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Pathogenic fungi inhabit a wide range of environments across the world, and their ranges have been slowly expanding in recent decades due, in part, to climate change. Despite these links between increasing temperature and higher prevalence of fungal disease, the direct effects of rising environmental temperatures on the evolution of pathogenic fungi remain unclear. In this study, we investigated how increasing temperatures drive adaptive evolution in the human fungal pathogen Cryptococcus neoformans. First, we performed serial passages of a C. neoformans environmental isolate with gradual changes in temperature over the course of 38 days. Through this approach, we identified several distinct thermally adapted isolates with competitive growth advantages over the parental strain at high temperatures. We then characterized the phenotypic and genetic changes acquired in these evolved isolates, which included alteration of cell size, colony morphology, and, notably, antifungal resistance. Our genetic analyses further revealed distinct genes that facilitate thermoadaptation in different populations\u2014identifying new molecular players in the regulation of this trait and revealing that there are multiple independent routes to gaining thermotolerance. These results highlight the remarkable flexibility of fungi to adapt rapidly to new environments and raise pressing questions about the impacts of rising environmental temperatures on the future of infectious diseases and human health.<\/jats:p>","DOI":"10.1093\/genetics\/iyaf165","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T18:32:20Z","timestamp":1755801140000},"source":"Crossref","is-referenced-by-count":7,"title":["Distinct routes to thermotolerance in the fungal pathogen\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1093","volume":"231","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-1354","authenticated-orcid":false,"given":"Mara J W","family":"Schwiesow","sequence":"first","affiliation":[{"name":"Department of Human Genetics, The University of Utah , Salt Lake City, UT 84112 ,","place":["United States"]},{"name":"Howard Hughes Medical Institute , Salt Lake City, UT 84112 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah A","family":"Farinella","sequence":"additional","affiliation":[{"name":"Department of Biology, Boston College , Chestnut Hill, MA 02467 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ruzic","sequence":"additional","affiliation":[{"name":"Department of Biology, Boston College , Chestnut Hill, MA 02467 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake T","family":"Leinas","sequence":"additional","affiliation":[{"name":"Department of Biology, Boston College , Chestnut Hill, MA 02467 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nels C","family":"Elde","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, The University of Utah , Salt Lake City, UT 84112 ,","place":["United States"]},{"name":"Howard Hughes Medical Institute , Salt Lake City, UT 84112 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3833-6912","authenticated-orcid":false,"given":"Zo\u00eb A","family":"Hilbert","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, The University of Utah , Salt Lake City, UT 84112 ,","place":["United States"]},{"name":"Howard Hughes Medical Institute , Salt Lake City, UT 84112 ,","place":["United States"]},{"name":"Department of Biology, Boston College , Chestnut Hill, MA 02467 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"2025112406270204300_iyaf165-B1","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13073-014-0100-8","article-title":"YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens","volume":"6","author":"Abbey","year":"2014","journal-title":"Genome Med"},{"key":"2025112406270204300_iyaf165-B2","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.1128\/ec.00349-07","article-title":"Ssk2 mitogen-activated protein kinase kinase kinase governs divergent patterns of the stress-activated Hog1 signaling pathway in Cryptococcus neoformans","volume":"6","author":"Bahn","year":"2007","journal-title":"Eukaryot Cell"},{"key":"2025112406270204300_iyaf165-B3","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1128\/EC.00218-13","article-title":"Stress signaling pathways for the pathogenicity of cryptococcus","volume":"12","author":"Bahn","year":"2013","journal-title":"Eukaryot Cell"},{"key":"2025112406270204300_iyaf165-B4","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1091\/mbc.E04-11-0987","article-title":"Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans","volume":"16","author":"Bahn","year":"2005","journal-title":"Mol Biol Cell"},{"key":"2025112406270204300_iyaf165-B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1558-5646.1993.tb01194","article-title":"Evolutionary adaptation to temperature II. 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