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题名	哺乳动物Tas2R基因家族及酸耐受相关基因Nav1.7的分子进化模式及机制
作者	王维
学位类别	博士
答辩日期	2015-04
授予单位	中国科学院研究生院
授予地点	北京
导师	施鹏
关键词	灵长类 苦味受体 冬眠动物 酸耐受 Nav1.7
其他题名	The Molecular Evolutionary Patterns and Mechanisms of Tas2R gene family & acid insensitivity related gene Nav1.7 in Mammals
中文摘要	动物适应性进化的核心就是提高动物本身的生存能力。抵抗外界不良因素对有机体的伤害是动物提高自身生存能力的最基本环节。 苦味受体作为化学能感觉受体大家族的一员，是一个与食性紧密相关且与外界因素相互作用频繁并受到各种选择压力作用的基因家族。苦味物质与苦味受体相互作用刺激动物做出厌恶反应，进而避免摄入有毒物质。哺乳动物的食性存在巨大差异，苦味受体基因家族也在选择压力的作用下不断演化。本研究结合了进化基因组学、遗传学和体外细胞功能实验分析，从序列水平到功能实验水平全面的阐述了哺乳动物苦味受体基因家族的进化模式。我们的研究发现：苦味受体基因家族在灵长目动物中展现出不断强化的进化模式。首先是在人科动物和狭鼻下目中，苦味受体基因家族成员数量增加，其次，狭鼻下目和类人猿下目共同祖先一对一直系同源基因整体上受到正选择作用，并且灵敏度上升。这意味着高级灵长类可能不仅具有识别更多苦味物质的能力，同时还对某些苦味物质有更高的识别灵敏度。在灵长类化学能受体普遍退化的背景下，我们发现了灵长类中第一个不断强化的化学能感受器受体家族——苦味受体基因家族。此外，在胎盘哺乳类中苦味受体一对一直系同源基因Tas2R38在劳亚兽中产生了新功能。这可能提示着新功能对劳亚兽类有重要价值。我们对这种功能分化的机制进行了初步探究。结果显示，Tas2R38的第三、第六和第七跨膜区协同作用导致了新功能的产生和原有功能的变化。 冬眠哺乳动物与地下穴居哺乳动物长期生活于高CO2环境中，面临着由恶劣的生存环境和代谢速率降低导致的pH下降的考验。因此，酸耐受能力对于长期生活于高CO2环境中的动物而言极为重要。我们通过分析覆盖了17个目42个科的71种哺乳动物鉴定出了与哺乳动物冬眠酸耐受相关的钠离子通道Nav1.7。我们的研究发现冬眠动物与裸鼹鼠有相似的Nav1.7演化模式和相似的酸耐受机制。冬眠动物Nav1.7的功能趋同在我们分析的73个物种中至少独立发生了6次。这是迄今最大规模的哺乳动物基因功能趋同现象。我们的研究使得现有的关于大进化尺度下表型趋同的分子机制的理解得到了进一步的延伸。 本文结合了进化基因组学、遗传学、生物信息学和体外细胞功能实验分析，从序列水平到功能实验水平全面的阐述了哺乳动物抵抗外界有毒物质侵害和自身酸积累的机制和进化模式，为仅一步探讨哺乳动物适应性进化提供了新的证据和研究思路。
英文摘要	The core of animal adaptive evolution is to improve survival ability of them. It is the most basic part to improve survival ability by resistance to the damage by adverse external factors. Bitter taste receptor gene family, which belongs to chemical sensory receptor super-family, is associated with feeding and under diversity selective pressure. The interaction between bitter taste receptor and bitter compounds can cause aversion behavior which help animals avoid toxin substance. Bitter taste receptors evolved under different selective pressure for the divergence of feeding habit between mammals. We combined evolutionary genomics, genetics and cell function in vitro analyze together to illustrate the evolutionary pattern from sequences level to function level. Our results show that Tas2R gene family is enhanced gradually in primates. We found that the number of Tas2R gene family member increased in Hominidae and Catarrhini firstly. Secondly, the one-to-one orthologs genes of Tas2R are under positive selection on the branches of common ancestor of Catarrhini and Simiiformes. Thirdly, the sensitivity of Tas2R16 and Tas2R38 which belong to one-to-one orthologs genes is improved. All the evidence implies that senior primates may have the ability to detect more bitter compounds with higher sensitivity. This is the first gene family is found under the process of enhancement gradually in primates. In addition, the neofunction of Tas2R38 that may be important to Laurasiatheria is discovered in Laurasiatheria. We also found the molecular mechanism of the appearances of Tas2R38’s neofunction is due to the interaction of TM3, TM6 and TM7. Hibernating mammals need to be insensitive to acid in order to cope with conditions of high CO2; however, the molecular basis of acid tolerance remains largely unknown. The African naked mole-rat (Heterocephalus glaber) and hibernating mammals share similar environments and physiological features. In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel Nav1.7. In this study, we tested for functional convergence of Nav1.7 in 71 species of mammals, including 22 species that hibernate. Our analyses revealed a functional convergence of amino acid sequences, which occurred at least six times independently in mammals that hibernate. Evolutionary analyses determined that the convergence results from both parallel and divergent evolution of residues in the functional motif. Our findings not only identify the functional molecules responsible for acid insensitivity in hibernating mammals, but also open new avenues to elucidate the molecular underpinnings of acid insensitivity in mammals. We combine the analyze of evolutionary genomics, genetics, bioinformatics and function assay in vitro to explain these two examples in order to illustrate the evolutionary patter and mechanism of damage resistance. It is a new way to study the adaptive evolution of mammals.
语种	中文
内容类型	学位论文
源URL	[http://159.226.149.26:8080/handle/152453/10134]
专题	昆明动物研究所_进化与功能基因组学
推荐引用方式 GB/T 7714	王维. 哺乳动物Tas2R基因家族及酸耐受相关基因Nav1.7的分子进化模式及机制[D]. 北京. 中国科学院研究生院. 2015.

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