| 题名 | 人类智力起源遗传进化机制的初步研究 |
| 作者 | 杨立新 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-11 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 宿兵 |
| 关键词 | IQGAP1 miR-124 认知相关分析 梭形神经元 转录组比较分析 |
| 其他题名 | Preliminary study of evolutionary and genetic mechanisms of human intelligence |
| 中文摘要 | 人类显著提高的认知能力在人类起源的过程中发挥了非常关键的作用。现在一般认为，人类超级大脑的形成是受到达尔文正选择作用的结果，但人类高级认知能力的起源一直是个未解之谜。 因此人类高级认知能力也就是智力的起源毫无疑问是研究人类起源中最重要及最吸引人的领域，也是长期以来生命科学领域的重大课题之一。 本文从两个不同的角度入手，通过对认知相关的候选基因和神经元转录组的研究来探索人类大脑及高级认知的起源与进化的分子机制：1、从单个认知相关基因出发，研究人类认知能力的遗传特性。前人的研究表明，IQGAP1基因的表达量可以影响小鼠的学习记忆能力，且在该基因的3’UTR区存在一个单核苷酸多态位点可能影响microRNA（miR-124）对IQGAP1的表达调控。我们推测该位点不仅可以改变IQGAP1的表达，也可能会在人群中造成学习记忆能力的表型差异。2、从分析认知相关脑区不同类型神经元的转录组出发，研究高级认知的细胞及遗传学基础。研究发现在人和非人灵长类以及某些大型群居哺乳动物大脑的特定区域中存在一类特殊神经元，这类神经元可能在许多认知过程（如洞察力和声音识别能力等）中行驶至关重要的作用；并且已经证实它与许多精神疾病相关，例如，难语症、自闭症和额颞叶痴呆等。但是由于技术的限制这类神经元的转录组一直没有得到解析，我们利用激光捕获显微切割和单细胞测序技术对这类神经元及其周围神经元的转录组进行全面系统的比较分析。 IQGAP1是广泛表达的细胞骨架蛋白，它参与很多细胞行为，例如细胞粘附、细胞迁移及细胞骨架调节。 该基因的表达与否直接影响到神经元上神经突触棘的数量，同时IQGAP1敲除小鼠表现出学习记忆的缺失。我们推测位于该基因3’UTR区的一个单核苷酸突变可能会影响与之相互作用的microRNA对它的表达调控，进而影响该基因的表达，甚至可能有与之相关的认知表型。为了证明这个推测，我们首先对该位点做了群体进化分析，发现该位点所在的基因区域可能存在近期的达尔文正选择；然后我们进行了体内和体外表达差异实验，证明了该多态位点可以影响到IQGAP1的表达；最后我们利用行为学实验证明了该位点与中国男性的触觉记忆相关。 梭形神经元是一类胞体很长且可以远距离传递信息的神经元, 在人脑中这类神经元的数量和细胞体积都显著大于其他非人灵长类。 目前发现这类神经元仅存在于具有高级认知能力的大型群居哺乳动物大脑的三个脑区，前扣带回、前岛叶皮层和背外侧前额叶。 梭形神经元在智力的发育、对环境改变的适应能力和认知失调中扮演着重要角色。 由于技术的限制该类细胞的转录组一直没有得到解析。为了能够解析不同神经元的转录组，找出更多认知相关基因，了解不同类型神经元在认知过程中所起的作用，我们将激光捕获显微切割和单细胞测序技术有效结合，得到了高质量的cDNA并且经过二代测序得到了3个人脑B24区梭形神经元、大锥体神经元、小锥体神经元和B32区大锥体神经元四类神经元的转录组数据。 通过初步的数据分析，我们发现不同类型神经元的表达谱存在一定的差异。 这些差异基因的真实性和功能还有待于进一步验证。 |
| 英文摘要 | Improvement of human cognitive ability has played a key role during human origin. It has become a common wisdom that the large brain of human is the consequence of adaptive evolution, i.e. Darwinian positive selection. However, the origin of human’s highly developed cognitive ability remains unsolved, which is the most intriguing field in the research of human origin, and also one of the important fields in life science. In this study, we aim to tackle this question from two different aspects, the study of cognition gene and dissection of transcriptomes of neurons involves in higher cognition, in order to explore the evolutionary and molecular mechanisms of human cognitive ability. Firstly, we analyzed the correlation between different genotypes and cognitive ability of a cognition-related gene, IQGAP1. Previous studies have shown that the level of IQGAP1 expression can affect the ability of learning and memory in mice. In addition, it was demonstrated that there was a single nucleotide polymorphism(SNP)in the 3’UTR of IQGAP1, and this SNP can effect expression regulation of IQGAP1 by a microRNA (miR-124), and the genomic region containing this SNP was likely subject to recent Darwinian positive selection. We speculated that this SNP can not only change the expression of IQGAP1, but may also cause phenotypic difference in learning and memory of humans. Secondly, we intend to compare the transcriptomes of different neuronal cell types of different brain areas in order to understand the celluar basis of human cognition. It has been reported that there is a special neuron(spindle neuron), distributed in three specific areas of large social mammals, e.g. human and nonhuman primates. It is generally believed that the spindle neuron play a key role in cognitive processes, e.g. insight and voice recognition. Furthermore, it has been confirmed that the spindle neurons were associated with neurological disorders, such as dyslexia, autism and frontotemporal dementia. We used laser capture microdissection and single cell sequencing technology to analyse the transcriptomes of spindle neurons and pyramidal neurons. IQGAP1 is a widely expressed scaffold protein that has important neuron specific functions. It is involved in multiple fundamental cellular activies, such as cell adhesion, cell migration and regulation of cytoskeleton. The level of IQGAP1 expression directly affects the number of neuron synapase on the spine. IQGAP1 knockout mice showed deficits in learning and memory. We speculated that a SNP in the 3’UTR region of IQGAP1 may affect the microRNA regulation ability, and therefore affect gene expression, and it may even contribute to differences in cognitive performance in humans. We analyzed the pattern of molecular evolution of IQGAP1 and observed signatureof Darwinian positive selection on IQGAP1 in human populations. With the use of both in vitro and in vivo experiments, we demonstrated that the IQGAP1 SNP could affect its expression regulation by miR-124, and this SNP was significantly associated with tactile memory in Chinese males. Spindle neuron has a long cell body, and it can transmit neural signals over a long distance. Different from other type of neurons, spindle neurons in human brain are larger in volume and more in number compared with other primates. Spindle neurons have only been found in three brain regions of large social mammals, such as humans and nonhuman primates. These regions include anterior cingulate cortex, fronto-issular cortex and dorsolateral perfrontal cortex. Spindle neurons have been implicated as playing an important role in many cognitive abilities and disabilities generally unique to humans. However, due to the limitation of molecular technology, the transcriptome of spindle neurons remains unsolved. We utilized laser capture microdissection and single cell sequence technology and obtained high quality cDNA from spindle neurons. With the use of next generation sequencing, we acquir |
| 语种 | 中文 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10188]  |
| 专题 | 昆明动物研究所_比较基因组学 |
| 推荐引用方式 GB/T 7714 | 杨立新. 人类智力起源遗传进化机制的初步研究[D]. 北京. 中国科学院研究生院. 2014. |
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