Noncoding Elements Shaping Brain Aging

项目摘要 在美国，与阿尔茨海默病相关的费用估计每年超过2430亿美元。 所涉及的因素尚未完全了解，但代谢过程起着重要作用。事实上，肥胖 和II型糖尿病是阿尔茨海默病的主要危险因素。更深入地了解 相关机制是紧迫的，因为肥胖影响17%的儿童，约30%的美国成年人，特别是 老人基因调控机制正在成为人类疾病的主要驱动因素，但它们在人类疾病中的作用 肥胖症和阿尔茨海默氏病的关系还知之甚少。在这里，我们提出了一项研究，将揭示新的 基因组中重要的非编码元件和基因调控机制， 哺乳动物肥胖和年龄相关的神经退行性变。我们的研究建立在我们最近在Cell上发表的文章上 报告（Ferris等人，2018），其中我们进行了加速的全基因组比较分析， 具有高度独特性状的物种中的AR区域，以定义哺乳动物非编码元件， 临床上重要的表型。AR是保守的基因组元件，具有显著增加的核苷酸序列， 在特定谱系中的取代，通常是由于选择性效应。在一项未发表的研究中， 通过研究揭示哺乳动物肥胖和神经退行性变的调控因素的方法 冬眠动物冬眠者进化出代谢和行为适应，导致可逆的肥胖 表型它们还进化出了防止脑损伤的神经保护机制。我们确认了2370号 哺乳动物基因组中在多个物种中经历平行加速进化的50bp元件 独立进化出冬眠我们称这些非编码元件为冬眠加速区 (ARs)并发现了一个与人类肥胖和阿尔茨海默病风险基因座相关的子集。我们的研究 检验了一个假设，即在肥胖和阿尔茨海默氏症附近， 疾病风险基因是控制不同组织和形状中基因表达的关键调节元件 肥胖行为、代谢活动和年龄相关的神经变性。我们的研究意义重大 因为这些结果将定义重要的新的非编码机制， 导致老年痴呆症从长远来看，我们的结果预计将有助于揭示基因的改善 和表观遗传生物标志物和治疗策略，以预防年龄相关的肥胖和神经变性。

PROJECT SUMMARY The costs associated with Alzheimer's disease are estimated at over $243 billion annually in the United States. The factors involved are not fully understood, but metabolic processes play an important role. Indeed, obesity and type II diabetes are major risk factors for Alzheimer's disease. Gaining a deeper understanding of the mechanisms involved is urgent, because obesity affects 17% of children, ~30% of US adults and especially the elderly. Gene regulatory mechanisms are emerging as major drivers of human disease, but their roles in obesity and Alzheimer's disease are poorly understood. Here, we propose a study that will uncover new and important noncoding elements and gene regulatory mechanisms in the genome that underlie mammalian obesity and age-related neurodegeneration. Our study builds on our recent publication in Cell Reports (Ferris et al., 2018), in which we performed a comparative genome-wide analysis of accelerated regions (ARs) in species with highly distinctive traits to define mammalian noncoding elements that shape clinically important phenotypes. ARs are conserved genomic elements with significantly increased nucleotide substitutions in a specific lineage, typically due to selective effects. In an unpublished study, we built on our approach to uncover regulatory elements shaping mammalian obesity and neurodegeneration by studying hibernators. Hibernators evolved metabolic and behavioral adaptations that resulted in a reversible obesogenic phenotype. They also evolved neuroprotective mechanisms that prevent brain damage. We identified 2370 50bp elements in the mammalian genome that underwent parallel accelerated evolution in multiple species that independently evolved hibernation. We call these noncoding elements hibernator accelerated regions (ARs) and found a subset associated with risk loci for human obesity and Alzheimer's disease. Our study tests the hypothesis that the conserved elements impacted by hibernator ARs near obesity and Alzheimer's disease risk genes are critical regulatory elements that control gene expression in different tissues and shape obesogenic behaviors, metabolic activity and age-related neurodegeneration. Our study is significant because the results will define important new noncoding mechanisms that regulate biological processes contributing to Alzheimer's disease. In the long-term, our results are expected to help reveal improved genetic and epigenetic biomarkers and therapeutic strategies to prevent age-related obesity and neurodegeneration.