Nature Genetics
31, 400 - 404 (2002)
Published online: 22 July 2002; | doi:10.1038/ng929
Systematic screen for human disease genes in yeastLars M. Steinmetz1, 3, 5, Curt Scharfe2, 3, 5, Adam M. Deutschbauer1, Dejana Mokranjac4, Zelek S. Herman3, Ted Jones3, Angela M. Chu2, Guri Giaever3, Holger Prokisch4, Peter J. Oefner2, 3
& Ronald W. Davis1, 2, 31
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. 2
Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA. 3
Stanford Genome Technology Center, Palo Alto, California 94304, USA. 4
Insitute of Physiological Chemistry, University of Munich, Munich, Germany. 5
These authors contributed equally to this work.
Correspondence should be addressed to Lars M. Steinmetz larsms@stanford.edu or Curt Scharfe curts@stanford.eduHigh 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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