of Genome Sciences, University of Washington jbloom@fredhutch.org.

MeSH Terms

  • Amino Acid Sequence
  • Amino Acids / genetics
  • Animals
  • Biological Evolution
  • Computer Simulation
  • Evolution, Molecular
  • Horses
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Phylogeny
  • Proteins / genetics
  • Sequence Homology, Amino Acid
  • Swine

Grant Funding

  • P30 CA015704 / NCI NIH HHS
  • T32 AI083203 / NIAID NIH HHS
  • R01 GM102198 / NIGMS NIH HHS
  • S10 OD020069 / NIH HHS
  • T32 GM007266 / NIGMS NIH HHS

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This article has been cited 54 times.
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