Histoplasmosis is a serious infectious disease in humans caused by Histoplasma spp. (Onygenales), whose natural reservoirs are thought to be soil enriched with bird and bat guano. The true global burden of histoplasmosis is underestimated and frequently the pulmonary manifestations are misdiagnosed as tuberculosis. Molecular data on epidemiology of Histoplasma are still scarce, even though there is increasing recognition of histoplasmosis in recent years in areas distant from the traditional endemic regions in the Americas. We used multi-locus sequence data from protein coding loci (ADP-ribosylation factor, H antigen precursor, and delta-9 fatty acid desaturase), DNA barcoding (ITS1/2+5.8s), AFLP markers and mating type analysis to determine the genetic diversity, population structure and recognise the existence of different phylogenetic species among 436 isolates of Histoplasma obtained globally. Our study describes new phylogenetic species and the molecular characteristics of Histoplasma lineages causing outbreaks with a high number of severe outcomes in Northeast Brazil between 2011 and 2015. Genetic diversity levels provide evidence for recombination, common ancestry and clustering of Brazilian isolates at different geographic scales with the emergence of LAm C, a new genotype assigned to a separate population cluster in Northeast Brazil that exhibited low diversity indicative of isolation. The global survey revealed that the high genetic variability among Brazilian isolates along with the presence of divergent cryptic species and/or genotypes may support the hypothesis of Brazil being the center of dispersion of Histoplasma in South America, possibly with the contribution of migratory hosts such as birds and bats. Outside Brazil, the predominant species depends on the region. We confirm that histoplasmosis has significantly broadened its area of occurrence, an important feature of emerging pathogens. From a practical point of view, our data point to the emergence of histoplasmosis caused by a plethora of genotypes, and will enable epidemiological analysis focused on understanding the processes that lead to histoplasmosis. Further, the description of this diversity opens avenues for comparative genomic studies, which will allow progress toward a consensus taxonomy, improve understanding of the presence of hybrids in natural populations of medically relevant fungi, test reproductive barriers and to explore the significance of this variation.

组织胞浆菌病是由组织胞浆菌属引起的一种严重的人类传染病。（Onygenales），其天然水库被认为是富含鸟类和蝙蝠鸟粪的土壤。低估了组织胞浆菌病的真正全球负担，经常将肺部表现误诊为结核病。组织胞浆菌流行病学的分子数据尽管近年来在远离美洲传统流行地区的地区，人们对组织胞浆菌病的认识不断提高，但仍很稀缺。我们使用了来自蛋白质编码基因座（ADP-核糖基化因子，H抗原前体和delta-9脂肪酸去饱和酶），DNA条形码（ITS1 / 2 + 5.8s），AFLP标记和交配类型分析的多基因座序列数据来确定遗传多样性，种群结构并认识到全球获得的436个组织胞浆菌分离株中存在不同的系统发育物种。我们的研究描述了新的系统发生种和组织胞浆菌的分子特征在2011年至2015年之间，导致巴西东北部爆发暴发的血统，具有大量严重后果。随着LAm C的出现，遗传多样性水平为不同地理尺度的巴西分离株的重组，共同血统和聚类提供了证据。巴西东北部的独立种群集群，其多样性低，表明存在隔离。全球调查显示，巴西分离株之间的高遗传变异性以及不同的隐性物种和/或基因型的存在可能支持巴西为组织胞浆菌扩散中心的假说在南美洲，可能是鸟类和蝙蝠等迁徙寄主的贡献。在巴西以外，主要物种取决于该地区。我们证实，组织胞浆菌病已大大扩大了其发生范围，这是新兴病原体的重要特征。从实际的角度来看，我们的数据指出了由过多基因型引起的组织胞浆菌病的出现，并将使流行病学分析着重于了解导致组织胞浆菌病的过程。此外，对这种多样性的描述为比较基因组学研究开辟了途径，这将有助于朝着共识分类学的方向发展，增进对医学相关真菌自然种群中杂种存在的了解，测试生殖障碍并探索这种变异的重要性。