Single-cell comparative genomics of the neuron

神经元的单细胞比较基因组学

基本信息

批准号：
7917429
负责人：
JAMES H EBERWINE
金额：
$ 31.03万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-18 至 2013-04-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：哺乳动物的行为涵盖了从复杂的语言处理，到社交和性行为到简单刺激反应的绝妙功能和能力。关于这种多样性机制的传统解释包括大脑大小，神经解剖结构和功能性神经解剖学，包括连通性模式。建立这些神经解剖学差异需要指导发育过程的基因进化差异。但是，在非发育环境中，几乎没有比较研究集中在单个神经元功能上。以前，我们启动了一个项目，以了解哪些序列基序控制mRNA在大鼠神经元中的树突的亚细胞定位。令人惊讶的是，我们发现证据表明进化新颖的元素可能部分控制树突定位。此外，该元素在大鼠基因组中很丰富，但在小鼠基因组中的数量级较少。小鼠神经元的微观划分和表达阵列调查似乎表明，在小鼠树突中发现的同源mRNA与大鼠树突之间只有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规模分子生理具有广泛的差异，并且从进化的新元素得出的功能性非编码RNA在建立这些差异中起着作用。如果是真的，这将对将动物神经生物学研究转化为人类会产生重要的后果，还表明进化上新的元素（例如逆转录病毒源性元素）在脑功能和功能障碍中可能很重要。我们建议使用比较单细胞定位测定，单细胞转录组测定，全转录组测序和功能分析来检验假设。公共卫生相关性：在这个项目中，我们假设来自不同组织和紧密相关物种的神经元的基因组规模分子生理具有广泛的差异，并且功能性的非编码RNA来自进化的新元素在确定这些差异方面起作用。我们建议使用比较单细胞定位测定，单细胞转录组测定，全转录组测序和功能分析来检验假设。我们的调查结果将对将动物模型神经生物学研究转化为人类疾病产生重要的后果，并表明病毒衍生的元素在脑功能和神经退行性疾病中可能很重要。