Single-cell comparative genomics of the neuron

描述(申请人提供)：哺乳动物的行为跨越了一系列奇妙的功能和能力，从复杂的语言处理，到社会和性行为，再到简单的刺激反应。对这种多样性的机制的传统解释包括大脑大小、神经解剖学和功能神经解剖学，包括连接模式。建立这些神经解剖学差异需要指导发育过程的基因的进化差异。然而，很少有比较研究集中在非发育背景下的个体神经元功能。在此之前，我们启动了一个项目，以了解是什么序列基序控制了大鼠神经元中树突的mRNA在亚细胞内的定位。令人惊讶的是，我们发现了一种进化上的新元素可能部分控制树突定位的证据。此外，这种元素在大鼠基因组中大量存在，但在小鼠基因组中的含量要低一个数量级。对小鼠神经元的显微解剖和表达阵列调查似乎表明，在小鼠树突和大鼠树突中发现的同源mRNA之间只有36%的重叠。因此，我们假设来自不同组织和密切相关物种的神经元的基因组水平的分子生理学有很大的差异，而来自进化上新的元件的功能性非编码RNA在建立这些差异中发挥了作用。如果这是真的，这将对将动物神经生物学研究转化为人类产生重要影响，并表明逆转录病毒衍生元素等进化上的新元素可能在大脑功能和功能障碍中发挥重要作用。我们建议使用比较的单细胞定位分析、单细胞转录组分析、整体转录组测序和功能分析来检验我们的假设。 公共卫生相关性：在这个项目中，我们假设来自不同组织和密切相关物种的神经元的基因组规模的分子生理学有很大的差异，来自进化上新的元素的功能性非编码RNA在建立这些差异中发挥了作用。我们建议使用比较的单细胞定位分析、单细胞转录组分析、整体转录组测序和功能分析来检验我们的假设。我们的研究结果将对将动物模型神经生物学研究转化为人类疾病具有重要意义，并表明病毒衍生元件可能在脑功能和神经退行性疾病中发挥重要作用。

DESCRIPTION (provided by applicant): Mammalian behavior spans a fantastic range of function and ability, from complex linguistic processing, to social and sexual behavior, to simple stimulus-response. Traditional explanations of the mechanisms for this diversity include brain size, neuro- anatomy, and functional neuro-anatomy including connectivity patterns. Establishing these neuro-anatomical differences requires evolutionary differences in the genes guiding developmental processes. However, there has been little comparative studies focused on individual neuronal function in a non-developmental context. Previously, we initiated a project to understand what sequence motifs govern sub-cellular localization of mRNA to dendrites in rat neurons. Surprisingly, we found evidence that an evolutionarily novel element may partly govern dendritic localization. Furthermore, this element is abundant in the rat genome but an order of magnitude less abundant in the mouse genome. A micro-dissection and expression array survey of the mouse neurons seem to suggest that there is only 36% overlap between the homologous mRNA found in the mouse dendrites and the rat dendrites. Thus, we hypothesize that the genome-scale molecular physiology of neurons from different tissues and closely related species have broad differences and functional non-coding RNA derived from evolutionarily novel elements plays a role in establishing these differences. If true, this would have important consequences for translating animal neurobiological studies to humans and also suggest that evolutionarily novel elements such as retroviral-derived elements may be important in brain function and dysfunction. We propose to test our hypothesis using comparative single-cell localization assays, single-cell transcriptome assays, whole-transcriptome sequencing, and functional analysis. PUBLIC HEALTH RELEVANCE: In this project, we hypothesize that the genome-scale molecular physiology of neurons from different tissues and closely related species have broad differences and functional non-coding RNA derived from evolutionarily novel elements plays a role in establishing these differences. We propose to test our hypothesis using comparative single-cell localization assays, single-cell transcriptome assays, whole-transcriptome sequencing, and functional analysis. The results of our investigation will have important consequences for translating animal model neurobiological studies to humans diseases and also suggest that viral-derived elements may be important in brain function and neurodegenerative diseases.