Steenwyk Jacob L, Knowles Sonja, Bastos Rafael W, Balamurugan Charu, Rinker David, Mead Matthew E, Roberts Christopher D, Raja Huzefa A, Li Yuanning, Colabardini Ana Cristina, de Castro Patrícia Alves, Dos Reis Thaila Fernanda, Canóvas David, Sanchez Rafael Luperini, Lagrou Katrien, Torrado Egídio, Rodrigues Fernando, Oberlies Nicholas H, Zhou Xiaofan, Goldman Gustavo H, Rokas Antonis
Howards Hughes Medical Institute and the Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Vanderbilt University, Department of Biological Sciences, VU Station B #35-1634, Nashville, TN 37235, United States of America.
bioRxiv. 2023 Jul 3:2023.07.03.547508. doi: 10.1101/2023.07.03.547508.
Cryptic fungal pathogens pose significant identification and disease management challenges due to their morphological resemblance to known pathogenic species while harboring genetic and (often) infectionrelevant trait differences. The cryptic fungal pathogen , an allodiploid hybrid originating from and an unknown close relative of within section , remains poorly understood. The absence of accurate diagnostics for has led to misidentifications, hindering epidemiological studies and the design of effective treatment plans. We conducted an in-depth investigation of the genomes and phenotypes of 44 globally distributed isolates (41 clinical isolates and three type strains) from section . We found that 21 clinical isolates were ; notably, standard methods of pathogen identification misidentified all isolates. The remaining isolates were identified as (8), (1), or (11). Phylogenomic analyses shed light on the origin of , indicating one or two hybridization events gave rise to the species during the Miocene, approximately 15.4 to 8.8 million years ago. Characterizing the pangenome uncovered substantial genetic diversity within gene families and biosynthetic gene clusters. Transcriptomic analysis revealed that both parental genomes are actively expressed in nearly equal proportions and respond to environmental stimuli. Further investigation into infection-relevant chemical and physiological traits, including drug resistance profiles, growth under oxidative stress conditions, and secondary metabolite biosynthesis, highlight distinct phenotypic profiles of the hybrid compared to its parental and closely related species. Leveraging our comprehensive genomic and phenotypic analyses, we propose five genomic and phenotypic markers as diagnostics for species identification. These findings provide valuable insights into the evolutionary origin, genomic outcome, and phenotypic implications of hybridization in a cryptic fungal pathogen, thus enhancing our understanding of the underlying processes contributing to fungal pathogenesis. Furthermore, our study underscores the effectiveness of extensive genomic and phenotypic analyses as a promising approach for developing diagnostics applicable to future investigations of cryptic and emerging pathogens.
隐匿性真菌病原体因其形态与已知致病物种相似，但却存在遗传和（通常）与感染相关的性状差异，给鉴定和疾病管理带来了重大挑战。隐匿性真菌病原体是一种异源二倍体杂种，起源于section 内的 和一个未知的近缘种，目前人们对它的了解仍然很少。缺乏针对 的准确诊断方法导致了错误鉴定，阻碍了流行病学研究和有效治疗方案的设计。我们对来自section 的44株全球分布的分离株（41株临床分离株和3株模式菌株）的基因组和表型进行了深入研究。我们发现21株临床分离株为 ；值得注意的是，病原体鉴定的标准方法将所有 分离株都错误鉴定了。其余分离株被鉴定为 （8株）、 （1株）或 （11株）。系统基因组分析揭示了 的起源，表明在大约1540万至880万年前的中新世期间，发生了一到两次杂交事件产生了该物种。对 泛基因组的表征揭示了基因家族和生物合成基因簇内存在大量遗传多样性。转录组分析表明，两个亲本基因组都以几乎相等的比例活跃表达，并对环境刺激做出反应。对与感染相关的化学和生理性状的进一步研究，包括耐药性谱、氧化应激条件下的生长以及次级代谢产物的生物合成，突出了杂种 与其亲本及近缘物种相比独特的表型特征。利用我们全面的基因组和表型分析，我们提出了五个基因组和表型标记作为鉴定 物种的诊断方法。这些发现为隐匿性真菌病原体杂交的进化起源、基因组结果和表型影响提供了有价值的见解，从而增进了我们对导致真菌致病的潜在过程的理解。此外，我们的研究强调了广泛的基因组和表型分析作为一种有前景的方法在开发适用于未来隐匿性和新出现病原体研究的诊断方法方面的有效性。
