Interactions between polymorphisms at different quantitative trait loci (QTLs) are thought to contribute to the genetics of many traits, and can markedly affect the power of genetic studies to detect QTLs1. Interacting loci have been identified in many organisms1,2,3,4,5. However, the prevalence of interactions6,7,8, and the nucleotide changes underlying them9,10, are largely unknown. Here we search for naturally occurring genetic interactions in a large set of quantitative phenotypes—the levels of all transcripts in a cross between two strains of Saccharomyces cerevisiae7. For each transcript, we searched for secondary loci interacting with primary QTLs detected by their individual effects. Such locus pairs were estimated to be involved in the inheritance of 57% of transcripts; statistically significant pairs were identified for 225 transcripts. Among these, 67% of secondary loci had individual effects too small to be significant in a genome-wide scan. Engineered polymorphisms in isogenic strains confirmed an interaction between the mating-type locus MAT and the pheromone response gene GPA1. Our results indicate that genetic interactions are widespread in the genetics of transcript levels, and that many QTLs will be missed by single-locus tests but can be detected by two-stage tests that allow for interactions.
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We thank D. Botstein and J. Broach for reading the manuscript and for discussions, E. Smith for constructing plasmids, and E. Foss for providing strains. The experiments were performed when J.W. and L.K. were at the Fred Hutchinson Cancer Research Center and the Howard Hughes Medical Institute. This work was supported by funding from the Howard Hughes Medical Institute (to L.K.) and grants from the National Institutes of Health (to L.K. and J.D.S.). L.K. is a James S. McDonnell Centennial Fellow. R.B. is supported by a Burroughs-Wellcome Career Award at the Scientific Interface.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Comparison of transcript levels in segregants and engineered strains for the 18 transcripts with significant linkage to the MAT-GPA1 locus pair under the two-stage linkage test, including the silenced gene YCL066W/HMLα1. Symbols are as in Figure 2 in the main text. (PPT 772 kb)
This file contains details regarding an error in the Supplementary Figure at the time of publication. (DOC 20 kb)
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Brem, R., Storey, J., Whittle, J. et al. Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436, 701–703 (2005). https://doi.org/10.1038/nature03865
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