Jackson Katrina M, Kabbale Kisakye Diana, Macchietto Marissa, Meya David, Tiffin Peter, Nielsen Kirsten
Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA.
Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, USA.
Microbiol Spectr. 2025 Jan 7;13(1):e0170924. doi: 10.1128/spectrum.01709-24. Epub 2024 Nov 27.
is a pathogenic yeast that is the causative agent of cryptococcal meningitis. While it is well known that the genotype of impacts patient outcomes, the reason for this association has not been well elucidated. In this study, we examined the relationship between two subpopulations in the sequence type 93 clade of : ST93A and ST93B. We found extensive linkage disequilibrium (LD) among the single nucleotide polymorphisms (SNPs) that differentiate ST93A from ST93B. We also found differences in the extent of linkage among SNPs within each subpopulation; LD was more extensive within ST93B than ST93A. SNPs associated with virulence were in long-range linkage disequilibrium with less frequency than recurrent SNPs not associated with virulence. We investigated the karyotype of ST93A and ST93B using contour-clamped gel electrophoresis and long-read sequencing and found that the extensive long-range linkage was not due to chromosomal rearrangements. Overall, we found that the two subpopulations in ST93 are driven by SNPs in LD. We additionally found that recurrent SNPs associated with virulence were less frequently evolutionarily linked and were two times more likely to be independent, congruent mutations rather than tied to phylogeny.IMPORTANCE is an important pathogen that is widely distributed and ubiquitous in the environment. The majority of the human population has a latent, controlled infection suggesting that is uniquely adapted to cause infection. In spite of this, the reason is a pathogen remains unknown; interestingly, most environmental isolates are avirulent but are genetically very similar to disease-causing virulent isolates. Recent evidence from genome-wide association studies shows that small mutations in key virulence-associated genes are associated with the virulence of specific isolates. The data presented here provide an evolutionary framework for those small mutations. The mutations that impact disease are not being collected over long-term evolution. The mutations may instead occur independently during infection. Identifying these genes that are more likely to be mutated during infection will be fundamental for understanding virulence.
是一种致病性酵母，是隐球菌性脑膜炎的病原体。虽然众所周知的基因型会影响患者的治疗结果，但这种关联的原因尚未得到充分阐明。在本研究中，我们研究了序列类型93分支中的两个亚群：ST93A和ST93B之间的关系。我们发现区分ST93A和ST93B的单核苷酸多态性（SNP）之间存在广泛的连锁不平衡（LD）。我们还发现每个亚群内SNP之间的连锁程度存在差异；ST93B内的LD比ST93A更广泛。与毒力相关的SNP处于长程连锁不平衡状态的频率低于与毒力无关的复发SNP。我们使用轮廓夹位凝胶电泳和长读长测序研究了ST93A和ST93B的核型，发现广泛的长程连锁不是由于染色体重排。总体而言，我们发现ST93中的两个亚群是由LD中的SNP驱动的。我们还发现，与毒力相关的复发SNP在进化上的连锁频率较低，并且独立、一致突变的可能性是与系统发育相关的两倍。重要性是一种重要的病原体，在环境中广泛分布且无处不在。大多数人群都有潜在的、可控的感染，这表明特别适合引起感染。尽管如此，成为病原体的原因仍然未知；有趣的是，大多数环境分离株无毒力，但在基因上与致病的毒力分离株非常相似。全基因组关联研究的最新证据表明，关键毒力相关基因中的小突变与特定分离株的毒力有关。此处提供的数据为这些小突变提供了一个进化框架。影响疾病的突变不是在长期进化过程中积累的。相反，这些突变可能在感染期间独立发生。识别这些在感染期间更可能发生突变的基因对于理解毒力至关重要。
