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Letters to Nature

Nature 416, 326-330 (21 March 2002) | doi:10.1038/416326a; Received 9 August 2001; Accepted 25 January 2002

Dissecting the architecture of a quantitative trait locus in yeast

Lars M. Steinmetz1,2, Himanshu Sinha3, Dan R. Richards1, Jamie I. Spiegelman2, Peter J. Oefner2,4, John H. McCusker3 & Ronald W. Davis1,2,4

  2. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
  3. Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA
  4. Stanford Genome Technology Center, 855 California Avenue, Palo Alto, California 94304, USA
  5. Department of Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA

Correspondence to: Lars M. Steinmetz1,2John H. McCusker3 Correspondence and requests for materials should be addressed to J.H.M. (e-mail: Email: mccus001@mc.duke.edu) or L.M.S. (e-mail: Email: larsms@stanford.edu). Sequences have been deposited in GenBank under the following accession numbers: S96 (AF458969), YJM280 (AF458970), YJM320 (AF458971), YJM326 (AF458972), YJM339 (AF458973), YJM421 (AF458974), YJM789 (AF458975), SK1 (AF458976), W303 (AF458977), YJM1129 (AF458978), YJM269 (AF458979), YJM270 (AF458980), YJM627 (AF458981).

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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.