Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles

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• dc.contributor.author Xie, Xuan
• dc.contributor.author Sun, Xia
• dc.contributor.author Wang, Yuheng
• dc.contributor.author Lehner, Ben, 1978-
• dc.contributor.author Li, Xianghua
• dc.date.accessioned 2023-12-19T07:04:31Z
• dc.date.available 2023-12-19T07:04:31Z
• dc.date.issued 2023
• dc.description.abstract An important challenge in genetics, evolution and biotechnology is to understand and predict how mutations combine to alter phenotypes, including molecular activities, fitness and disease. In diploids, mutations in a gene can combine on the same chromosome or on different chromosomes as a "heteroallelic combination". However, a direct comparison of the extent, sign, and stability of the genetic interactions between variants within and between alleles is lacking. Here we use thermodynamic models of protein folding and ligand-binding to show that interactions between mutations within and between alleles are expected in even very simple biophysical systems. Protein folding alone generates within-allele interactions and a single molecular interaction is sufficient to cause between-allele interactions and dominance. These interactions change differently, quantitatively and qualitatively as a system becomes more complex. Altering the concentration of a ligand can, for example, switch alleles from dominant to recessive. Our results show that intra-molecular epistasis and dominance should be widely expected in even the simplest biological systems but also reinforce the view that they are plastic system properties and so a formidable challenge to predict. Accurate prediction of both intra-molecular epistasis and dominance will require either detailed mechanistic understanding and experimental parameterization or brute-force measurement and learning.
• dc.format.mimetype application/pdf
• dc.identifier.citation Xie X, Sun X, Wang Y, Lehner B, Li X. Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles. Nat Commun. 2023 Sep 9;14(1):5551. DOI: 10.1038/s41467-023-41188-8
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-023-41188-8
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/58591
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2023 Sep 9;14(1):5551
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Mutació (Biologia)
• dc.subject.other Genètica
• dc.title Dominance vs epistasis: the biophysical origins and plasticity of genetic interactions within and between alleles
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion