Hsp90 and complex birth defects: A plausible mechanism for the interaction of genes and environment

How genes and environment interact to cause birth defects is not well understood, but key to developing new strategies to modify risk. The threshold model has been proposed to represent this complex interaction. This model stipulates that while environmental exposure or genetic mutation alone may not result in a defect, factors in combination increase phenotypic variability resulting in more individuals crossing the disease threshold where birth defects manifest. Many environmental factors that contribute to birth defects induce widespread cellular stress and misfolding of proteins. Yet, the impact of the stress response on the threshold model is not typically considered in discephering the etiology of birth defects. This mini-review will explore a potential mechanism for gene-environment interactions co-opted from studies of evolution. This model stipulates that heat shock proteins that mediate the stress response induced by environmental factors can influence the number of individuals that cross disease thresholds resulting in increased incidence of birth defects. Studies in the field of evolutionary biology have demonstrated that heat shock proteins and Hsp90 in particular provide a link between environmental stress, genotype and phenotype. Hsp90 is a highly expressed molecular chaperone that assists a wide variety of protein clients with folding and conformational changes needed for proper function. Hsp90 also chaperones client proteins with potentially deleterious amino acid changes to suppress variation caused by genetic mutations. However, upon exposure to stress, Hsp90 abandons its normal physiological clients and is diverted to assist with the misfolded protein response. This can impact the activity of signaling pathways that involve Hsp90 clients as well as unmask suppressed protein variation, essentially creating complex traits in a single step. In this capacity Hsp90 acts as an evolutionary capacitor allowing stored variation to accumulate and then become expressed in times of stress. This mechanism provides a substrate which natural selection can act upon at the population level allowing survival of the species with selective pressure. However, at the level of the individual, this mechanism can result in simultaneous expression of deleterious variants as well as reduced activity of a variety of Hsp90 chaperoned pathways, potentially shifting phenotypic variability over the disease threshold resulting in birth defects.