Hsp90 as a capacitor of phenotypic variation
Abstract
Heat-shock protein 90 (Hsp90) chaperones the maturation of many regulatory proteins and, in the fruitfly Drosophila melanogaster, buffers genetic variation in morphogenetic pathways. Levels and patterns of genetic variation differ greatly between obligatorily outbreeding species such as fruitflies and self-fertilizing species such as the plant Arabidopsis thaliana. Also, plant development is more plastic, being coupled to environmental cues. Here we report that, in Arabidopsis accessions and recombinant inbred lines, reducing Hsp90 function produces an array of morphological phenotypes, which are dependent on underlying genetic variation. The strength and breadth of Hsp90's effects on the buffering and release of genetic variation suggests it may have an impact on evolutionary processes. We also show that Hsp90 influences morphogenetic responses to environmental cues and buffers normal development from destabilizing effects of stochastic processes. Manipulating Hsp90's buffering capacity offers a tool for harnessing cryptic genetic variation and for elucidating the interplay between genotypes, environments and stochastic events in the determination of phenotype.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hsp90 can buffer the effects of genetic or epigenetic variation, keeping it silent until released when the chaperone reservoir is compromised in response to stress.
“First, Hsp90 can buffer the effects of genetic or epigenetic variation, keeping it silent until released when the chaperone reservoir is compromised in response to stress.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [130]
Hsp90's role as a capacitor for variation has been observed in diverse eukaryotes including flies, plants, and fungi.
“This role as a capacitor for variation has been observed in diverse eukaryotes including flies, plants, and fungi18,19,129-134.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [130]
Cites
CANALIZATION OF DEVELOPMENT AND THE INHERITANCE OF ACQUIRED CHARACTERS
WADDINGTON, C. H. (1942) · Nature · doi:10.1038/150563a0 · Cited by 3,255 · see citing works
Hsp90 as a capacitor for morphological evolution
Rutherford, S. L., & Lindquist, S. (1998) · Nature · doi:10.1038/24550 · Cited by 2,270 · see citing works
Self-citationGENETIC ASSIMILATION OF AN ACQUIRED CHARACTER
Waddington, C. H. (1953) · Evolution · doi:10.1111/j.1558-5646.1953.tb00070.x · Cited by 1,187 · see citing works
Roe, S. M., Prodromou, C., O'Brien, R., Ladbury, J. E., Piper, P. W., & Pearl, L. H. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm980403y · Cited by 1,004 · see citing works
Young, J. C., Moarefi, I., & Hartl, F. U. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200104079 · Cited by 826 · see citing works
GHKL, an emergent ATPase/kinase superfamily
DUTTA, R., & Inouye, M. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(99)01503-0 · Cited by 767 · see citing works
Heat Shock Protein 101 Plays a Crucial Role in Thermotolerance in Arabidopsis
Queitsch, C., Hong, S., Vierling, E., et al. (2000) · The Plant Cell · doi:10.1105/tpc.12.4.479 · Cited by 721 · see citing works
Self-citationHsp90 & Co. – a holding for folding
Büchner, J. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(99)01373-0 · Cited by 625 · see citing works
Evidence for stabilizing selection in a eukaryotic enhancer element
Ludwig, M. Z., Bergman, C., Patel, N. H., & Kreitman, M. (2000) · Nature · doi:10.1038/35000615 · Cited by 563 · see citing works
Genetical control of stability in development
Mather, K. (1953) · Heredity · doi:10.1038/hdy.1953.41 · Cited by 457 · see citing works
Keeping up with the neighbours: phytochrome sensing and other signalling mechanisms
Ballaré, C. L. (1999) · Trends in Plant Science · doi:10.1016/s1360-1385(99)01383-7 · Cited by 440 · see citing works
Alonso‐Blanco, C., Peeters, A. J. M., Koornneef, M., Lister, C., Dean, C., van den Bosch, N., Pot, J., & Kuiper, M. T. R. (1998) · The Plant Journal · doi:10.1046/j.1365-313x.1998.00115.x · Cited by 368 · see citing works
Population genetic structure and outcrossing rate of Arabidopsis thaliana (L.) Heynh.
