Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Quantitative trait loci mapped to single-nucleotide resolution in yeast

Nature Genetics volume 37, pages 1333–1340 (2005)Cite this article

Abstract

Identifying the genetic variation underlying quantitative trait loci remains problematic. Consequently, our molecular understanding of genetically complex, quantitative traits is limited. To address this issue directly, we mapped three quantitative trait loci that control yeast sporulation efficiency to single-nucleotide resolution in a noncoding regulatory region (RME1) and to two missense mutations (TAO3 and MKT1). For each quantitative trait locus, the responsible polymorphism is rare among a diverse set of 13 yeast strains, suggestive of genetic heterogeneity in the control of yeast sporulation. Additionally, under optimal conditions, we reconstituted ∼92% of the sporulation efficiency difference between the two genetically distinct parents by engineering three nucleotide changes in the appropriate yeast genome. Our results provide the highest resolution to date of the molecular basis of a quantitative trait, showing that the interaction of a few genetic variants can have a profound phenotypic effect.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Yeast sporulation efficiency is a quantitative trait.
Figure 2: Identification of sporulation QTLs.
Figure 3: QTL fine-mapping.
Figure 4: RME1, TAO3 and MKT1 are sporulation quantitative trait genes.
Figure 5: Comparative sequence analysis of RME1, TAO3 and MKT1.
Figure 6: Genetic interactions between QTNs.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Mackay, T.F. The genetic architecture of quantitative traits. Annu. Rev. Genet. 35, 303–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Glazier, A.M., Nadeau, J.H. & Aitman, T.J. Finding genes that underlie complex traits. Science 298, 2345–2349 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Page, G.P., George, V., Go, R.C., Page, P.Z. & Allison, D.B. “Are we there yet?”: Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. Am. J. Hum. Genet. 73, 711–719 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Flint, J. & Mott, R. Finding the molecular basis of quantitative traits: successes and pitfalls. Nat. Rev. Genet. 2, 437–445 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Risch, N.J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Esposito, R.E. & Klapholz, S. Meiosis and Ascospore Development (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1981).

    Google Scholar 

  7. Winzeler, E.A. et al. Direct allelic variation scanning of the yeast genome. Science 281, 1194–1197 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Goffeau, A. et al. Life with 6000 genes. Science 274, 546, 563–567 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Steinmetz, L.M. et al. Dissecting the architecture of a quantitative trait locus in yeast. Nature 416, 326–330 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Mewes, H.W., Albermann, K., Heumann, K., Liebl, S. & Pfeiffer, F. MIPS: a database for protein sequences, homology data and yeast genome information. Nucleic Acids Res. 25, 28–30 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cliften, P. et al. Finding functional features in Saccharomyces genomes by phylogenetic footprinting. Science 301, 71–76 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Kellis, M., Patterson, N., Endrizzi, M., Birren, B. & Lander, E.S. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423, 241–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Hirschhorn, J.N. & Daly, M.J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  15. Winzeler, E.A. et al. Genetic diversity in yeast assessed with whole-genome oligonucleotide arrays. Genetics 163, 79–89 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. McCusker, J.H., Clemons, K.V., Stevens, D.A. & Davis, R.W. Genetic characterization of pathogenic Saccharomyces cerevisiae isolates. Genetics 136, 1261–1269 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farrall, M. Quantitative genetic variation: a post-modern view. Hum. Mol. Genet. 13, R1–R7 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Singer, J.B. et al. Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445–448 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Tabor, H.K., Risch, N.J. & Myers, R.M. Opinion: Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat. Rev. Genet. 3, 391–397 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Mitchell, A.P. & Herskowitz, I. Activation of meiosis and sporulation by repression of the RME1 product in yeast. Nature 319, 738–742 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Du, L.L. & Novick, P. Pag1p, a novel protein associated with protein kinase Cbk1p, is required for cell morphogenesis and proliferation in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 503–514 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wickner, R.B. MKT1, a nonessential Saccharomyces cerevisiae gene with a temperature-dependent effect on replication of M2 double-stranded RNA. J. Bacteriol. 169, 4941–4945 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tadauchi, T., Inada, T., Matsumoto, K. & Irie, K. Posttranscriptional regulation of HO expression by the Mkt1-Pbp1 complex. Mol. Cell. Biol. 24, 3670–3681 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chu, S. et al. The transcriptional program of sporulation in budding yeast. Science 282, 699–705 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Primig, M. et al. The core meiotic transcriptome in budding yeasts. Nat. Genet. 26, 415–423 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Briza, P. et al. Systematic analysis of sporulation phenotypes in 624 non-lethal homozygous deletion strains of Saccharomyces cerevisiae. Yeast 19, 403–422 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Deutschbauer, A.M., Williams, R.M., Chu, A.M. & Davis, R.W. Parallel phenotypic analysis of sporulation and postgermination growth in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 99, 15530–15535 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Enyenihi, A.H. & Saunders, W.S. Large-scale functional genomic analysis of sporulation and meiosis in Saccharomyces cerevisiae. Genetics 163, 47–54 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Brachmann, C.B. et al. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast 14, 115–132 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Goldstein, A.L. & McCusker, J.H. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 15, 1541–1553 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Storici, F., Lewis, L.K. & Resnick, M.A. In vivo site-directed mutagenesis using oligonucleotides. Nat. Biotechnol. 19, 773–776 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Guthrie, C. & Fink, G.R. (eds.). Guide to Yeast Genetics and Molecular and Cell Biology (Academic, San Diego, 1991).

