Genetic variation in the cysteine biosynthesis pathway causes sensitivity to pharmacological compounds

作者：Kim Hyun Seok; Fay Justin C^*

来源：Proceedings of the National Academy of Sciences, 2007, 104(49): 19387-19391.

DOI：10.1073/pnas.0708194104

• CYS4
• population variation in drug response
• transsulfuration pathway

Complex traits are the product of multiple genes with effects that depend on both the genetic and environmental background. Although this complexity makes a comprehensive genetic analysis difficult, identification of even a single gene provides insight into the biochemical and/or signaling pathway underlying a trait. However, it is unknown whether multiple pathways, and consequently multiple genes, must be identified to adequately understand a trait's molecular basis. Using crosses between three natural isolates of Saccharomyces cerevisiae, we mapped sensitivity to a number of pharmacologically active compounds to a single non-synonymous polymorphism in cystathione-beta-synthase (CYS4), which is required for the first committed step in the cysteine biosynthesis pathway. Drug sensitivity is mediated by a deficiency in cysteine and consequently glutathione production, because drug sensitivity is abrogated by cysteine or glutathione supplementation. Within a diverse panel of 60 natural yeast isolates, the drug-sensitive CYS4 allele is rare, and glutathione supplementation failed to alleviate drug-dependent growth defects in two other drug-sensitive strains. These results implicate the cysteine/glutathione biosynthesis pathway as a significant, but not the sole contributor to pharmacological variation in yeast.

• 出版日期2007-12-4