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Epistasis between genes is traditionally studied with mutations that eliminate protein activity, but most natural genetic variation is in cis-regulatory DNA and influences gene expression and function quantitatively. In this study, we used natural and engineered cis-regulatory alleles in a plant stem-cell circuit to systematically evaluate epistatic relationships controlling tomato fruit size. Combining a promoter allelic series with two other loci, we collected over 30,000 phenotypic data points from 46 genotypes to quantify how allele strength transforms epistasis. We revealed a saturating dose-dependent relationship but also allele-specific idiosyncratic interactions, including between alleles driving a step change in fruit size during domestication. Our approach and findings expose an underexplored dimension of epistasis, in which cis-regulatory allelic diversity within gene regulatory networks elicits nonlinear, unpredictable interactions that shape phenotypes.
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This content will become publicly available on November 5, 2026
Interchromosomal Linkage Disequilibrium Analysis Reveals Strong Indications of Sign Epistasis in Wheat Breeding Families
Abstract Additive gene action is assumed to underly quantitative traits, but the eventual poor performance of elite wheat lines as parents suggests that epistasis could be the underlying genetic architecture. Sign epistasis is characterized by alleles having either a beneficial or detrimental effect depending on the genetic background, which can result in elite lines that fail as parents in certain parental combinations. Hence, the objective of this study were to test the existence of sign epistasis and examine its consequences to wheat breeding. The presence of sign epistasis is expected to distort the allele frequency distribution between two interacting genes compared to neutral sites, creating strong linkage disequilibrium (LD). To test this hypothesis, analysis of interchromosomal LD in breeding families was performed and detected 19 regions in strong disequilibrium, whose allele frequency distribution matched the sign epistasis prediction and falsified the competing hypothesis of additive selection. To validate these candidate interactions while avoiding the biases of a circular analysis and the confounding effects of genetic drift, two independent sets of populations were analyzed. Genetic drift was attributed to creating the sign epistasis patterns observed in eleven interactions, but there was not sufficient evidence to reject the sign epistasis hypothesis in eight interactions. Sign epistasis may explain the poor performance of elite lines as parents, as crossing lines with complementary allelic combination re-establishes epistatic variance in the offspring. Reduction in the effective population size in certain crosses may also occur when unfavorable sign epistatic combinations are deleterious. The potential existence of di-genic and higher order epistatic interactions in elite germplasm can tremendously impact breeding strategies as managing epistasis becomes imperative for success.
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- Award ID(s):
- 2421208
- PAR ID:
- 10650825
- Editor(s):
- Ingvarsson, Pär
- Publisher / Repository:
- G3
- Date Published:
- Journal Name:
- G3: Genes, Genomes, Genetics
- ISSN:
- 2160-1836
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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