A genome-wide survey of haploinsufficiency in yeast.
Adam M. Deutschbauer, Daniel F. Jaramillo, Michael Proctor, Jochen Kumm, Ronald W. Davis, Corey Nislow, Guri Giaever
Biochemistry, Stanford Genome Technology Cen, 855 California Ave., Palo Alto, CA, 94304, US
Haploinsufficiency refers to a dominant phenotype in a diploid organism heterozygous for a loss-of-function allele. We surveyed the genome for haploinsufficiency via fitness profiling of the complete S. cerevisiae heterozygous deletion collection in both rich media (YPD) and minimal media to identify strains with relative growth defects. Our genomic analysis reveals ~3% of all heterozygous strains are haploinsufficient in YPD. These genes are enriched for essential genes, while the remaining nonessential haploinsufficient genes comprise a subset of the ~20% of homozygous diploids that exhibit slow growth in YPD. Functional classes associated with haploinsufficiency show enrichment for genes involved in protein complexes including the ribosome, the CCT folding complex, RNA polymerases, and the exosome. Slowing the growth rate in minimal media alleviates much of the haploinsufficiency associated with YPD, suggesting certain functional classes are rate-limiting for growth in YPD. Although the etiology of haploinsufficiency is under debate (whether insufficient protein product from a single gene or imbalance of protein subunits is the cause), our results suggest that insufficient amounts of protein products are the basis of the effect. We see a core set of haploinsufficient genes across several growth conditions suggesting that critical cellular functions are prone to this phenomenon. This observation is supported by the fact that many of these genes have human counterparts.
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