Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans
Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans
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DOI：
10.1101/gr.218727.116
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发表时间：
2017-07-01
期刊：
影响因子：
7
通讯作者：
Cuomo, Christina A.
中科院分区：
文献类型：
--
作者：
Desjardins, Christopher A.;Giamberardino, Charles;Cuomo, Christina A.
新型隐球菌是一种机会性真菌病原体，每年约有625，000人死于神经系统感染。在这里，我们利用了一个独特的，遗传多样性的C。来自撒哈拉以南非洲的neoformans，通常从mopane树中分离出来，以确定环境中的选择压力如何巧合地适应C。对人类的毒性。代表全球VNI和非洲VNB谱系的387株分离株的基因组测序和系统发育分析突出了VNB（本文中，VNBI和VNBII）中的深度非重组分裂。相对于VNBI，VNBII富集了临床样品，而183株分离株的表型分析表明，VNBI分离株对氧化应激的抗性显著高于VNBII分离株，并且黑化程度更重。两个谱系中黑变的缺乏与BZP4转录因子中的功能缺失突变相关。对所有VNB分离株的全基因组关联研究揭示了临床和环境分离株在毒力因子和应激反应基因方面的序列差异。肌醇转运蛋白和catalysts基因，加工存在于植物和人类神经系统中的糖，被确定为所有三个谱系的选择目标。进一步的系统发育和群体基因组分析显示，VNBI的遗传多样性广泛丧失，暗示了人口瓶颈的历史，沿着交配型位点的独特进化轨迹。这些数据强调了适应自然环境和机会性感染之间复杂的进化相互作用，以及对特定途径的选择可能使分离株对人类的毒力易感。
Cryptococcus neoformans is an opportunistic fungal pathogen that causes approximately 625,000 deaths per year from nervous system infections. Here, we leveraged a unique, genetically diverse population of C. neoformans from sub-Saharan Africa, commonly isolated from mopane trees, to determine how selective pressures in the environment coincidentally adapted C. neoformans for human virulence. Genome sequencing and phylogenetic analysis of 387 isolates, representing the global VNI and African VNB lineages, highlighted a deep, nonrecombining split in VNB (herein, VNBI and VNBII). VNBII was enriched for clinical samples relative to VNBI, while phenotypic profiling of 183 isolates demonstrated that VNBI isolates were significantly more resistant to oxidative stress and more heavily melanized than VNBII isolates. Lack of melanization in both lineages was associated with loss-of-function mutations in the BZP4 transcription factor. A genome-wide association study across all VNB isolates revealed sequence differences between clinical and environmental isolates in virulence factors and stress response genes. Inositol transporters and catabolism genes, which process sugars present in plants and the human nervous system, were identified as targets of selection in all three lineages. Further phylogenetic and population genomic analyses revealed extensive loss of genetic diversity in VNBI, suggestive of a history of population bottlenecks, along with unique evolutionary trajectories for mating type loci. These data highlight the complex evolutionary interplay between adaptation to natural environments and opportunistic infections, and that selection on specific pathways may predispose isolates to human virulence.