The molecular mechanism of a cis-regulatory adaptation in yeast.
Despite recent advances in our ability to detect adaptive evolution involving the cis-regulation of gene expression, our knowledge of the molecular mechanisms underlying these adaptations has lagged far behind. Across all model organisms, the causal mutations have been discovered for only a handful of gene expression adaptations, and even for these, mechanistic details (e.g. the trans-regulatory factors involved) have not been determined. We previously reported a polygenic gene expression adaptation involving down-regulation of the ergosterol biosynthesis pathway in the budding yeast Saccharomyces cerevisiae. Here we investigate the molecular mechanism of a cis-acting mutation affecting a member of this pathway, ERG28. We show that the causal mutation is a two-base deletion in the promoter of ERG28 that strongly reduces the binding of two transcription factors, Sok2 and Mot3, thus abolishing their regulation of ERG28. This down-regulation increases resistance to a widely used antifungal drug targeting ergosterol, similar to mutations disrupting this pathway in clinical yeast isolates. The identification of the causal genetic variant revealed that the selection likely occurred after the deletion was already present at high frequency in the population, rather than when it was a new mutation. These results provide a detailed view of the molecular mechanism of a cis-regulatory adaptation, and underscore the importance of this view to our understanding of evolution at the molecular level.
Department of Biology, Stanford University, Stanford , California, United States of America.
Jessica
J
Chang
Yiqi
Y
Zhou
Xiaoli
X
Hu
Lucia
L
Lam
Cameron
C
Henry
Erin M
EM
Green
Ryosuke
R
Kita
Michael S
MS
Kobor
Hunter B
HB
Fraser
D000222:Adaptation, Physiological / Q000235:genetics*; D000935:Antifungal Agents / Q000494:pharmacology; D015536:Down-Regulation; D025141:Drug Resistance, Fungal / Q000235:genetics; D004875:Ergosterol / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D015966:Gene Expression Regulation, Fungal; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000935:Antifungal Agents; C429044:ERG28 protein, S cerevisiae; C112006:MOT3 protein, S cerevisiae; D008565:Membrane Proteins; D012097:Repressor Proteins; C097076:SOK2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004875:Ergosterol