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Epistasis and physico-chemical constraints contribute to spatial clustering of amino acid substitutions in protein evolution

View ORCID ProfileAndrew M. Taverner, View ORCID ProfileLogan J. Blaine, View ORCID ProfilePeter Andolfatto
doi: https://doi.org/10.1101/2020.08.05.237594
Andrew M. Taverner
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
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  • For correspondence: a.taverner.pi@gmail.com
Logan J. Blaine
2Department of Molecular Biology, Princeton University, Princeton, NJ 08544
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Peter Andolfatto
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
3Department of Biological Sciences, Columbia University, New York, NY 10027
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Abstract

The causes of rate variation among sites within proteins are as yet poorly understood. Here, we compare the spatial autocorrelation of non-synonymous substitutions among species within diverse phylogenetic groups: Saccharomyces, Drosophila, Arabidopsis, and primates. Across these taxa, we find that amino acid substitutions exhibit excess clustering that extends over a 20-30 codon length (10-20 Angstrom distance) scale. We show that these substitutions cluster more strongly and exhibit compensatory dynamics within species lineages but exhibit patterns of convergent evolution between lineages. We evaluate a simple model of thermodynamic constraints on protein folding and conclude that it is unable to recapitulate the observed spatial clustering of substitutions. While pairs of substitutions with the strongest epistasis tend to spatially cluster in these simulations, the magnitude and length scale are smaller than that observed in real data. Additionally, we show that the pattern of convergent substitution is also not expected under this model, suggesting it is likely caused by factors other than these simple thermodynamic constraints. Our results support a prevalent role for epistasis and convergent evolution in shaping protein evolution across the tree of life.

Competing Interest Statement

The authors have declared no competing interest.

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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-ND 4.0 International license.
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Posted August 05, 2020.
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Epistasis and physico-chemical constraints contribute to spatial clustering of amino acid substitutions in protein evolution
Andrew M. Taverner, Logan J. Blaine, Peter Andolfatto
bioRxiv 2020.08.05.237594; doi: https://doi.org/10.1101/2020.08.05.237594
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Epistasis and physico-chemical constraints contribute to spatial clustering of amino acid substitutions in protein evolution
Andrew M. Taverner, Logan J. Blaine, Peter Andolfatto
bioRxiv 2020.08.05.237594; doi: https://doi.org/10.1101/2020.08.05.237594

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