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Science 18 April 2008:
Vol. 320. no. 5874, pp. 362 - 365
DOI: 10.1126/science.1150021
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Reports

The Chemical Genomic Portrait of Yeast: Uncovering a Phenotype for All Genes

Maureen E. Hillenmeyer1,2, Eula Fung1, Jan Wildenhain3*, Sarah E. Pierce1,4, Shawn Hoon1,4, William Lee1,4, Michael Proctor1, Robert P. St.Onge1, Mike Tyers3,5*, Daphne Koller6, Russ B. Altman2,4, Ronald W. Davis2,4, Corey Nislow5,7,8 and Guri Giaever5,8,9{dagger}

1 Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
2 Program in Biomedical Informatics, Stanford University, PaloAlto, CA94305, USA.
3 SamuelLunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G1X5, Canada.
4 Department of Genetics, Stanford University, Stanford, CA 94305, USA.
5 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S1A8, Canada.
6 Department of Computer Science, Stanford University, Palo Alto, CA 94305, USA.
7 Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5S3E1, Canada.
8 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S3E1, Canada.
9 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S3M2, Canada.


Figure 1 Fig. 1. Fraction of genome required for optimal growth under experimental conditions. (A) Percent of gene deletion strains that exhibit significant sensitivity in at least one treatment as a function of number of experiments performed, ordered by date. We used a significance threshold (z score P < 1 x 10–5 and P < 1 x 10–6 for homozygous and heterozygous experiments, respectively) that limited the FDR of genes exhibiting any phenotype to ~0.1 (figs. S2 and S3). Treatment experiments measure the growth of the deletion strains in a drug or altered environmental conditions; control experiments measure growth of the same deletion strains in no-drug rich medium (8). The percent of strains exhibiting a phenotype begins at the percentage previously observed in rich medium (3% for heterozygotes and 34% for homozygotes). (B) Percentage of yeast genes with a phenotype under particular conditions: 19% are essential genes, 15% exhibited a growth defect as homozygous deletions in rich medium, and 63% exhibited a phenotype as either homozygous or heterozygous deletions under particular conditions in this study. [View Larger Version of this Image (22K GIF file)]
 

Figure 2 Fig. 2. Genes required for optimal growth in multiple conditions. (A) The percent of deletion strains inhibited by the given percent of unique conditions at P < 0.01 (z score). Most strains are perturbed by multiple distinct conditions. Genes whose deletion strains showed sensitivity to at least 20% of the unique small molecules are defined as MDR genes. (B) Enriched functions of the homozygous MDR genes. Shown are the important GO biological processes, molecular functions, and cellular components, the hypergeometric enrichment P value, and the locations of the processes in the cell. AP, adaptor protein; ESCRT, endosomal sorting complex required for transport. [View Larger Version of this Image (40K GIF file)]
 

Figure 3 Fig. 3. Gene clusters with similar co-fitness profiles and similar biological functions, extracted from two-way hierarchical clustering on the complete data set (using all genes and all experiments). Each cell in the matrix is a sensitivity score of the deletion strain in the experiment: yellow indicates that the strain was sensitive; blue indicates resistance. Essential genes are marked with asterisks, and open reading frames (ORFs) that overlap a dubious ORF are in parentheses. (A) CCT complex genes, mediators of cytoskeletal assembly, cluster as heterozygous deletion strains primarily because of sensitivity to the cytoskeletal disrupting agents latrunculin and benomyl. (B) Genes of theproteasomecorecomplex clusterinthe heterozygous deletion assays because of sensitivity to three structurally similar compounds that target the lipid synthesis pathway. (C) Peroxisomal genes clustered as homozygous deletions because of sensitivity to hydrogen peroxide, high pH, and oxidative stress-inducing conditions. [View Larger Version of this Image (63K GIF file)]
 

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Science. ISSN 0036-8075 (print), 1095-9203 (online)