Genomic approaches for dissecting regulatory variation

剖析调控变异的基​​因组方法

• 批准号: 9751898
• 负责人: Frank Wolfgang Albert
• 金额: $ 38.5万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751898
• 关键词: Address; Autoimmune Diseases; Cardiovascular Diseases; Cellular biology; Complex; DNA; Disease; Environment; Eukaryota; Gene Expression; Genetic; Genetic Diseases; Genetic Risk; Genetic Variation; Genome; Genomic approach; Goals; Health; Human; Individual; Knowledge; Laboratories; Maps; Messenger RNA; Methods; Molecular; Nature; Proteins; Reading; Research; Risk; Role; Saccharomyces cerevisiae; Sample Size; Source; Techniques; Translating; Variant; Vision; Work; Writing; Yeasts; causal variant; disorder risk; fitness; genome editing; human disease; improved; nervous system disorder; trait

Project Summary / Abstract Much of the risk for common human disease arises from genetic variation among individuals. Research in my laboratory is focused on regulatory genetic variation. This type of variation causes differences in gene expression among individuals and contributes a substantial portion of the genetic risk for human diseases including cardiovascular, autoimmune, and neurological disease. In spite of its critical importance for human disease genetics, fundamental questions about regulatory variation remain unanswered. Because of low statistical power due to the small sample sizes commonly used when mapping regulatory variation in the genome, the source of most regulatory variation remains unknown. The regulatory loci that have been mapped typically span dozens of sequence variants, and we neither know the identity of the actual causal variants, nor the molecular mechanisms through which they alter expression. Nearly all work on regulatory variation is focused on mRNA levels, and it is unclear to what extent it translates to protein levels and cell biology. Finally, our knowledge of how the environment can modulate the effects of regulatory variation remains severely limited. This proposal outlines a research strategy to tackle these critical questions. We plan to combine methods from quantitative and statistical genetics with experimental approaches that leverage emerging techniques for reading, writing, and editing genomes. We will use powerful methods in the yeast Saccharomyces cerevisiae to reveal principles of regulatory variation that are shared among eukaryotes, and that are challenging to address in other species including humans. Our goals for the next five years are to dissect the influence of regulatory variation on the molecular cascade from DNA to mRNA, proteins and cellular fitness. We plan to comprehensively identify causal regulatory variants, understand genetic influences on mRNA and protein levels with high statistical power and across different environments, and evaluate the effects of regulatory variation on cellular fitness. Our long term vision is to turn yeast into the first eukaryotic species in which we can accurately predict the consequences of natural genetic variation. The lessons to emerge from this work are expected to be highly valuable for interpreting the role of regulatory variation in human health.

项目摘要 /摘要 常见人类疾病的大部分风险来自个体之间的遗传差异。我的研究 实验室专注于调节遗传变异。这种类型的变异会导致基因差异 个人表达并贡献了人类疾病遗传风险的很大一部分 包括心血管，自身免疫和神经系统疾病。尽管对人类至关重要 疾病遗传学，有关监管变异的基本问题仍未得到答复。 由于映射时通常使用的小样本量引起的统计功率较低 基因组的调节变化，大多数调节变化的来源仍然未知。监管 映射的基因座通常跨越数十个序列变体，我们都不知道 实际因果变异，也是它们改变表达的分子机制。几乎所有工作 在调节性方面的差异集中在mRNA水平上，目前尚不清楚它在多大程度上转化为蛋白质水平 和细胞生物学。最后，我们对环境如何调节监管的影响的了解 差异仍然受到严重限制。 该建议概述了解决这些关键问题的研究策略。我们计划结合 通过实验方法从定量和统计遗传学中的方法利用新出现的方法 阅读，写作和编辑基因组的技术。我们将在酵母中使用强大的方法 酿酒酵母揭示了真核生物之间共享的调节变化原则， 在包括人类在内的其他物种中要解决的挑战。 我们未来五年的目标是剖析调节变化对分子的影响 从DNA到mRNA，蛋白质和细胞适应性。我们计划全面识别因果关系 调节性变体，了解具有高统计能力的mRNA和蛋白质水平的遗传影响， 在不同的环境中，并评估调节性变异对细胞适应性的影响。我们的长期 视觉是将酵母变成第一个真核生物，在其中我们可以准确预测的后果 自然遗传变异。从这项工作中汲取的教训对 解释监管变异在人类健康中的作用。