Under cover: causes, effects and implications of Hsp90‐mediated genetic capacitance

Abstract

The environmentally responsive molecular chaperone Hsp90 assists the maturation of many key regulatory proteins. An unexpected consequence of this essential biochemical function is that genetic variation can accumulate in genomes and can remain phenotypically silent until Hsp90 function is challenged. Notably, this variation can be revealed by modest environmental change, establishing an environmentally responsive exposure mechanism. The existence of diverse cryptic polymorphisms with a plausible exposure mechanism in evolutionarily distant lineages has implications for the pace and nature of evolutionary change. Chaperone-mediated storage and release of genetic variation is undoubtedly rooted in protein-folding phenomena. As we discuss, proper protein folding crucially affects the trajectory from genotype to phenotype. Indeed, the impact of protein quality-control mechanisms and other fundamental cellular processes on evolution has heretofore been overlooked. A true understanding of evolutionary processes will require an integration of current evolutionary paradigms with the many new insights accruing in protein science.

The androgen receptor and prostate cancer: A role for sexual selection and sexual conflict?

“…This association with growth and replication also applies to a tumor suppressor gene, LATS1 [89], and the insulin-like growth factor 1 receptor [90]. The expression of one of these genes, CDC37, is mediated by the gene HSP90 [91], which is intimately involved in carcinogenesis [92] and has evolved under positive selection in some mammals [93].…”

Embryo stability and vulnerability in an always changing world

“…HSP90 is unique because its buffering action also prevents expression of genetic variants that become apparent only when HSP90 is overwhelmed. The resulting expression of these previously quiescent mutations results in radically altered phenotypes (77). This generation of new phenotypes is a ''lottery approach,'' meaning that most of these phenotypes are not adaptive.…”

Hsp90—From signal transduction to cell transformation

“…As a chaperone for many proteins that lie along broad-reaching signal cascades, the function of Hsp90 is central to key developmental processes [4,5]. Therefore, when the activity of Hsp90 is compromised due to environmental stress or the application of Hsp90 inhibitors, the effects are often pleiotropic [58]. In this capacity, Hsp90 has been portrayed as a 'capacitor for evolution' [57].…”

“…In this capacity, Hsp90 has been portrayed as a 'capacitor for evolution' [57]. Since a significant portion of mutated proteins stabilized by Hsp90 likely result from genetic mutations, Hsp90 has also been described as a 'genetic capacitor' [58]. This adds to the ever-increasing convolution involved with the translation of genotype to phenotype.…”