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Although the evolutionary importance of copy-number variation is known, little is understood about how genetic background influences its tolerance. Here, we measured fitness costs of over 4000 overexpressed genes in 15\n                    <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                    strains representing different lineages, to explore natural variation in tolerating gene overexpression (OE). Strain-specific effects dominated the fitness costs of gene OE. We report global differences in the consequences of gene OE, independent of the amplified gene, as well as gene-specific effects that were dependent on the genetic background. Natural variation in the response to gene OE could be explained by several models, including strain-specific physiological differences, resource limitations, and regulatory sensitivities. This work provides new insight on how genetic background influences tolerance to gene amplification and the evolutionary trajectories accessible to different backgrounds.\n                  <\/jats:p>","DOI":"10.7554\/elife.70564","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T08:01:42Z","timestamp":1627891302000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.70564","source":"Crossref","is-referenced-by-count":33,"title":["Natural variation in the consequences of gene overexpression and its implications for evolutionary trajectories"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0476-3908","authenticated-orcid":true,"given":"DeElegant","family":"Robinson","sequence":"first","affiliation":[{"name":"Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, United 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