Global population genomics of Cryptococcus neoformans var. grubii reveals new biogeographic relationships and finely maps hybridization. Global population genomics of Cryptococcus neoformans var grubii

Cryptococcus neoformans var. grubii is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically HIV/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterized the major subdivisions, their relative diversity and the level of genetic exchange between them. While most isolates of C. neoformans var. grubii belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of C. neoformans var. grubii (serotype A/A) and of hybrids with C. neoformans var. neoformans (serotype A/D) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil reveal that the previously ‘African’ VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions demonstrating the highly dispersive nature of this pathogen.

新型隐球菌格鲁布变种（Cryptococcus neoformans var. grubii）是隐球菌脑膜炎（cryptococcal meningitis）的致病菌，该疾病是免疫功能低下人群（通常为发展中国家的艾滋病患者）的重要致死病因。尽管这一广泛分布的感染在全球范围内出现流行，但学界对该真菌病原体的全球分子流行病学仍知之甚少。本研究对188株不同来源的分离株进行了基因组测序，并对其主要分支、相对多样性以及各分支间的基因交流水平进行了系统表征。多数新型隐球菌格鲁布变种（C. neoformans var. grubii）分离株隶属于三大主要谱系（VNI、VNII及VNB），但部分单倍体分离株呈现杂交祖先背景，其中部分菌株显示出近期杂交的特征——这一结论基于每条染色体上均检测到来自双方祖先的大片段序列。多数分离株均表现出非整倍体（aneuploidy）特征，且所有染色体均被检出存在非整倍体变异。在新型隐球菌格鲁布变种的二倍体分离株（血清型A/A）以及与新型隐球菌新型变种（Cryptococcus neoformans var. neoformans）的杂交株（血清型A/D）中，这类非整倍体变异可引发杂合性缺失（loss of heterozygosity），即某一染色体区域仅呈现单一亲本分离株的基因型。对巴西分离株的系统发育与群体基因组分析显示，此前被认为仅分布于非洲的VNB谱系在南美环境中自然存在。这表明VNB谱系在发生分化之前，曾在非洲与南美之间发生过迁移，这一推论得到了不同谱系及不同区域分离株之间存在祖先重组事件的支持。本研究结果证实该真菌存在显著的群体结构，所有谱系均呈现跨大陆分布特征，表明这一病原体具备极强的扩散能力。