Global epistasis emerges from a generic model of a complex trait

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Abstract

Epistasis between mutations makes adaptation contingent on evolutionary history. Yet despite widespread 'microscopic' epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this 'global' epistasis remains unknown. Here we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by re-analyzing existing data. We further show that the distribution of fitness effects has a universal form when epistasis is widespread, and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity.

Data availability

The code and data used to generate the figures are available at https://github.com/greddy992/global_epistasis.

The following previously published data sets were used

(2013) Long-term dynamics of adaptation in asexual populations
DOI: 10.1126/science.1243357.

https://science.sciencemag.org/content/342/6164/1364
(2014) Global epistasis makes adaptation predictable despite sequence-level stochasticity
DOI: 10.1126/science.1250939.

https://science.sciencemag.org/content/344/6191/1519.full
(2019) Higher-fitness yeast genotypes are less robust to deleterious mutations
DOI: 10.1126/science.aay4199.

https://science.sciencemag.org/content/366/6464/490

Article and author information

Author details

Gautam Reddy

Organismic and Evolutionary Biology, Harvard University, Cambridge, United States

For correspondence
gautam_nallamala@fas.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1276-9613
Michael M Desai

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, United States

For correspondence
mdesai@oeb.harvard.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9581-1150

Funding

Simons Foundation (NSF-Simons Center at Harvard #1764269)

Gautam Reddy

Simons Foundation (376196)

Michael M Desai

National Science Foundation (PHY-1914916)

Michael M Desai

National Institutes of Health (R01GM104239)

Michael M Desai

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.