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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Carlborg, O. & Haley, C. S. Epistasis: too often neglected in complex trait studies? Nature Rev. Genet. 5, 618–625 (2004)
Leamy, L. J., Workman, M. S., Routman, E. J. & Cheverud, J. M. An epistatic genetic basis for fluctuating asymmetry of tooth size and shape in mice. Heredity 94, 316–325 (2005)
Montooth, K. L., Marden, J. H. & Clark, A. G. Mapping determinants of variation in energy metabolism, respiration and flight in Drosophila. Genetics 165, 623–635 (2003)
Shook, D. R. & Johnson, T. E. Quantitative trait loci affecting survival and fertility-related traits in Caenorhabditis elegans show genotype–environment interactions, pleiotropy and epistasis. Genetics 153, 1233–1243 (1999)
Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer, Sunderland, Massachusetts, 1998)
Gibson, G. et al. Extensive sex-specific nonadditivity of gene expression in Drosophila melanogaster. Genetics 167, 1791–1799 (2004)
Brem, R. B. & Kruglyak, L. The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc. Natl Acad. Sci. USA 102, 1572–1577 (2005)
Kroymann, J. & Mitchell-Olds, T. Epistasis and balanced polymorphism influencing complex trait variation. Nature 435, 95–98 (2005)
Rawson, P. D. & Burton, R. S. Functional coadaptation between cytochrome c and cytochrome c oxidase within allopatric populations of a marine copepod. Proc. Natl Acad. Sci. USA 99, 12955–12958 (2002)
Caicedo, A. L., Stinchcombe, J. R., Olsen, K. M., Schmitt, J. & Purugganan, M. D. Epistatic interaction between Arabidopsis FRI and FLC flowering time genes generates a latitudinal cline in a life history trait. Proc. Natl Acad. Sci. USA 101, 15670–15675 (2004)
Brem, R. B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)
Yvert, G. et al. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 35, 57–64 (2003)
Storey, J. D., Akey, J. M. & Kruglyak, L. Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol. 3, e267 (2005)
Storey, J. D. A direct approach to false discovery rates. J. R. Statist. Soc. B 64, 479–498 (2002)
Schadt, E. E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003)
Csank, C. et al. Three yeast proteome databases: YPD, PombePD, and CalPD (MycoPathPD). Methods Enzymol. 350, 347–373 (2002)
Bardwell, L., Cook, J. G., Inouye, C. J. & Thorner, J. Signal propagation and regulation in the mating pheromone response pathway of the yeast Saccharomyces cerevisiae. Dev. Biol. 166, 363–379 (1994)
Zeitlinger, J. et al. Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signalling. Cell 113, 395–404 (2003)
Velculescu, V. E. et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997)
Roberts, C. J. et al. Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles. Science 287, 873–880 (2000)
Hagen, D. C. & Sprague, G. F. Jr Induction of the yeast alpha-specific STE3 gene by the peptide pheromone a-factor. J. Mol. Biol. 178, 835–852 (1984)
Sudarsanam, P., Iyer, V. R., Brown, P. O. & Winston, F. Whole-genome expression analysis of snf/swi mutants of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 97, 3364–3369 (2000)
Broman, K. W., Wu, H., Sen, S. & Churchill, G. A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003)
Troyanskaya, O. et al. Missing value estimation methods for DNA microarrays. Bioinformatics 17, 520–525 (2001)
Storey, J. D. The positive false discovery rate: A Bayesian interpretation and the q-value. Ann. Stat. 31, 2013–2035 (2003)
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)
About this article
Cite this article
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
An enhanced machine learning tool for cis ‐eQTL mapping with regularization and confounder adjustments
Genetic Epidemiology (2020)
Systematic identification of cis-regulatory variants that cause gene expression differences in a yeast cross
Nature Communications (2019)
Frontiers in Genetics (2019)
Compensatory trans ‐regulatory alleles minimizing variation in TDH3 expression are common within Saccharomyces cerevisiae
Evolution Letters (2019)