Abbott, R. J., & Gomes, M. F. (1989) · Heredity · doi:10.1038/hdy.1989.56 · Cited by 327 · see citing works
PLASTICITY TO LIGHT CUES AND RESOURCES IN ARABIDOPSIS THALIANA: TESTING FOR ADAPTIVE VALUE AND COSTS
Dorn, L. A., Pyle, E. H., & Schmitt, J. (2000) · Evolution · doi:10.1111/j.0014-3820.2000.tb01242.x · Cited by 271 · see citing works
The environmental induction of heritable change in Linum
DURRANT, A. (1962) · Heredity · doi:10.1038/hdy.1962.2 · Cited by 240 · see citing works
Donohue, K., Messiqua, D., Pyle, E. H., Heschel, M. S., & Schmitt, J. (2000) · Evolution · doi:10.1111/j.0014-3820.2000.tb01240.x · Cited by 224 · see citing works
Gene Families from the Arabidopsis thaliana Pollen Coat Proteome
Mayfield, J. A., Fiebig, A., Johnstone, S. E., & Preuss, D. (2001) · Science · doi:10.1126/science.1060972 · Cited by 217 · see citing works
Kimura, M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.14.5969 · Cited by 163 · see citing works
Molecular chaperones: The busy life of Hsp90
Mayer, M. P., & Bukau, B. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80203-6 · Cited by 156 · see citing works
Developmental phenotypic plasticity: Where ecology and evolution meet molecular biology
Callahan, H. S., Pigliucci, M., & Schlichting, C. D. (1997) · BioEssays · doi:10.1002/bies.950190611 · Cited by 129 · see citing works
Genomic organization of hsp90 gene family in Arabidopsis
Milioni, D., & Hatzopoulos, P. (1997) · Plant Molecular Biology · doi:10.1023/a:1005874521528 · Cited by 119 · see citing works
Kuittinen, H., Mattila, A., & Savolainen, O. (1997) · Heredity · doi:10.1038/hdy.1997.137 · Cited by 111 · see citing works
Reaction norm functions and QTL–environment interactions for flowering time in Arabidopsis thaliana
Stratton, D. A. (1998) · Heredity · doi:10.1046/j.1365-2540.1998.00369.x · Cited by 87 · see citing works
McLaren, A. L. D. (1999) · Trends in Genetics · doi:10.1016/s0168-9525(99)01732-1 · Cited by 49 · see citing works
Gene Conversion may aid Adaptive Peak Shifts
Hansen, T. F., Carter, A. J. R., & Chiu, C.-H. (2000) · Journal of Theoretical Biology · doi:10.1006/jtbi.2000.2189 · Cited by 28 · see citing works
Pigliucci, M. (1998) · Biological Journal of the Linnean Society · doi:10.1006/bijl.1997.0193 · Cited by 28 · see citing works
Kumar, P., Ward, B. K., Minchin, R. F., & Ratajczak, T. (2001) · Cell Stress and Chaperones · doi:10.1379/1466-1268(2001)006 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences
Raj, A., & van Oudenaarden, A. (2008) · Cell · doi:10.1016/j.cell.2008.09.050 · Cited by 2,593 · see citing works
Adapting Proteostasis for Disease Intervention
Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. (2008) · Science · doi:10.1126/science.1141448 · Cited by 2,495 · see citing works
Kitano, H. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1471 · Cited by 2,278 · see citing works
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
Taipale, M., Jarosz, D. F., & Lindquist, S. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2918 · Cited by 1,818 · see citing works
Self-citationSchopf, F. H., Biebl, M. M., & Buchner, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.20 · Cited by 1,540 · see citing works
Early Developmental Conditioning of Later Health and Disease: Physiology or Pathophysiology?
Hanson, M. A., & Gluckman, P. D. (2014) · Physiological Reviews · doi:10.1152/physrev.00029.2013 · Cited by 1,188 · see citing works
Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007) · American Journal of Human Biology · doi:10.1002/ajhb.20590 · Cited by 1,006 · see citing works
Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K. D., Karras, G. I., & Lindquist, S. (2012) · Cell · doi:10.1016/j.cell.2012.06.047 · Cited by 879 · see citing works
Self-citationHsp90 Potentiates the Rapid Evolution of New Traits: Drug Resistance in Diverse Fungi
Cowen, L. E., & Lindquist, S. (2005) · Science · doi:10.1126/science.1118370 · Cited by 698 · see citing works
Self-citationDiscovering susceptibility genes for asthma and allergy
Vercelli, D. (2008) · Nature Reviews Immunology · doi:10.1038/nri2257 · Cited by 635 · see citing works
A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease
Brehme, M., Voisine, C., Rolland, T., Wachi, S., Soper, J. H., Zhu, Y., Orton, K., Villella, A., Garza, D., Vidal, M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.042 · Cited by 584 · see citing works
Uncovering cryptic genetic variation
Gibson, G., & Dworkin, I. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1426 · Cited by 546 · see citing works
Regulatory circuitry governing fungal development, drug resistance, and disease.
