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Detecting high-order epistasis in nonlinear genotype-phenotype maps

Zachary R. Sailer, Michael J. Harms
doi: https://doi.org/10.1101/072256
Zachary R. Sailer
1Institute of Molecular Biology, University of Oregon, Eugene, OR, USA
2Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR, USA
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Michael J. Harms
1Institute of Molecular Biology, University of Oregon, Eugene, OR, USA
2Department of Chemistry and Biochemistry, University of Oregon, Eugene, OR, USA
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Abstract

High-order epistasis has been observed in many genotype-phenotype maps. These multi-way interactions between mutations may be useful for dissecting complex traits and could have profound implications for evolution. Alternatively, they could be a statistical artifact. High-order epistasis models assume the effects of mutations should add, when they could in fact multiply or combine in some other nonlinear way. A mismatch in the “scale” of the epistasis model and the scale of the underlying map would lead to spurious epistasis. In this paper, we develop an approach to estimate the nonlinear scales of arbitrary genotype-phenotype maps. We can then linearize these maps and extract high-order epistasis. We investigated seven experimental genotype-phenotype maps for which high-order epistasis had been reported previously. We find that five of the seven maps exhibited nonlinear scales. Interestingly, even after accounting for nonlinearity, we found statistically significant high-order epistasis in all seven maps. The contributions of high-order epistasis to the total variation ranged from 2.2% to 31.0%, with an average across maps of 12.7%. Our results provide strong evidence for extensive high-order epistasis, even after nonlinear scale is taken into account. Further, we describe a simple method to estimate and account for nonlinearity in genotype-phenotype maps.

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  • ↵* harms{at}uoregon.edu

Copyright 
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 December 02, 2016.
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Detecting high-order epistasis in nonlinear genotype-phenotype maps
Zachary R. Sailer, Michael J. Harms
bioRxiv 072256; doi: https://doi.org/10.1101/072256
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Detecting high-order epistasis in nonlinear genotype-phenotype maps
Zachary R. Sailer, Michael J. Harms
bioRxiv 072256; doi: https://doi.org/10.1101/072256

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