A fundamental and theoretical framework for mutation interactions and epistasis

Christopher J Giacoletto; Ronald Benjamin; Jerome I Rotter; Martin R Schiller

doi:10.1016/j.ygeno.2024.110963

A fundamental and theoretical framework for mutation interactions and epistasis

Genomics. 2024 Nov 17;116(6):110963. doi: 10.1016/j.ygeno.2024.110963. Online ahead of print.

Authors

Christopher J Giacoletto¹, Ronald Benjamin², Jerome I Rotter³, Martin R Schiller⁴

Affiliations

¹ Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA.
² Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA.
³ Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁴ Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA. Electronic address: martin.schiller@unlv.edu.

PMID: 39561884
DOI: 10.1016/j.ygeno.2024.110963

Abstract

Many pathological conditions are a result of intragenic epistasis; however, there are ambiguities in current epistasis models. Herein, the new Mutation Interaction Spectrum model defines a discrete outcome, named a Mutation Interaction, for each double point mutation in a gene and its component single mutations. The model is a universal genetic model of all types of mutation interactions and their functional outcomes and is derived from digital logic, commonly used in electrical engineering. Mutation interactions are normally classified as positive and negative epistasis. The model logics unifies common genetic relationships into one model, normalizing biological nomenclature, and disambiguates them with the 16 possible logic-based interactions. The model was tested by assaying transcriptional activity induced by HIV-1 Tat protein, for a random sampling of 3429 double mutations and all 1615 single mutations. All possible types of logic were observed for the Tat mutation interactions.

Keywords: Digital logic; Drug resistance; Evolution; Genetics; HIV; Intragenic epistasis; Mutants; Phylogenetic trees; Tat.