Originally published as Genetics Published Articles Ahead of Print on February 16, 2005.

Genetics, Vol. 169, 1915-1925, April 2005, Copyright © 2005
doi:10.1534/genetics.104.036871

Mechanisms of Haploinsufficiency Revealed by Genome-Wide Profiling in Yeast

Adam M. Deutschbauer^*,, Daniel F. Jaramillo, Michael Proctor, Jochen Kumm, Maureen E. Hillenmeyer, Ronald W. Davis^*,, Corey Nislow and Guri Giaever^,1

^* Department of Genetics, Stanford University School of Medicine, Stanford, California 94305
Stanford Genome Technology Center, Palo Alto, California 94304-1103

¹ Corresponding author: Stanford Genome Technology Center, 855 California Ave., Palo Alto, CA 94304-1103.
E-mail: ggiaever{at}stanford.edu

Haploinsufficiency is defined as a dominant phenotype in diploid organisms that are heterozygous for a loss-of-function allele. Despite its relevance to human disease, neither the extent of haploinsufficiency nor its precise molecular mechanisms are well understood. We used the complete set of Saccharomyces cerevisiae heterozygous deletion strains to survey the genome for haploinsufficiency via fitness profiling in rich (YPD) and minimal media to identify all genes that confer a haploinsufficient growth defect. This assay revealed that 3% of all 5900 genes tested are haploinsufficient for growth in YPD. This class of genes is functionally enriched for metabolic processes carried out by molecular complexes such as the ribosome. Much of the haploinsufficiency in YPD is alleviated by slowing the growth rate of each strain in minimal media, suggesting that certain gene products are rate limiting for growth only in YPD. Overall, our results suggest that the primary mechanism of haploinsufficiency in yeast is due to insufficient protein production. We discuss the relevance of our findings in yeast to human haploinsufficiency disorders.

This article has been cited by other articles:

				W. Qian and J. Zhang Gene Dosage and Gene Duplicability Genetics, August 1, 2008; 179(4): 2319 - 2324. [Abstract] [Full Text] [PDF]

				Y. Chen and N. V. Dokholyan Natural Selection against Protein Aggregation on Self-Interacting and Essential Proteins in Yeast, Fly, and Worm Mol. Biol. Evol., August 1, 2008; 25(8): 1530 - 1533. [Abstract] [Full Text] [PDF]

				E. M. Torres, B. R. Williams, and A. Amon Aneuploidy: Cells Losing Their Balance Genetics, June 1, 2008; 179(2): 737 - 746. [Abstract] [Full Text] [PDF]

				M. E. Hillenmeyer, E. Fung, J. Wildenhain, S. E. Pierce, S. Hoon, W. Lee, M. Proctor, R. P. St.Onge, M. Tyers, D. Koller, et al. The Chemical Genomic Portrait of Yeast: Uncovering a Phenotype for All Genes Science, April 18, 2008; 320(5874): 362 - 365. [Abstract] [Full Text] [PDF]

				M. Gustavsson and H. Ronne Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast RNA, April 1, 2008; 14(4): 666 - 674. [Abstract] [Full Text] [PDF]

				M. J. Lercher and C. Pal Integration of Horizontally Transferred Genes into Regulatory Interaction Networks Takes Many Million Years Mol. Biol. Evol., March 1, 2008; 25(3): 559 - 567. [Abstract] [Full Text] [PDF]

				L. A. Estrella, S. Krishnamurthy, C. R. Timme, and M. Hampsey The Rsp5 E3 Ligase Mediates Turnover of Low Affinity Phosphate Transporters in Saccharomyces cerevisiae J. Biol. Chem., February 29, 2008; 283(9): 5327 - 5334. [Abstract] [Full Text] [PDF]

				J.-y. Lu, Y.-y. Lin, J. Qian, S.-c. Tao, J. Zhu, C. Pickart, and H. Zhu Functional Dissection of a HECT Ubiquitin E3 Ligase Mol. Cell. Proteomics, January 1, 2008; 7(1): 35 - 45. [Abstract] [Full Text] [PDF]

				P. Martin-Marcos, A. G. Hinnebusch, and M. Tamame Ribosomal Protein L33 Is Required for Ribosome Biogenesis, Subunit Joining, and Repression of GCN4 Translation Mol. Cell. Biol., September 1, 2007; 27(17): 5968 - 5985. [Abstract] [Full Text] [PDF]

