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Discovery and characterisation of gene by environment and epistatic genetic effects in a vertebrate model

Phenotypic variation arises from the interplay between genetic and environmental factors. However, disentangling these interactions for complex traits remains challenging in observational cohorts such as human biobanks. Instead, model organisms where genetic and environmental variation can be contro...

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Main Authors: Welz, Bettina (Author) , Pierotti, Saul (Author) , Fitzgerald, Tomas (Author) , Thumberger, Thomas (Author) , Suzuki, Risa (Author) , Watson, Philip (Author) , Fuß, Jana (Author) , Cordeiro da Trindade, Tiago (Author) , Defranoux, Fanny (Author) , Ferreira, Márcio Soares (Author) , Naruse, Kiyoshi (Author) , Gierten, Jakob (Author) , Loosli, Felix (Author) , Wittbrodt, Joachim (Author) , Birney, Ewan (Author)
Format: Article (Journal) Chapter/Article
Language:English
Published: April 26, 2025
In: bioRxiv beta
Year: 2025, Pages: 1-43
DOI:10.1101/2025.04.24.650462
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1101/2025.04.24.650462
Verlag, lizenzpflichtig, Volltext: https://www.biorxiv.org/content/10.1101/2025.04.24.650462v1
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Author Notes:Bettina Welz, Saul Pierotti, Tomas Fitzgerald, Thomas Thumberger, Risa Suzuki, Philip Watson, Jana Fuss, Tiago Cordeiro da Trindade, Fanny Defranoux, Marcio Ferreira, Kiyoshi Naruse, Jakob Gierten, Felix Loosli, Joachim Wittbrodt, Ewan Birney
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Summary:Phenotypic variation arises from the interplay between genetic and environmental factors. However, disentangling these interactions for complex traits remains challenging in observational cohorts such as human biobanks. Instead, model organisms where genetic and environmental variation can be controlled offer a valuable complement to human studies in the analysis of higher-order genetic effects such as GxE interactions, dominance, and epistasis. Here, we utilized 76 medaka strains of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel, to compare heart rate plasticity across temperatures. An F2 segregation analysis identified 16 quantitative trait loci (QTLs), with many exhibiting dominance, GxE, GxG, and GxGxE interactions. We experimentally validated four candidate genes using gene editing, revealing their temperature-sensitive impact on heart function. Finally, we devised simulations to assess how GWAS discovery power is influenced by the choice of statistical models. This work demonstrates the value of controlled model organism studies for dissecting the genetics of complex traits and provides guidance on the design of genetic association studies.
Item Description:Gesehen am 21.05.2025
Physical Description:Online Resource
DOI:10.1101/2025.04.24.650462

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