Paper
Sangster, T.A., Lindquist, S. and Queitsch, C. (2004). Under cover: causes, effects and implications of Hsp90-mediated
genetic capacitance. BioEssays 26:348–362.
PDF
2004_Sangster_etal_molecular_chaperones.pdf
Summary
This paper deals with the interplay of genotype and environment to yield phenotypes, and in particular the role of
molecular chaperones in stabilizing the phenotype in the face of genotypic and environmental variation.
The authors ask how it is that a phenotype can be stably expressed despite genetic and environmental variation? They
draw upon the work of Waddington who first coined the concept of canalization. At the population level, canalization is a
genome’s ability to produce a regular phenotype regardless of genetic or environmental perturbation. At the individual
level, developmental stability is the ability of an individual to produce invariant repeated characters throughout
development. In this paper, the authors focus on the implications of chaperone-mediated buffering for canalization. The
paper focuses on HSP90, but the arguments apply more generally to any buffering mechanism.
Several authors support an evolved origin of canalization, but debate whether canalization primarily results from
redundancy of duplicated genes (86,88) or environmentally imposed stabilizing selection leading to the formation of
complex regulatory networks(89–92). In contrast, Siegal and Bergman(2) proposed that canalization is a fundamental,
intrinsic feature of functional genetic networks. Both empirical and computational data agree that evolved networks are
extremely robust to perturbation, and a more densely connected network is often associated with increased canalization.
The paper begins by noting that evolution draws upon phenotypic variation among individuals, and that phenotypic
diversity depends upon the interplay of genetic and environmental factors. The authors cite cases in insects and plants
where variation in the activity of HSP90 can have major and wide-ranging effects on phenotype, and suggest that these
effects may result from preexisting genetic polymorphism whose influence on pathway function is normally hidden. When
Hsp90 activity is taxed, diverse pathways become sensitive to the effects of cryptic genetic variation. That is, Hsp90 acts
to buffer the expression of much genetic variation, which accumulates under normal circumstances with little phenotypic
consequence, only to be revealed in times of environmental stress or through mutations affecting Hsp90 activity.
One example given by the authors involves larval development of Drosophila melanogaster. Larval development is
normally monotonically faster with increasing temperature. Selection for more rapid development failed at most
temperatures. However, under conditions of heat-stress (32C), selection yielded heritable increases in development rate
that persisted at both high and normal temperatures, presumably through selection acting on genetic variation released
by overstretching the buffering capacity of molecular chaperones.
Wild isolates of Drosophila and Arabidopsis show accumulation of buffered variation and morphologies specific to Hsp90
genetic mutations can be alternatively uncovered by temperature change. The authors present a case of this in their
Figure 3. Indeed, environmentally-mediated alteration of Hsp90 is likely to occur more frequently in nature than Hsp90
mutations. The reversibility of environmental challenges affecting Hsp90 activity fundamentally distinguishes storage and
release of Hsp90-buffered variation from other suggested buffering mechanisms.
The synchronized exposure of multiple polymorphisms could allow substantial shifts in phenotype without passage
through intermediate forms. Most combinations no doubt will be deleterious, but very rare ones may be advantageous.
The model presented by the authors of accumulation of cryptic genetic variation and synchronized release provides a
mechanism whereby phenotypic transitions that require multiple mutational steps can be achieved, when intermediate
states are deleterious or have reduced fitness.
The authors note that traits can become Hsp90-independent after only a few generations of selection, very short-lived
extreme environmental changes or fluctuating environments may have an oversized evolutionary impact due to the
storage and release of cryptic genetic variation.
Comments
This paper has obvious relevance to understanding evolutionary responses to climate change. An environmental shift in
the context of a genetic buffer against temperature variation can, under this model, release otherwise cryptic variation.
That variation will be in the form of accumulated genetic variation, and so will include novel combinations of genes
leading to phenotypic changes that might otherwise have not been possible because of the inviability of forms arising
through the normal process of stepwise sequence of mutation accumulation. Vestigial developmental pathways may be
reactivated (refer to the papers cited by Lambert and Hughes). The evolution, involving synchronized release of novel
genetic variation, could potentially be rapid.
Key Cited References
Waddington CH. 1942. Canalization of development and the inheritance of acquired characters. Nature 150:563–565.
Siegal ML, Bergman A. 2002. Waddington’s canalization revisited: developmental stability and evolution. Proc Natl Acad
Sci USA 99:10528–10532.
Rutherford SL, Lindquist S. 1998. Hsp90 as a capacitor for morphological evolution. Nature 396:336–342.
Queitsch C, Sangster TA, Lindquist S. 2002. Hsp90 as a capacitor of phenotypic variation. Nature 417:618–624.
Bergman A, Siegal ML. 2003. Evolutionary capacitance as a general feature of complex gene networks. Nature
424:549–552.
Sollars V, Lu X, Xiao L, Wang X, Garfinkel MD, Ruden DM. 2003. Evidence for an epigenetic mechanism by which
Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33:70–74.
Rutherford SL. 2003. Between genotype and phenotype: protein chaperones and evolvability. Nat Rev Genet 4:263–274.
Gould SJ, Lewontin RC. 1979. The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist
programme. Proc R Soc Lond B Biol Sci 205:581–598.
Queitsch C. 2001. Thermotolerance, buffering of genetic variation and developmental stability—different aspects of
chaperone function in the plant Arabidopsis thaliana. Thesis. Department of Molecular Genetics
and Cell Biology. University of Chicago.
Whittle JRS. 1998. How is developmental stability sustained in the face of genetic variation? Int J Dev Biol 42:495–499.
Gu Z, Steinmetz LM, Gu X, Scharfe C, Davis RW, Li WH. 2003. Role of duplicate genes in genetic robustness against
null mutations. Nature 421:63–66.
Kawecki TJ. 2000. The evolution of genetic canalization under fluctuating selection. Evolution 54:1–12.
Eshel I, Matessi C. 1998. Canalization, genetic assimilation and preadaptation. A quantitative genetic model. Genetics
149:2119–2133.
Wagner A. 1996. Does evolutionary plasticity evolve? Evolution 50:1008–1023.
Wagner A. 2000. Robustness against mutations in genetic networks of yeast. Nat Genet 24:355–361.