				S. Jezewski, M. von der Heide, S. Poltermann, A. Hartl, W. Kunkel, P. F. Zipfel, and R. Eck Role of the Vps34p-interacting protein Ade5,7p in hyphal growth and virulence of Candida albicans Microbiology, July 1, 2007; 153(7): 2351 - 2362. [Abstract] [Full Text] [PDF]

				J. B. Plotkin and H. B. Fraser Assessing the Determinants of Evolutionary Rates in the Presence of Noise Mol. Biol. Evol., May 1, 2007; 24(5): 1113 - 1121. [Abstract] [Full Text] [PDF]

				J. M. Rizzo, M. Tarsio, G. A. Martinez-Munoz, and P. M. Kane Diploids Heterozygous for a vma13{Delta} Mutation in Saccharomyces cerevisiae Highlight the Importance of V-ATPase Subunit Balance in Supporting Vacuolar Acidification and Silencing Cytosolic V1-ATPase Activity J. Biol. Chem., March 16, 2007; 282(11): 8521 - 8532. [Abstract] [Full Text] [PDF]

				S. Komili and F. P. Roth Genetic interaction screens advance in reverse Genes & Dev., January 15, 2007; 21(2): 137 - 142. [Full Text] [PDF]

				B. Haarer, S. Viggiano, M. A. Hibbs, O. G. Troyanskaya, and D. C. Amberg Modeling complex genetic interactions in a simple eukaryotic genome: actin displays a rich spectrum of complex haploinsufficiencies Genes & Dev., January 15, 2007; 21(2): 148 - 159. [Abstract] [Full Text] [PDF]

				R. Bax, H. A. Raue, and J. C. Vos Slx9p facilitates efficient ITS1 processing of pre-rRNA in Saccharomyces cerevisiae RNA, November 1, 2006; 12(11): 2005 - 2013. [Abstract] [Full Text] [PDF]

				K. Julenius and A. G. Pedersen Protein Evolution Is Faster Outside the Cell Mol. Biol. Evol., November 1, 2006; 23(11): 2039 - 2048. [Abstract] [Full Text] [PDF]

				A. D. Mozdy and T. R. Cech Low abundance of telomerase in yeast: Implications for telomerase haploinsufficiency RNA, September 1, 2006; 12(9): 1721 - 1737. [Abstract] [Full Text] [PDF]

				K. Juneau, M. Miranda, M. E. Hillenmeyer, C. Nislow, and R. W. Davis Introns Regulate RNA and Protein Abundance in Yeast Genetics, September 1, 2006; 174(1): 511 - 518. [Abstract] [Full Text] [PDF]

				T. Pramila, W. Wu, S. Miles, W. S. Noble, and L. L. Breeden The Forkhead transcription factor Hcm1 regulates chromosome segregation genes and fills the S-phase gap in the transcriptional circuitry of the cell cycle. Genes & Dev., August 15, 2006; 20(16): 2266 - 2278. [Abstract] [Full Text] [PDF]

				J. J. Stewart, J. A. Fischbeck, X. Chen, and L. A. Stargell Non-optimal TATA Elements Exhibit Diverse Mechanistic Consequences J. Biol. Chem., August 11, 2006; 281(32): 22665 - 22673. [Abstract] [Full Text] [PDF]

				C. P. Semighini, M. Savoldi, G. H. Goldman, and S. D. Harris Functional Characterization of the Putative Aspergillus nidulans Poly(ADP-Ribose) Polymerase Homolog PrpA Genetics, May 1, 2006; 173(1): 87 - 98. [Abstract] [Full Text] [PDF]

				E. Krasley, K. F. Cooper, M. J. Mallory, R. Dunbrack, and R. Strich Regulation of the Oxidative Stress Response Through Slt2p-Dependent Destruction of Cyclin C in Saccharomyces cerevisiae Genetics, March 1, 2006; 172(3): 1477 - 1486. [Abstract] [Full Text] [PDF]

				X. He and J. Zhang Higher Duplicability of Less Important Genes in Yeast Genomes Mol. Biol. Evol., January 1, 2006; 23(1): 144 - 151. [Abstract] [Full Text] [PDF]

International Access Link

Online ISS 1091-6490
Copyright 2008 by the Genetics Society of America
phone: 412-268-1812   fax: 412-268-1813   email: genetics-gsa{at}andrew.cmu.edu