Systematic screen for human disease genes in yeast

Lars M. Steinmetz1,3*, Curt Scharfe2,3*, Adam M. Deutschbauer1, Dejana Mokranjac4, Zelek S. Herman3, Ted Jones3, Angela M. Chu2, Guri Giaever3, Holger Prokisch4, Peter J. Oefner2,3 & Ronald W. Davis1,2,3

1Department of Genetics; and 2Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA
3Stanford Genome Technology Center, 855 California Avenue, Palo Alto, California 94304, USA
4Insitute of Physiological Chemistry, University of Munich, Munich, D-81377, Germany

*These authors contributed equally to this work

Nature Genetics 31:400-404 (2002).

High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans. 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 identified. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants 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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