{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:51:28Z","timestamp":1792457488363,"version":"4.5.0"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI039115-27"],"award-info":[{"award-number":["AI039115-27"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI050113-20"],"award-info":[{"award-number":["AI050113-20"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI133654-07"],"award-info":[{"award-number":["AI133654-07"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI133654-07"],"award-info":[{"award-number":["AI133654-07"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,19]]},"abstract":"<jats:p>\n                    While increased mutation rates typically have negative consequences in multicellular organisms, hypermutation can be advantageous for microbes adapting to the environment. Previously, we identified two hypermutator\n                    <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                    clinical isolates that rapidly develop drug resistance due to transposition of a retrotransposon, Cnl1. Cnl1-mediated hypermutation is caused by a nonsense mutation in a gene encoding an RNA interference (RNAi) component,\n                    <jats:italic>ZNF3<\/jats:italic>\n                    , combined with a tremendous transposon burden. To elucidate adaptive mechanisms following RNAi loss, two bioinformatic pipelines were developed to identify RNAi loss-of-function (LOF) mutations in a collection of 387 sequenced\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    isolates. Remarkably, several RNAi-loss isolates were identified that are not hypermutators and have not accumulated transposons. To test whether these RNAi LOF mutations can cause hypermutation, the mutations were introduced into a nonhypermutator strain with a high transposon burden, which resulted in a hypermutator phenotype. To further investigate whether RNAi-loss isolates can become hypermutators, in vitro passaging was performed. Although no hypermutators were found in two\n                    <jats:italic>C. neoformans<\/jats:italic>\n                    RNAi-loss strains after short-term passage, hypermutation was observed in a passaged\n                    <jats:italic>Cryptococcus deneoformans<\/jats:italic>\n                    strain with an increased transposon burden. Consistent with a two-step evolution, when an RNAi-loss isolate was crossed with an isolate containing a high Cnl1 burden, F1 hypermutator progeny inheriting a high transposon burden were identified. In addition to Cnl1 transpositions, insertions of a gigantic DNA transposon KDZ1 (~11 kb) contributed to hypermutation in the progeny. Our results suggest that RNAi loss is relatively common (7\/387, ~1.8%) and enables distinct evolutionary trajectories: hypermutation following transposon accumulation or survival without hypermutation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2416656121","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T13:46:17Z","timestamp":1731505577000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":21,"title":["Distinct evolutionary trajectories following loss of RNA interference in\n                    <i>Cryptococcus neoformans<\/i>"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4071-0926","authenticated-orcid":false,"given":"Jun","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor J.","family":"Larmore","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby J.","family":"Priest","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred S.","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-9035","authenticated-orcid":false,"given":"Vikas","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-2589","authenticated-orcid":false,"given":"Paul M.","family":"Magwene","sequence":"additional","affiliation":[{"name":"Department of Biology, Duke University, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2895-1153","authenticated-orcid":false,"given":"Sheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6369-5995","authenticated-orcid":false,"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26108-y"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuac035"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.276992.122"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.28802"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg446"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms10020442"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220475120"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10577-013-9388-2"},{"key":"e_1_3_4_9_2","first-page":"291","article-title":"Flavonoid genes in petunia: Addition of a limited number of gene copies may lead to a suppression of gene expression","volume":"2","author":"Van Der Krol A. 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A.","year":"2018","unstructured":"E. A. Radchenko, R. J. McGinty, A. Y. Aksenova, A. J. Neil, S. M. Mirkin, \"Quantitative analysis of the rates for repeat-mediated genome instability in a yeast experimental system\" in , Methods in Molecular Biology, M. Muzi-Falconi, G. W. Brown, Eds. (Springer, New York, 2018), pp. 421\u2013438."},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2015.04.002"},{"key":"e_1_3_4_64_2","doi-asserted-by":"crossref","unstructured":"J. Huang Distinct evolutionary trajectories following loss of RNA interference in Cryptococcus neoformans. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/?term=PRJNA1138746. Deposited 22 July 2024.","DOI":"10.1101\/2024.08.15.608186"},{"key":"e_1_3_4_65_2","unstructured":"S. J. Priest Rampant transposition following RNAi loss cause hypermutation and antifungal drug resistance in Cryptococcus neoformans. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/?term=PRJNA749953. Accessed 1 January 2024."},{"key":"e_1_3_4_66_2","unstructured":"J. Huang Cryptococcus neoformans strain Bt65 transposon KDZ1 complete sequence. NCBI. https:\/\/www.ncbi.nlm.nih.gov\/nuccore\/PQ181658. Deposited 9 August 2024."},{"key":"e_1_3_4_67_2","unstructured":"J. Huang Cryptococcus neoformans var. neoformans strain XL280alpha transposon KDZx1 complete sequence. NCBI. https:\/\/www.ncbi.nlm.nih.gov\/nuccore\/PQ181659. Deposited 10 August 2024."},{"key":"e_1_3_4_68_2","unstructured":"J. Huang Cryptococcus neoformans strain Bt65 transposon KDZ2 complete sequence. NCBI. https:\/\/www.ncbi.nlm.nih.gov\/nuccore\/PQ181660. Deposited 10 August 2024."},{"key":"e_1_3_4_69_2","unstructured":"J. Huang Cryptococcus neoformans strain Bt65 transposon KDZ3 complete sequence. NCBI. https:\/\/www.ncbi.nlm.nih.gov\/nuccore\/PQ181661. 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