Systematic screen for human disease genes in yeast.
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.
Steinmetz
Lars M
LM
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. larsms@stanford.edu
Scharfe
Curt
C
Deutschbauer
Adam M
AM
Mokranjac
Dejana
D
Herman
Zelek S
ZS
Jones
Ted
T
Chu
Angela M
AM
Giaever
Guri
G
Prokisch
Holger
H
Oefner
Peter J
PJ
Davis
Ronald W
RW
D001692:Biological Transport; D002455:Cell Division / Q000235:genetics; D002952:Citric Acid Cycle; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D016681:Genome, Fungal; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics*; D016366:Open Reading Frames; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D017384:Sequence Deletion
D005656:Fungal Proteins