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Dissecting the architecture of a quantitative trait locus in yeast

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

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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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