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Site-specific amino-acid preferences are mostly conserved in two closely related protein homologs

Michael B. Doud, Orr Ashenberg, Jesse D. Bloom
doi: https://doi.org/10.1101/018457
Michael B. Doud
1Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA
3Medical Scientist Training Program, University of Washington School of Medicine, Seattle, WA
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Orr Ashenberg
1Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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Jesse D. Bloom
1Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA
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  • For correspondence: jbloom@fredhutch.org
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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 non-homologous 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 non-site-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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 16, 2015.
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Site-specific amino-acid preferences are mostly conserved in two closely related protein homologs
Michael B. Doud, Orr Ashenberg, Jesse D. Bloom
bioRxiv 018457; doi: https://doi.org/10.1101/018457
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Site-specific amino-acid preferences are mostly conserved in two closely related protein homologs
Michael B. Doud, Orr Ashenberg, Jesse D. Bloom
bioRxiv 018457; doi: https://doi.org/10.1101/018457

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