Distinct evolutionary trajectories following loss of RNA interference in Cryptococcus neoformans

• 成果类型: Article
• 署名作者: Huang, Jun; Larmore, Connor J.; Priest, Shelby J.; Xu, Ziyan; Dietrich, Fred S.; Yadav, Vikas; Magwene, Paul M.; Sun, Sheng; Heitman, Joseph
• 署名单位: Duke University; Duke University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13887
• DOI: 10.1073/pnas.2416656121
• 发表日期: 2024-11-19
• 关键词: fungal pathogen cryptococcus; silencing components; population genomics; drug-resistance; reproduction; suppression; meningitis; genes; rates; sex

摘要

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 Cryptococcus neoformans 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, ZNF3, 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 C. neoformans 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 C. neoformans RNAi-loss strains after short-term passage, hypermutation was observed in a passaged Cryptococcus deneoformans 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 (similar to 11 kb) contributed to hypermutation in the progeny. Our results suggest that RNAi loss is relatively common (7/387, similar to 1.8%) and enables distinct evolutionary trajectories: hypermutation following transposon accumulation or survival without hypermutation.