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Originally published as Genetics Published Articles Ahead of Print on February 1, 2008.

Genetics, Vol. 178, 1193-1207, March 2008, Copyright © 2008
doi:10.1534/genetics.107.084103

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Heterozygous Screen in Saccharomyces cerevisiae Identifies Dosage-Sensitive Genes That Affect Chromosome Stability

Erin D. Strome*,{dagger}, Xiaowei Wu{ddagger}, Marek Kimmel{ddagger},§ and Sharon E. Plon{dagger},**,1

* Cell and Molecular Biology, {dagger} Texas Children's Cancer Center and ** Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, {ddagger} Department of Statistics, Rice University, Houston, Texas 77005 and § Systems Engineering Group, Silesian University of Technology, 44-100 Gliwice, Poland

1 Corresponding author: Baylor College of Medicine, MC3-3320, 6621 Fannin St., Houston, TX 77030.
E-mail: splon{at}bcm.edu

Current techniques for identifying mutations that convey a small increased cancer risk or those that modify cancer risk in carriers of highly penetrant mutations are limited by the statistical power of epidemiologic studies, which require screening of large populations and candidate genes. To identify dosage-sensitive genes that mediate genomic stability, we performed a genomewide screen in Saccharomyces cerevisiae for heterozygous mutations that increase chromosome instability in a checkpoint-deficient diploid strain. We used two genome stability assays sensitive enough to detect the impact of heterozygous mutations and identified 172 heterozygous gene disruptions that affected chromosome fragment (CF) loss, 45% of which also conferred modest but statistically significant instability of endogenous chromosomes. Analysis of heterozygous deletion of 65 of these genes demonstrated that the majority increased genomic instability in both checkpoint-deficient and wild-type backgrounds. Strains heterozygous for COMA kinetochore complex genes were particularly unstable. Over 50% of the genes identified in this screen have putative human homologs, including CHEK2, ERCC4, and TOPBP1, which are already associated with inherited cancer susceptibility. These findings encourage the incorporation of this orthologous gene list into cancer epidemiology studies and suggest further analysis of heterozygous phenotypes in yeast as models of human disease resulting from haplo-insufficiency.






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