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Dissecting the architecture of a quantitative trait locus in yeast

Nature volume 416, pages 326–330 (2002)Cite this article

Abstract

Most phenotypic diversity in natural populations is characterized by differences in degree rather than in kind. Identification of the actual genes underlying these quantitative traits has proved difficult1,2,3,4,5. As a result, little is known about their genetic architecture. The failures are thought to be due to the different contributions of many underlying genes to the phenotype and the ability of different combinations of genes and environmental factors to produce similar phenotypes6,7. This study combined genome-wide mapping and a new genetic technique named reciprocal-hemizygosity analysis to achieve the complete dissection of a quantitative trait locus (QTL) in Saccharomyces cerevisiae. A QTL architecture was uncovered that was more complex than expected. Functional linkages both in cis and in trans were found between three tightly linked quantitative trait genes that are neither necessary nor sufficient in isolation. This arrangement of alleles explains heterosis (hybrid vigour), the increased fitness of the heterozygote compared with homozygotes. It also demonstrates a deficiency in current approaches to QTL dissection with implications extending to traits in other organisms, including human genetic diseases.

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Figure 1: Analysis of the high-temperature-growth phenotype (Htg).
Figure 2: Detection by genome-wide mapping and detailed analysis by fine-structure mapping of the chromosome XIV Htg QTL.
Figure 3: Sequence variations in chromosome XIV QTL between YJM789 (YJM145 genetic background), S96 (S288c background) and five other Htg+ and six other Htg- yeast strains.
Figure 4: Reciprocal-hemizygosity analysis.
Figure 5: Comparisons of the protein sequence polymorphisms for identified Htg+ genes among Htg+ and Htg- strains.

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Acknowledgements

We thank N. Risch, E. Mignot, K. White, R. Hyman, J. Haber, C. Scharfe, T. Jones and M. Mindrinos for helpful discussion, and M. Trebo for help in preparing the website. This work was supported by the NIH (P.J.O, J.H.M. and R.W.D) and by a Howard Hughes Medical Institute predoctoral fellowship awarded to L.M.S. Strain phenotyping and reciprocal-hemizygosity analysis were performed at Duke University; mapping, expression and sequence analysis were done at Stanford University.

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Authors and Affiliations

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

    Lars M. Steinmetz, Dan R. Richards & Ronald W. Davis

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

    Peter J. Oefner & Ronald W. Davis

  3. Stanford Genome Technology Center, 855 California Avenue, Palo Alto, California, 94304, USA

    Lars M. Steinmetz, Jamie I. Spiegelman, Peter J. Oefner & Ronald W. Davis

  4. Department of Microbiology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Himanshu Sinha & John H. McCusker

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  1. Lars M. Steinmetz
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  2. Himanshu Sinha
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  3. Dan R. Richards
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  4. Jamie I. Spiegelman
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  7. Ronald W. Davis
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Corresponding authors

Correspondence to Lars M. Steinmetz or John H. McCusker.

Supplementary information

Yeast Strains (HTM 35 KB)

Construction of reciprocal hemizygous strains

(JPG 315.66 KB)

Phylogenetic relationships of strains

(GIF 13.20 KB)

Gene expression levels (HTM 21.4 KB)

Gene expression dosages

END3 gene dosage control

(GIF 7.81 KB)

Deletions were made in YJM145 homozygous diploid strain background.

MKT1 gene dosage control

(GIF 7.16 KB)

Htg- allele deletion control

(GIF 5.97 KB)

Deletion of Htg- alleles has no affect on high temperature growth.

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Steinmetz, L., Sinha, H., Richards, D. et al. Dissecting the architecture of a quantitative trait locus in yeast. Nature 416, 326–330 (2002). https://doi.org/10.1038/416326a

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