التفاصيل البيبلوغرافية
| العنوان: |
Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation. |
| المؤلفون: |
Jakobson CM; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; These authors contributed equally., Aguilar-Rodríguez J; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Biology, Stanford University, Stanford, CA, USA.; These authors contributed equally., Jarosz DF; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA. |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 02. Date of Electronic Publication: 2023 Nov 02. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
The essential stress-responsive chaperone Hsp90 impacts development and adaptation from microbes to humans. Yet despite evidence of its role in evolution, pathogenesis, and oncogenic transformation, the molecular mechanisms by which Hsp90 alters the consequences of mutations remain vigorously debated. Here we exploit the power of nucleotide-resolution genetic mapping in Saccharomyces cerevisiae to uncover more than 1,000 natural variant-to-phenotype associations governed by this molecular chaperone. Strikingly, Hsp90 more frequently modified the phenotypic effects of cis -regulatory variation than variants that altered protein sequence. Moreover, these interactions made the largest contribution to Hsp90-dependent heredity. Nearly all interacting variants-both regulatory and protein-coding-fell within clients of Hsp90 or targets of its direct binding partners. Hsp90 activity affected mutations in evolutionarily young genes, segmental deletions, and heterozygotes, highlighting its influence on variation central to evolutionary novelty. Reconciling the diverse epistatic effects of this chaperone, synthetic transcriptional regulation and reconstructions of natural alleles by genome editing revealed a central role for Hsp90 in regulating the fundamental relationship between activity and phenotype. Our findings establish that non-coding variation is a core driver of Hsp90's influence on heredity, offering a mechanistic explanation for the chaperone's strong effects on evolution and development across species. |
| معلومات مُعتمدة: |
DP2 GM119140 United States GM NIGMS NIH HHS; F32 GM125162 United States GM NIGMS NIH HHS; R01 HG012366 United States HG NHGRI NIH HHS; RF1 AG057334 United States AG NIA NIH HHS |
| تواريخ الأحداث: |
Date Created: 20231114 Latest Revision: 20240210 |
| رمز التحديث: |
20240210 |
| مُعرف محوري في PubMed: |
PMC10634948 |
| DOI: |
10.1101/2023.10.30.564848 |
| PMID: |
37961536 |
| قاعدة البيانات: |
MEDLINE |
