生物
毒力
遗传学
基因
新生隐球菌
全基因组测序
基因组
基因座(遗传学)
序列分析
DNA测序
计算生物学
作者
Daniel Paiva Agustinho,Holly Brown,Guohua Chen,Elizabeth A Gaylord,Jennifer Geddes‐McAlister,Michael R. Brent,Tamara L. Doering
标识
DOI:10.1016/j.chom.2023.10.002
摘要
Isolates of Cryptococcus neoformans, a fungal pathogen that kills over 112,000 people each year, differ from a 19-Mb reference genome at a few thousand up to almost a million DNA sequence positions. We used bulked segregant analysis and association analysis, genetic methods that require no prior knowledge of sequence function, to address the key question of which naturally occurring sequence variants influence fungal virulence. We identified a region containing such variants, prioritized them, and engineered strains to test our findings in a mouse model of infection. At one locus, we identified a 4-nt variant in the PDE2 gene that occurs in common laboratory strains and severely truncates the encoded phosphodiesterase. The resulting loss of phosphodiesterase activity significantly impacts virulence. Our studies demonstrate a powerful and unbiased strategy for identifying key genomic regions in the absence of prior information and provide significant sequence and strain resources to the community.
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