Buffering the Path to Evolution: Hsp90 as a Genetic Capacitor in Facilitating Adaptive Mutations in Yeast
by Chun-Hsin Yang | Fu-Hsuan Ko | Jun-Yi Leu | Institute of Molecular Biology, Academia Sinica | Institute of Molecular Biology, Academia Sinica | Institute of Molecular Biology, Academia Sinica
Abstract ID: 145
Event: The 3rd AsiaEvo Conference
Topic: Fitness landscapes bridge evolution and molecular biology
Presenter Name: Chun-Hsin Yang

Maintaining protein homeostasis is vital for cellular survival. Heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, facilitates the maturation of a wide variety of protein clients, and therefore engages in numerous cellular process. By maintaining protein stability and/or folding, Hsp90 can buffer the detrimental effects of genetic mutations. Cryptic genetic variations were released under stress conditions of Hsp90 activity insufficiency. Yet, our knowledge in the molecular mechanism underlying Hsp90 buffering is limited.
In this study, we aimed to seek mutations which can be buffered by Hsp90. Through EMS-mutagenesis, we collected clones with growth defects under Hsp90 inhibition condition. To further investigate the causal mutations, we conducted bulk-segregant analysis coupling with whole-genome sequencing. We identified a mutation on ACS2, which is an essential gene encoding acetyl-coA synthetase, as one of the Hsp90 buffering targets. Via error-prone PCR library screening, we found another two putative single mutations on ACS2 buffered by Hsp90. We hypothesized that the Hsp90 buffering system allows cells to accumulate additional mutations to compensate the deleterious effect of the initial one during evolution. In the future, we would like to further dissect the molecular mechanism of Hsp90 buffering effect and its impact on evolution.