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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\u2013Aldrich 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\u2013Aldrich 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.<\/jats:p>","DOI":"10.15252\/msb.20156444","type":"journal-article","created":{"date-parts":[[2015,10,13]],"date-time":"2015-10-13T14:54:47Z","timestamp":1444748087000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Evolutionary rescue by compensatory mutations is\u00a0constrained by genomic and environmental backgrounds"],"prefix":"10.1038","volume":"11","author":[{"given":"Marie","family":"Filteau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Christine","family":"Pouliot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Gagnon\u2010Arsenault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre K","family":"Dub\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian R","family":"Landry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,12]]},"reference":[{"key":"BFMSB156444_CR1","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/MOH.0b013e32834114bc","volume":"18","author":"MH Albert","year":"2011","unstructured":"Albert MH, Notarangelo LD, Ochs HD (2011) Clinical spectrum, pathophysiology and treatment of the Wiskott\u2013Aldrich syndrome. 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