Shapiro, R. S., Robbins, N., & Cowen, L. E. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00045-10 · Cited by 576 · see citing works
Lehner, B., Crombie, C., Tischler, J., Fortunato, A., & Fraser, A. G. (2006) · Nature Genetics · doi:10.1038/ng1844 · Cited by 502 · see citing works
The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones
Li, J., Soroka, J., & Buchner, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.003 · Cited by 498 · see citing works
Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution
Sollars, V., Lu, X., Xiao, L., Wang, X., Garfinkel, M. D., & Ruden, D. M. (2003) · Nature Genetics · doi:10.1038/ng1067 · Cited by 409 · see citing works
Robustness: mechanisms and consequences
Masel, J., & Siegal, M. L. (2009) · Trends in Genetics · doi:10.1016/j.tig.2009.07.005 · Cited by 348 · see citing works
Hsp90 and Environmental Stress Transform the Adaptive Value of Natural Genetic Variation
Jarosz, D. F., & Lindquist, S. (2010) · Science · doi:10.1126/science.1195487 · Cited by 346 · see citing works
Self-citationNear-neutrality in evolution of genes and gene regulation
Ohta, T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252626899 · Cited by 333 · see citing works
Network biology concepts in complex disease comorbidities
Hu, J. X., Thomas, C. E., & Brunak, S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.87 · Cited by 328 · see citing works
Hsp90 Orchestrates Temperature-Dependent Candida albicans Morphogenesis via Ras1-PKA Signaling
Shapiro, R. S., Uppuluri, P., Zaas, A. K., Collins, C., Senn, H., Perfect, J. R., Heitman, J., & Cowen, L. E. (2009) · Current Biology · doi:10.1016/j.cub.2009.03.017 · Cited by 311 · see citing works
The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype.
Cowen, L. E. (2008) · Nature Reviews Microbiology · doi:10.1038/nrmicro1835 · Cited by 311 · see citing works
Goldstone, J. V., Hamdoun, A., Cole, B. J., Howard-Ashby, M., Nebert, D. W., Scally, M., Dean, M., Epel, D., Hahn, M. E., & Stegeman, J. J. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.066 · Cited by 280 · see citing works
System-wide molecular evidence for phenotypic buffering in Arabidopsis
Fu, J., Keurentjes, J. J. B., Bouwmeester, H., America, T., Verstappen, F. W. A., Ward, J. L., Beale, M. H., de Vos, R. C. H., Dijkstra, M., Scheltema, R. A., et al. (2009) · Nature Genetics · doi:10.1038/ng.308 · Cited by 265 · see citing works
Antifungal Drugs: The Current Armamentarium and Development of New Agents
Robbins, N., Wright, G. D., & Cowen, L. E. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.funk-0002-2016 · Cited by 271 · see citing works
Li, J., Zhao-Hui, C., Batoux, M., Nekrasov, V., Roux, M., Chinchilla, D., Zipfel, C., & Jones, J. D. G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905532106 · Cited by 273 · see citing works
Kassahn, K. S., Crozier, R. H., Pörtner, H. O., & Caley, M. J. (2009) · Biological Reviews · doi:10.1111/j.1469-185x.2008.00073.x · Cited by 263 · see citing works
Under cover: causes, effects and implications of Hsp90‐mediated genetic capacitance
Sangster, T. A., Lindquist, S., & Queitsch, C. (2004) · BioEssays · doi:10.1002/bies.20020 · Cited by 251 · see citing works
Self-citationFirefly luciferase mutants as sensors of proteome stress
Gupta, R., Kasturi, P., Bracher, A., Loew, C., Zheng, M., Villella, A., Garza, D., Hartl, F. U., & Raychaudhuri, S. (2011) · Nature Methods · doi:10.1038/nmeth.1697 · Cited by 219 · see citing works
Protein Homeostasis and the Phenotypic Manifestation of Genetic Diversity: Principles and Mechanisms
Jarosz, D. F., Taipale, M., & Lindquist, S. (2010) · Annual Review of Genetics · doi:10.1146/annurev.genet.40.110405.090412 · Cited by 179 · see citing works
