Influence of genetic variation on fungal MAPK signaling and virulence

描述（申请人提供）：天然遗传变异如何调节与人类疾病相关的细胞生物学性状？许多常见疾病，从自闭症到肥胖症，都受到多个序列变异的影响。全基因组关联（GWA）研究正在产生越来越多的人类疾病风险因素，但这些遗传变异如何共同作用以赋予疾病风险仍不清楚。在许多情况下，已确定的遗传变异只能解释疾病风险遗传性的一小部分。然而，个性化医疗的前景取决于我们是否能解释个体基因构成的影响。由于其遗传的柔韧性，芽殖酵母S。酿酒酵母是研究复杂性状基因组结构的理想模型系统。Leonid Kruglyak教授和他的实验室以前使用了两个不同的S。酿酒酵母分离株，以映射介导各种表型的遗传变异，包括基因表达的差异。然而，这两个菌株仅代表了沙门氏菌的一小部分。酿酒酵母的物种范围内的遗传和表型变异。我正在开发一种方法，它将使我能够从任何两个不同的S出发，生成单个分离体的大型作图群体。酿酒酵母分离物。这种方法将使我能够研究遗传变异如何调节核心MAPK信号级联，HOG高渗透压信号通路。HOG MAPK级联是高度保守的，其人类对应物在各种癌症中起关键作用，其等同物控制几种致病真菌的毒力。然而，遗传变异如何影响HOG通路活性尚不清楚。我将确定改变HOG通路活性的序列变体，然后将表征信号是如何特异性改变的。我将开发的测量HOG信号的方法可以在以后应用于其他MAPK信号通路的研究。致病真菌新生隐球菌的毒力是由几个复杂的性状。有趣的是，HOG途径活性是这种真菌完全毒力所必需的。我将鉴定调节C.新人类特别是，我将描述黑色素产生，胶囊大小和器官特异性感染的遗传贡献。这些分析可以扩展到这种病原体的其他医学相关特性，并有助于其他病原真菌的研究。目的1：建立快速将数量性状基因座（QTL）定位扩展到其它大豆品种的方法.酿酒酵母分离物。目的2：探讨遗传变异对MAPK信号通路的影响。目的3：鉴定调节克氏原杆菌毒力的QTL.新人类

DESCRIPTION (provided by applicant): How does naturally genetic variation modulate cell biological traits relevant to human disease? Many common diseases, ranging from autism to obesity, are influenced by multiple sequence variants. Genome-wide association (GWA) studies are yielding more and more human disease risk factors, but how these genetic variants act collectively to confer disease risk remains unclear. In many cases the identified genetic variants only explain a small fraction of the disease risk heritability. Yet, the promise of personalized medicine hinges on whether we can account for the effect of an individual's genetic makeup. Due to its genetic pliability the budding yeast S. cerevisiae is an ideal model system to investigate the genomic architecture of complex traits. Prof. Leonid Kruglyak and his lab have previously used two divergent S. cerevisiae isolates to map the genetic variation mediating various phenotypes, including differences in gene expression. However, these two strains only represent a minute fraction of the S. cerevisiae species-wide genetic and phenotypic variance. I am developing a method that will allow me to generate large mapping populations of individual segregants starting from any two divergent S. cerevisiae isolates. This approach will enable me to investigate how genetic variation modulates a core MAPK signaling cascade, the HOG high osmolarity signaling pathway. The HOG MAPK cascade is highly conserved, with its human counterpart playing a key role in various cancers and its equivalents controlling virulence in several pathogenic fungi. Yet, how genetic variation influences HOG pathway activity is unknown. I will identify sequence variants that alter HOG pathway activity and will then characterize how signaling is altered specifically. The approaches I will develop to measure HOG signaling could later be applied to the study of other MAPK signaling pathways. The virulence of the pathogenic fungus Cryptococcus neoformans is governed by several complex traits. Intriguingly, HOG pathway activity is required for full virulence of this fungus. I will idntify the genetic variations that modulate virulence attributes of C. neoformans. In particular, I will characterize the genetic contributions to melanin production, capsule size and organ-specific infectivity. These analyses could be extended to additional medically relevant properties of this pathogen and will aid the study of other pathogenic fungi. Aim 1: To develop methodology to rapidly extend quantitative trait loci (QTL) mapping to additional S. cerevisiae isolates. Aim 2: T characterize the effect of genetic variation on MAPK signaling. Aim 3: To identify QTL modulating virulence of C. neoformans.