Causes and consequences of regulatory genetic variation

调节性遗传变异的原因和后果

• 批准号: 10686875
• 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/10686875
• 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; 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.

项目总结/摘要 个体间的遗传变异塑造了重要的表型，包括普通人类的风险。 例如心血管、自身免疫和神经系统疾病。特别是调控基因 变异导致基因表达的个体间差异。由此产生的基因表达差异 解释了许多遗传复杂性状变异的很大一部分。 尽管监管变化至关重要，但许多基本问题仍然悬而未决。第一、 给定基因组中的大多数DNA差异可能没有影响。具体的变异的性质， 其影响仍然知之甚少。其次，遗传变异可以特异性地影响蛋白质 在不改变给定基因的mRNA丰度的情况下改变给定基因的丰度。的 负责这些蛋白质特异性作用的机制仍不清楚。第三，我们只有一个 对调控变异导致的基因表达差异如何影响 生物表型 在接下来的五年里，我的实验室的研究将集中在解决这些关键的差距， 知识具体来说，我们寻求识别和表征因果DNA变异，研究 遗传变异对蛋白质降解的影响，并定量研究如何精确丰度的给定 基因可以塑造生物体的特征。我们的工作结合了计算生物学，定量和统计 实验性全基因组方法的遗传学。我们用酿酒酵母作为 强大和易于处理的模型系统的监管变化，同时追求相关的方法，在人类 细胞 我们的长期愿景是提高我们对监管变化的理解， 准确预测个体基因组中DNA变异的后果是可能的。这种能力 将对基础研究和改善人类健康的个性化方法有价值。