Genetic interactions between polymorphisms that affect gene expression in yeast

Abstract

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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Figure 1: Genome distribution of QTL pairs detected by the two-stage linkage search.
Figure 2: Example transcripts showing genetic interaction between MAT and GPA1.

References

  1. 1

    Carlborg, O. & Haley, C. S. Epistasis: too often neglected in complex trait studies? Nature Rev. Genet. 5, 618–625 (2004)

    CAS  Article  Google Scholar 

  2. 2

    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)

    CAS  Article  Google Scholar 

  3. 3

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer, Sunderland, Massachusetts, 1998)

    Google Scholar 

  6. 6

    Gibson, G. et al. Extensive sex-specific nonadditivity of gene expression in Drosophila melanogaster. Genetics 167, 1791–1799 (2004)

    CAS  Article  Google Scholar 

  7. 7

    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)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Kroymann, J. & Mitchell-Olds, T. Epistasis and balanced polymorphism influencing complex trait variation. Nature 435, 95–98 (2005)

    ADS  CAS  Article  Google Scholar 

  9. 9

    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)

    ADS  CAS  Article  Google Scholar 

  10. 10

    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)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Brem, R. B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Yvert, G. et al. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 35, 57–64 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Storey, J. D., Akey, J. M. & Kruglyak, L. Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol. 3, e267 (2005)

    Article  Google Scholar 

  14. 14

    Storey, J. D. A direct approach to false discovery rates. J. R. Statist. Soc. B 64, 479–498 (2002)

    MathSciNet  Article  Google Scholar 

  15. 15

    Schadt, E. E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Csank, C. et al. Three yeast proteome databases: YPD, PombePD, and CalPD (MycoPathPD). Methods Enzymol. 350, 347–373 (2002)

    CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    Zeitlinger, J. et al. Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signalling. Cell 113, 395–404 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Velculescu, V. E. et al. Characterization of the yeast transcriptome. Cell 88, 243–251 (1997)

    CAS  Article  Google Scholar 

  20. 20

    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)

    ADS  CAS  Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    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)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Broman, K. W., Wu, H., Sen, S. & Churchill, G. A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003)

    CAS  Article  Google Scholar 

  24. 24

    Troyanskaya, O. et al. Missing value estimation methods for DNA microarrays. Bioinformatics 17, 520–525 (2001)

    CAS  Article  Google Scholar 

  25. 25

    Storey, J. D. The positive false discovery rate: A Bayesian interpretation and the q-value. Ann. Stat. 31, 2013–2035 (2003)

    MathSciNet  Article  Google Scholar 

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Acknowledgements

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.

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Correspondence to Rachel B. Brem or Leonid Kruglyak.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

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)

Corrigendum

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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