Self-citationHSP90 affects the expression of genetic variation and developmental stability in quantitative traits
Sangster, T. A., Salathia, N., Undurraga, S., Milo, R., Schellenberg, K., Lindquist, S., & Queitsch, C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712200105 · Cited by 174 · see citing works
Self-citationAn Adaptable Standard for Protein Export from the Endoplasmic Reticulum
Wiseman, R. L., Powers, E. T., Buxbaum, J. N., Kelly, J. W., & Balch, W. E. (2007) · Cell · doi:10.1016/j.cell.2007.10.025 · Cited by 155 · see citing works
Fitness Trade-Offs and Environmentally Induced Mutation Buffering in Isogenic <i>C. elegans</i>
Casanueva, M. O., Burga, A., & Lehner, B. (2012) · Science · doi:10.1126/science.1213491 · Cited by 146 · see citing works
HSP90-buffered genetic variation is common in <i>Arabidopsis thaliana</i>
Sangster, T. A., Salathia, N., Lee, H. N., Watanabe, E., Schellenberg, K., Morneau, K., Wang, H., Undurraga, S., Queitsch, C., & Lindquist, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712210105 · Cited by 131 · see citing works
Self-citationHsp90 orchestrates stress response signaling governing fungal drug resistance
Cowen, L. E. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000471 · Cited by 130 · see citing works
Diezmann, S., Michaut, M., Shapiro, R. S., Bader, G. D., & Cowen, L. E. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002562 · Cited by 112 · see citing works
Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs
Leach, M. D., Klipp, E., Cowen, L. E., & Brown, A. J. P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2875 · Cited by 107 · see citing works
Comprehensive fitness maps of Hsp90 show widespread environmental dependence
Flynn, J. M., Rossouw, A., Cote-Hammarlof, P., Fragata, I., Mavor, D., Hollins, C., Bank, C., & Bolon, D. N. (2020) · eLife · doi:10.7554/elife.53810 · Cited by 91 · see citing works
Taxa-function robustness in microbial communities
Eng, A., & Borenstein, E. (2018) · Microbiome · doi:10.1186/s40168-018-0425-4 · Cited by 89 · see citing works
Massey, S. (2015) · Life · doi:10.3390/life5021301 · Cited by 38 · see citing works
Evolutionary Adaptation to Freeze‐Thaw‐Growth Cycles in<i>Escherichia coli</i>
Sleight, S. C., & Lenski, R. E. (2007) · Physiological and Biochemical Zoology · doi:10.1086/518013 · Cited by 32 · see citing works
- Authors
- Queitsch, C., Sangster, T. A., & Lindquist, S.
- Affiliations
- University of Chicago (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lindquist, Susan
- ORCID
- Queitsch, Christine
- Venue
- Nature
- Published
- 2002-05-12
- Volume
- 417
- Issue
- 6889
- Pages
- 618-624
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1992909271
- Cited by
- 1,372
- References
- 27
- Citations by year
- 2026: 24 · 2025: 37 · 2024: 34 · 2023: 37 · 2022: 36 · 2021: 41 · 2020: 48 · 2019: 68 · 2018: 62 · 2017: 52 · 2016: 49 · 2015: 51 · 2014: 64 · 2013: 75 · 2012: 49
- FWCI
- 24.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Chicago
- Arizona Biomedical Research Commission
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Physical Sciences › Mathematics › Geometry and Topology › Morphological variations and asymmetry
- Keywords
- HSP90, phenotypic variability, genetic buffering, Arabidopsis thaliana, Drosophila melanogaster, cryptic genetic variation, environmental plasticity, developmental noise, gene-environment interaction, molecular chaperones, evolutionary processes
- MeSH terms
- Crosses, Genetic, Darkness, Environment, Biological Evolution, Genetic Engineering, Genotype, Light, Phenotype, Stochastic Processes, Genetic Variation, Genes, Plant, Arabidopsis, HSP90 Heat-Shock Proteins, Arabidopsis Proteins, Plants, Genetically Modified
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
