Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds

Since deleterious mutations may be rescued by secondary mutations during evolution, compensatory evolution could identify genetic solutions leading to therapeutic targets. Here, we tested this hypothesis and examined whether these solutions would be universal or would need to be adapted to one's genetic and environmental makeups. We performed experimental evolutionary rescue in a yeast disease model for the Wiskott–Aldrich syndrome in two genetic backgrounds and carbon sources. We found that multiple aspects of the evolutionary rescue outcome depend on the genotype, the environment, or a combination thereof. Specifically, the compensatory mutation rate and type, the molecular rescue mechanism, the genetic target, and the associated fitness cost varied across contexts. The course of compensatory evolution is therefore highly contingent on the initial conditions in which the deleterious mutation occurs. In addition, these results reveal biologically favored therapeutic targets for the Wiskott–Aldrich syndrome, including the target of an unrelated clinically approved drug. Our results experimentally illustrate the importance of epistasis and environmental evolutionary constraints that shape the adaptive landscape and evolutionary rate of molecular networks. Synopsis Experimental evolution to rescue a disease mutation in a Wiskott–Aldrich Syndrome yeast model highlights aspects of compensatory evolution that are constrained by the initial environment and genetic background and identifies potential therapeutic targets. The compensatory mutation rate and type and the molecular rescue mechanisms of deleterious mutations are context‐dependent. The genetic rescue remedies to a deleterious allele can be context‐dependent at the function, gene and allelic levels. The identification of genetic rescue mutations in a yeast model for the Wiskott–Aldrich syndrome lead to the reveal a drug that rescues the thermosensitive phenotype. Graphical Abstract Experimental evolution to rescue a disease mutation in a Wiskott–Aldrich Syndrome yeast model highlights aspects of compensatory evolution that are constrained by the initial environment and genetic background and identifies potential therapeutic targets.