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Systematic screen for human disease genes in yeast

Nature Genetics volume 31, pages 400–404 (2002)Cite this article

Abstract

High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease1. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans2. Many mitochondrial diseases remain unexplained, however, in part because only 40–60% of the presumed 700–1,000 proteins involved in mitochondrial function and biogenesis have been identified3. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants4,5,6 to identify mitochondrial proteins. Three million measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, of which 265 were new. Our approach gave higher selection than other systematic approaches, including fivefold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions.

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Figure 1: Categorization of the whole genome according to phenotypes associated with gene deletions.
Figure 2: Verification of mitochondrial candidates by import.
Figure 3: Distinction between mitochondrial and cytoplasmic pathway branches: glycolysis above and TCA cycle and mitochondrial respiratory chain below.
Figure 4: Human mitochondrial-related genes that give rise to disease and for which there is an associated quantitative deletion phenotype in yeast.

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Acknowledgements

We thank M. Mindrinos, E. Allen, T. Neklesa, Q. Wang, W. Neupert and T. Meitinger for helpful advice and M. Trebo for help with preparing the supplementary website. This work was supported by the US National Institutes of Health (P.J.O. and R.W.D.) and the Bundesministerium für Bildung und Forschung (H.P.). L.M.S. was supported as a Howard Hughes Medical Institute predoctoral fellow and C.S. as a Deutsche Forschungsgemeinschaft postdoctoral fellow.

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Author notes

  1. Lars M. Steinmetz and Curt Scharfe: These authors contributed equally to this work.

Authors and Affiliations

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

    Lars M. Steinmetz, Adam M. Deutschbauer & Ronald W. Davis

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

    Curt Scharfe, Angela M. Chu, Peter J. Oefner & Ronald W. Davis

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

    Lars M. Steinmetz, Curt Scharfe, Zelek S. Herman, Ted Jones, Guri Giaever, Peter J. Oefner & Ronald W. Davis

  4. Insitute of Physiological Chemistry, University of Munich, Munich, Germany

    Dejana Mokranjac & Holger Prokisch

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Steinmetz, L., Scharfe, C., Deutschbauer, A. et al. Systematic screen for human disease genes in yeast. Nat Genet 31, 400–404 (2002). https://doi.org/10.1038/ng929

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