Causes and consequences of regulatory genetic variation

调节性遗传变异的原因和后果

• 批准号: 10405363
• 负责人: Frank Wolfgang Albert
• 金额: $ 41.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405363
• 关键词: Address; Affect; Autoimmune Diseases; Biological Models; Cardiovascular Diseases; Cells; Complex; Computational Biology; DNA; DNA Sequence; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Health; Human; Individual; Individual Differences; Knowledge; Laboratories; Messenger RNA; Molecular; Nature; Phenotype; Proteins; Research; Risk; Saccharomyces cerevisiae; Shapes; Variant; Vision; Work; Yeasts; disorder risk; fundamental research; genetic predictors; genome-wide; human disease; improved; nervous system disorder; personalized approach; protein degradation; trait

Project Summary / Abstract Genetic variation among individuals shapes important phenotypes, including the risk for common human diseases such as cardiovascular, autoimmune, and neurological disease. In particular, regulatory genetic variation causes inter-individual differences in gene expression. The resulting gene expression differences account for a substantial portion of variation in many genetically complex traits. In spite of the critical importance of regulatory variation, many fundamental questions remain open. First, most DNA differences in a given genome likely have no effect. The nature of the specific variants that do have effects remains poorly understood. Second, genetic variation can specifically affect the protein abundance of a given gene without altering the abundance of the mRNA of the same gene. The mechanisms that are responsible for these protein-specific effects remain unclear. Third, we only have a crude understanding of how the differences in gene expression that result from regulatory variation affect organismal phenotypes. Over the next five years, research in my laboratory will focus on addressing these critical gaps in knowledge. Specifically, we seek to identify and characterize causal DNA variants, study the impact of genetic variation on protein degradation, and examine quantitatively how the precise abundance of a given gene can shape organismal traits. Our work combines computational biology, quantitative and statistical genetics with experimental genome-wide approaches. We use the yeast Saccharomyces cerevisiae as a powerful and tractable model system for regulatory variation, while pursuing related approaches in human cells. Our long-term vision is to improve our understanding of regulatory variation to the point at which it becomes possible to accurately predict the consequences of the DNA variants in an individual’s genome. This ability will be valuable for fundamental research and personalized approaches for improving human health.

项目摘要 /摘要 个体之间的遗传变异形成了重要的表型，包括人类普通的风险 心血管，自身免疫和神经系统疾病等疾病。特别是监管通用 变异会导致基因表达的个体间差异。产生的基因表达差异 在许多遗传复杂的特征中占很大一部分的变化。 尽管监管差异的重要性至关重要，但许多基本问题仍然开放。第一的， 给定基因组中的大多数DNA差异可能没有作用。特定变体的性质 效果仍然很了解。其次，遗传变异可以特别影响蛋白质 给定基因的丰度，而没有改变同一基因的mRNA的丰度。这 负责这些蛋白质特异性作用的机制尚不清楚。第三，我们只有一个 粗略理解调节变异导致的基因表达差异如何影响 生物体表型。 在接下来的五年中，我的实验室的研究将重点解决这些关键差距 知识。具体而言，我们寻求识别和表征因果DNA变异，研究的影响 蛋白质降解的遗传变异，并定量检查给定的精确抽象如何 基因可以塑造有机特征。我们的工作结合了计算生物学，定量和统计 具有实验性基因组方法的遗传学。我们将酿酒酵母的酵母菌用作 强大且可拖动的模型系统，用于监管变化，同时追求人类相关方法 细胞。 我们的长期愿景是提高我们对监管变化的理解至 可以准确预测个体基因组中DNA变体的后果。这个能力 对于改善人类健康的基本研究和个性化方法，将是有价值的。