Systematic screen for human disease genes in
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
of Genetics; and 2Department of Biochemistry, Stanford University
School of Medicine, Stanford, California 94305, USA
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.
online at Nature Genetics (subscription
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