Lindquist Lab--Research--Evolution

Conformational Change and Evolution

In the last several decades, mathematical modeling and DNA sequence analysis have transformed our view of evolutionary processes. The recent revolution in our understanding of protein folding mechanisms has the potential to have a similar impact. We have investigated two protein folding mechanisms that have a remarkable potential to act as capacitors for evolutionary change; that is, they allow organism to store genetic variation in a silent form and to uncover it on a global, genome-wide scale.

The molecular chaperone, Hsp90, was the first protein folding factor shown to influence the accumulation of genetic variation. Hsp90 is specialized to chaperone a distinct class of client proteins that have unstable tertiary and quaternary structures. These include a wide variety of signal transducers that only acquire their final structure and achieve their active states in response to specific signals. In Drosophila melanogaster, we found that Hsp90 buffers the effects of a multitude of silent polymorphisms at normal temperatures. When the organism is stressed, the effects of these polymorphisms are exposed, probably because Hsp90’s normal substrates become more unstable and because some Hsp90 is recruited to other, newly unstable proteins. Selection can then act on the traits these polymorphisms produce. We hypothesize that Hsp90 is a capacitor for morphogenetic evolution, allowing organisms to accumulate mutations that remain silent under optimal conditions and releasing their effects during stress when they might provide a survival advantage. Recently we have extended these investigations to Arabidopsis, where recombinant inbred lines offer an opportunity to identify groups of polymorphisms that function together to produce specific changes in traits.

In yeast we have discovered that Hsp90 potentiates the evolution of drug resistance by allowing new mutations to have immediate and beneficial consequences. New mutations confer resistance but produce stresses of their own that would otherwise kill the cells. We found that by chaperoning calcineurin, Hsp90 allows it to function in stress-response pathways that prevent the cellular stress from the mutations from becoming lethal.

An equally vast store of phenotypic variation was uncovered through our work with the yeast prion, Sup35. In more than 150 phenotyic assays [PSI⁺] produced a wide variety of phenotypes. Moreover, in each of the seven genetic backgrounds tested, the constellation of phenotypes produced was unique. We suggest that the epigenetic and metastable nature of [PSI⁺] inheritance allows yeast cells to exploit pre-existing genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI⁺] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits.

A clue to the puzzling phenomenon of episodes of rapid evolutionary diversification is provided by our results from flies, plants, and yeast, which suggest that folding mechanisms of molecular chaperones and yeast prions can allow organisms to reveal accumulated-but-hidden genetic variation in times of stress and evolve rapidly in response to changing environmental conditions.

Also see Prion Biology, Cancer, and Anti-Infectives projects.

Lectures

Susan Lindquist interviewed by Orli Bachall of Nature Genetics at Cold Spring Harbor, Evolution: the Molecular Landscape (May 2009)

"Protein Folding Driving Evolutionary Change" (Stanford University, December 2009), 1 hr, 18 mins (available from iTunes U--iTunes required for viewing)

"Protein Folding Sculpting Evolutionary Change" (The EPFL School of Life Science Inaugural Symposium, Lausanne, Switzerland, September 2009), 37 mins, 46 sec.

Podcasts

Futures in Biotech 77: How The Environment And A Single Protein Influence Evolution (March 2011)

Futures in Biotech 57: Mechanisms of Non-Mendelian Inheritance In Evolution (April 2010)

Selected Publications on Conformational Change and Evolution

Reviews:

Taipale M, Jarosz DF, Lindquist S, 2010. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11: 515-28. [PDF 724 KB]

Sangster TA, Lindquist S, Queitsch C, 2004. Under Cover: causes, effects and implications of Hsp90-mediated genetic capacitance. Bioessays 26: 348-62. [PDF 452 KB]

Viewpoint:

Nature selects Hsp90 & evolution as one of the 15 evolutionary gems published in the journal in the last couple of decades [#15 "Variation vs. Stability"]

Bussard AE, 2005. A Scientific Revolution? The prion anomaly may challenge the central dogma of molecular biology. EMBO Reports 6: 691-93. [PDF 172 KB]

Research Papers:

Jarosz DF, Lindquist S, 2010. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330: 1820-4. [Science PDF link]

Cowen LE, Singh SD, Köhler JR, Collins C, Zaas A, Schell W, Aziz H, Mylonakis E, Perfect JR, Whitesell L, Lindquist S, 2009. Harnessing Hsp90 Function as a Novel Therapeutic Strategy for Fungal Infectious Disease. Proc Natl Acad Sci USA106: 2818-23.[PDF 1.04 MB]

Sangster TA, Salathia N, Undurraga S, Schellenberg K, Lindquist S and Queitsch C, 2008. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits. Proc Natl Acad Sci USA 105: 2963-8.[PDF 1.6 MB]

Sangster TA, Salathia N, Lee HN, EWatanabe E, Schellenberg K, Morneau K, Wang H, Undurraga S, Queitsch C and Lindquist S, 2008. HSP90-buffered genetic variation is common in Arabidopsis thaliana. Proc Natl Acad Sci USA105: 2969-74. [PDF 1.0 MB]

Sangster TA, Bahrami A, Wilczek A, Watanabe E, Schellenberg K, McLellan C, Kelley A, Kong SW, Queitsch C and Lindquist S, 2007. Phenotypic diversity and altered environmental plasticity in Arabidopsis thaliana with reduced Hsp90 levels. PLoS ONE 2: e648. [PDF 812 KB]

Cowen LE, Carpenter AE, Matangkasombut O, Fink GR, and Lindquist S, 2006. Genetic Architecture of Hsp90-Dependent Drug Resistance. Eukaryot Cell 5: 2184-8. [PDF 374 KB]

Cowen LE and Lindquist S 2005. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185-89. [PDF 460 KB]

This paper was covered by three concurrent Perspectives/Research Highlights:

Heitman, J. A Fungal Achilles’ Heel. Science 309: 2175-76 (2005).

Owens, J. Evolution: A Helping Hand. Nat. Rev. Genet. 6: 801 (2005).[PDF 862KB]

Owens, J. Antifungal Drugs: A Helping Hand. Nat. Rev. Drug Discov. 4: 884-85 (2005).[PDF 766 KB]

True H, Berlin I and Lindquist S, 2004. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431: 184-87. [PDF 304 KB]

Queitsch C, Sangster TA and Lindquist S, 2002. Hsp90 as a capacitor of phenotypic variation. Nature 417: 618-24. [PDF 556 KB]

True HL and Lindquist SL, 2000. A yeast prion provides an exploratory mechanism for genetic variation and phenotypic diversity. Nature 407: 477-83. [PDF 324 KB]

Rutherford SL and Lindquist S 1998. Hsp90 as a capacitor for morphological evolution. Nature 396: 336-42. [PDF 552 KB]

Xu Y and Lindquist S, 1993. Heat-shock protein hsp90 governs the activity of pp60v-src kinase. Proc. Nat. Acad. Sci. USA 90: 7074-78. [PDF 2.8 MB]

Who's Working on Conformational Change and Evolution

Manoshi Datta Manoshi Datta Dan Jarosz Dan Jarosz Georgios Karras Georgios Karras