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U.S.A."],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"<jats:p>\n                    The human fungal pathogen\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                    <\/jats:italic>\n                    species complex (encompassing\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                    <\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">Cryptococcus deneoformans<\/jats:italic>\n                    , and the\n                    <jats:italic toggle=\"yes\">Cryptococcus gattii<\/jats:italic>\n                    species complexes) exhibits diversity in sexual reproduction, including \u03b1-\n                    <jats:bold>a<\/jats:bold>\n                    mating, pseudosexual reproduction, as well as unisexual reproduction initiated from a single isolate or between isolates of the same mating type. A central conundrum is that while most\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                    <\/jats:italic>\n                    natural populations exhibit significant \u03b1 mating-type bias, genetic and genomic analyses show recombination occurs in nature. The discovery of unisexual reproduction in\n                    <jats:italic toggle=\"yes\">C. deneoformans<\/jats:italic>\n                    provided insight; however, thus far, unisexual reproduction has never been directly observed in the predominant global pathogenic species\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                    <\/jats:italic>\n                    . Here, we provide evidence that mutating the\n                    <jats:italic toggle=\"yes\">RIC8<\/jats:italic>\n                    gene, which encodes a conserved guanine nucleotide exchange factor (GEF) involved in both chaperoning and activating G\u03b1 proteins, enables unisexual reproduction in\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                    <\/jats:italic>\n                    . Additionally, we show that genetic variation in the natural population promotes unisexual reproduction, and unisexual reproduction in\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                    <\/jats:italic>\n                    involves canonical meiotic recombination. Finally, we found that deletion of both\n                    <jats:italic toggle=\"yes\">GPA2<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">GPA3<\/jats:italic>\n                    in the\n                    <jats:italic toggle=\"yes\">MAT<\/jats:italic>\n                    \u03b1 background leads to self-filamentation without sporulation, suggesting that differential modulation of the G\u03b1 proteins, likely involving Ric8, could underlie the switch between different modes of sexual reproduction in\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                    <\/jats:italic>\n                    . Our study further highlights that the highly conserved Ric8 GEF can act as an important regulator of cellular development in response to environmental stimuli and could modulate sexual reproduction in nature. We hypothesize that unisexual reproduction occurs much more frequently in nature than currently appreciated, and possibly in other fungi and microbial eukaryotes as well.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2521779122","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T17:37:57Z","timestamp":1760463477000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Unisexual reproduction in the global human fungal pathogen\n                    <i>\n                      <i>Cryptococcus neoformans<\/i>\n                    <\/i>"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2895-1153","authenticated-orcid":false,"given":"Sheng","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuyun","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeseul","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center","place":["Durham"]}],"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","place":["Durham"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3852\/12-253"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/9781555819583.ch6"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/9781555819583.ch7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66234"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.07.032"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2219120120"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2025.04.061"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-110410-132536"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00005-10"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.000973"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1080\/00275514.1975.12019866"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1080\/00275514.1976.12019959"},{"key":"e_1_3_4_13_2","first-page":"943","article-title":"A new species of Filobasidiella, the sexual state of Cryptococcus neoformans B and C serotypes","volume":"68","author":"Kwon-Chung K. 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