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They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two\u2010component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with computational predictions, we find that: (i) intra\u2010module mutations target and eliminate the module if it confers only cost without any benefit to the cell; (ii) intra\u2010 and extra\u2010module mutations jointly activate the module if it is potentially beneficial and confers no cost; and (iii) a few specific mutations repeatedly fine\u2010tune the module's noisy response if it has excessive costs and\/or insufficient benefits. Overall, these findings reveal how the timing and mechanisms of stress response network evolution depend on the environment.<\/jats:p>","DOI":"10.15252\/msb.20156185","type":"journal-article","created":{"date-parts":[[2015,8,31]],"date-time":"2015-08-31T21:10:39Z","timestamp":1441055439000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Stress\u2010response balance drives the evolution of a network module and its host genome"],"prefix":"10.1038","volume":"11","author":[{"given":"Caleb","family":"Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe Christian J","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Manhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys M","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Nevozhay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre V","family":"Morozov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Bal\u00e1zsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,31]]},"reference":[{"key":"BFMSB156185_CR1","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1101\/gad.1586107","volume":"21","author":"CM Ajo\u2010Franklin","year":"2007","unstructured":"Ajo\u2010Franklin CM, Drubin DA, Eskin JA, Gee EP, Landgraf D, Phillips I, Silver PA (2007) Rational design of memory in eukaryotic cells. 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