title: Evolutionary rescue by compensatory mutations is constrained by genomic and environmental backgrounds.
abstract: 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 make-ups. 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.
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Filteau
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Hamel
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Pouliot
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gagnon-Arsenault
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada.
authors.forename: Alexandre K
authors.initials: AK
authors.lastname: Dubé
authors.affiliation: Département de Biologie, PROTEO and Institut de Biologie Intégrative et des Systèmes (IBIS) Université Laval, Québec, Qc, Canada christian.landry@bio.ulaval.ca.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Landry
mesh_terms: D019143:Evolution, Molecular; D023281:Genomics; D009154:Mutation
keywords: Wiskott–Aldrich syndrome; aneuploidy; epistasis; experimental evolution; genotype‐by‐environment interaction