Epistasis and cryptic QTL identified using modified bulk segregant analysis of copper resistance in budding yeast.

The contributions of genetic interactions to natural trait variation are challenging to estimate experimentally, as current approaches for detecting epistasis are often underpowered. Powerful mapping approaches such as bulk segregant analysis (BSA), wherein individuals with extreme phenotypes are pooled for genotyping, obscure epistasis by averaging over genotype combinations. To accurately characterize and quantify epistasis underlying natural trait variation, we have engineered strains of the budding yeast Saccharomyces cerevisiae to enable crosses where one parent's chromosome is fixed while the rest of the chromosomes segregate. These crosses allow us to use BSA to identify quantitative trait loci (QTL) whose effects depend on alleles on the fixed parental chromosome, indicating a genetic interaction with that chromosome. Our method, which we term epic-QTL (for epistatic-with-chromosome QTL) analysis, can thus identify interaction loci with high statistical power. Here, we perform epic-QTL analysis of copper resistance with chromosome I or VIII fixed in a cross between divergent naturally derived strains. We find 7 loci that interact significantly with chromosome VIII and none that interact with chromosome I, the smallest of the 16 budding yeast chromosomes. Each of the 7 interactions alters the magnitude, rather than the direction, of an additive QTL effect. We also show that fixation of one source of variation-in this case, chromosome VIII, which contains the large-effect QTL mapping to CUP1-increases power to detect the contributions of other loci to trait differences.

© The Author(s) 2025. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].