{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:33:20Z","timestamp":1790094800033,"version":"4.0.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T00:00:00Z","timestamp":1555977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epistasis is widely regarded as one of the most important phenomena in genetics. It proposes that the combined effects of mutations cannot be easily predicted from their individual effects. In the present study...<\/jats:p>\n                  <jats:p>Recent studies have affirmed that higher-order epistasis is ubiquitous and can have large effects on complex traits. Yet, we lack frameworks for understanding how epistatic interactions are influenced by central features of cell physiology. In this study, we assess how protein quality control machinery\u2014a critical component of cell physiology\u2014affects epistasis for different traits related to bacterial resistance to antibiotics. Specifically, we disentangle the interactions between different protein quality control genetic backgrounds and two sets of mutations: (i) SNPs associated with resistance to antibiotics in an essential bacterial enzyme (dihydrofolate reductase, or DHFR) and (ii) differing DHFR bacterial species-specific amino acid background sequences (Escherichia coli, Listeria grayi, and Chlamydia muridarum). In doing so, we improve on generic observations that epistasis is widespread by discussing how patterns of epistasis can be partly explained by specific interactions between mutations in an essential enzyme and genes associated with the proteostasis environment. These findings speak to the role of environmental and genotypic context in modulating higher-order epistasis, with direct implications for evolutionary theory, genetic modification technology, and efforts to manage antimicrobial resistance.<\/jats:p>","DOI":"10.1534\/genetics.119.302138","type":"journal-article","created":{"date-parts":[[2019,4,23]],"date-time":"2019-04-23T21:45:29Z","timestamp":1556055929000},"page":"565-575","source":"Crossref","is-referenced-by-count":41,"title":["Proteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance"],"prefix":"10.1093","volume":"212","author":[{"given":"Rafael F","family":"Guerrero","sequence":"first","affiliation":[{"name":"Department of Computer Science, Indiana University, Bloomington, Indiana 47408"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel V","family":"Scarpino","sequence":"additional","affiliation":[{"name":"Network Science Institute, Northeastern University, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o V","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Marine and Environmental Sciences, Northeastern University, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L","family":"Hartl","sequence":"additional","affiliation":[{"name":"Department of Physics, Northeastern University, Boston, Massachusetts 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C Brandon","family":"Ogbunugafor","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138"},{"name":"Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138"},{"name":"Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island 02912"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,23]]},"reference":[{"key":"2022011123564968400_bib1","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.molcel.2012.11.004","article-title":"Protein quality control acts on folding intermediates to shape the effects of mutations on organismal fitness.","volume":"49","author":"Bershtein","year":"2013","journal-title":"Mol. 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