    Google Scholar 

  35. Codon, A.C., Gasent-Ramirez, J.M. & Benitez, T. Factors which affect the frequency of sporulation and tetrad formation in Saccharomyces cerevisiae baker's yeasts. Appl. Environ. Microbiol. 61, 630–638 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Herskowitz, I. & Jensen, R.E. Putting the HO gene to work: practical uses for mating-type switching. Methods Enzymol. 194, 132–146 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. in Bioinformatics Methods and Protocols: Methods in Molecular Biology (eds. Krawetz, S. & Misener, S.) 365–386 (Humana Press, Totowa, New Jersey, 2000).

    Google Scholar 

  38. Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Winzeler, E.A. et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901–906 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Gray, M., Kupiec, M. & Honigberg, S.M. Site-specific genomic (SSG) and random domain-localized (RDL) mutagenesis in yeast. BMC Biotechnol. 4, 7 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jorgensen, P. et al. High-resolution genetic mapping with ordered arrays of Saccharomyces cerevisiae deletion mutants. Genetics 162, 1091–1099 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Issel-Tarver, L. et al. Saccharomyces Genome Database. Methods Enzymol. 350, 329–346 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. David, J. Dean, C. Nislow, G. Giaever, K. Gurley, W. Lee, L. Steinmetz, M. Drmanac and D. Richards for assistance and discussions. This work was supported by a National Human Genome Research Institute grant (to R.W.D.).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Stanford University School of Medicine, Stanford, 94305, California, USA

    Adam M Deutschbauer & Ronald W Davis

  2. Stanford Genome Technology Center, Palo Alto, 94304-1103, California, USA

    Adam M Deutschbauer & Ronald W Davis

Authors
  1. Adam M Deutschbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald W Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Adam M Deutschbauer or Ronald W Davis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Inheritance of congenic strains. (PDF 301 kb)

Supplementary Fig. 2

RME1 allelic exchange. (PDF 186 kb)

Supplementary Fig. 3

TAO3 allelic exchange. (PDF 186 kb)

Supplementary Fig. 4

Phenotyping yeast sporulation efficiency. (PDF 166 kb)

Supplementary Table 1

Strain list. (PDF 119 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deutschbauer, A., Davis, R. Quantitative trait loci mapped to single-nucleotide resolution in yeast. Nat Genet 37, 1333–1340 (2005). https://doi.org/10.1038/ng1674

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1674

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing