High throughput S. cerevisiae HAM, GWA & QT/QTL architecture

高通量酿酒酵母 HAM、GWA

• 批准号: 8158968
• 负责人: FRED S DIETRICH
• 金额: $ 59.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-11 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8158968
• 关键词: Address; Adverse effects; Affect; Antifungal Agents; Architecture; Biological Factors; Biological Models; Databases; Diploidy; Dissection; Drug usage; Epigenetic Process; Genes; Genetic Epistasis; Genetic Heterogeneity; Genome; Genotype; Haploidy; Health; Human; Hybrid Vigor; Malignant Neoplasms; Maps; Membrane; Modeling; Mouse-ear Cress; Mus; Oligonucleotides; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Population; Quantitative Trait Loci; Resistance; Resources; Saccharomyces; Saccharomyces cerevisiae; Testing; Variant; base; cost; drug efficacy; fluoropyrimidine; genetic resource; genome database; genome sequencing; genome wide association study; improved; inhibitor/antagonist; member; novel; stressor; trait

DESCRIPTION (provided by applicant): Broad long-term objectives: In Specific Aim 1, we will sequence and annotate the genomes of an additional 88 genetically diverse S. cerevisiae strains, bringing the total of such strains to 96, which will serve as the bases for Specific Aims 2-4. In Specific Aim 2, we will use haploid association mapping to identify candidate pharmacogenetic QTGs controlling resistance to 5- fluoropyrimidines, which are clinically used anti-cancer and/or antifungal agents, and membrane stressors, many of which are clinically used antifungal agents. In Specific Aim 3, we will use genome wide association, in a 4,560 member F1 population, to identify candidate pharmacogenetic QTGs. In parallel, we will QTL map, in 500 and 600 member F2 populations, pharmacogenetic QTLs. The haploid association mapping and genome wide association will identify candidate QTGs in many QTLs. Similarly, the QTL mapping will identify many haploid association mapping and genome wide association true/false associations and false negatives. Finally, in Specific Aim 4, we will use high throughput F1 RHA to test candidate QTGs, evaluate epistasis vs. genetic heterogeneity and determine F1 population-wide QT/QTL architecture. PUBLIC HEALTH RELEVANCE: Our understanding of quantitative traits, which includes pharmacogenetic variations in human drug efficacy and side effects, is poor. Improving our understanding of quantitative traits and of pharmacogenetics is aided by tractable model systems, such as Saccharomyces cerevisiae. In this study, we develop a novel S. cerevisiae genetic resource population that allows for high throughput haploid association mapping and genome wide association. The health relatedness of this project lies in our study in S. cerevisiae of quantitative pharmacogenetics of a set of anti-cancer and anti-fungal drugs. Therefore, our study in S. cerevisiae of quantitative pharmacogenetics will aid our understanding of quantitative traits in general and of pharmacogenetics in particular.

描述（由申请人提供）： 广泛的长期目标：在特定目标1中，我们将对另外88种遗传多样的酿酒酵母菌株的基因组进行测序和注释，这将使此类菌株的总数达到96，这将作为特定目标的基础2-4。在特定目标2中，我们将使用单倍体缔合映射来识别控制对5-氟吡啶抑制的候选药物遗传学QTG，这些氟吡啶是临床使用的抗癌和/或抗真菌剂，以及膜胁迫，其中许多是临床上使用的抗真菌剂。在特定目标3中，我们将在4,560个成员F1人群中使用宽基因组宽的关联来识别候选药物遗传学QTG。同时，我们将在500和600个成员F2种群中QTL地图，药物遗传学QTL。单倍体关联映射和基因组广泛的关联将在许多QTL中识别候选QTG。同样，QTL映射将识别许多单倍体映射和基因组广泛的关联true/false关联和假阴性。最后，在特定的目标4中，我们将使用高吞吐量F1 RHA测试候选QTG，评估遗传学与遗传异质性，并确定F1范围内的QT/QTL架构。 公共卫生相关性： 我们对定量性状的理解，包括人类药物疗效和副作用的药物遗传学变化，这是不良的。可以通过可诱导的模型系统（例如酿酒酵母）来帮助提高我们对定量性状和药物遗传学的理解。在这项研究中，我们开发了一种新型的酿酒酵母遗传资源人群，该人群可以进行高吞吐量单倍体映射和宽基因组的关联。该项目的健康相关性在于我们在一组抗癌和抗真菌药物的定量药物遗传学酿酒酵母中的研究。因此，我们在定量药物遗传学的酿酒酵母中的研究将有助于我们对一般的定量性状，尤其是对药物遗传学的理解。