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题名	哺乳动物回声定位的分子机制
作者	刘振
学位类别	博士
答辩日期	2012-11
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	哺乳动物 蝙蝠 回声定位 prestin KCNQ4 基因型 适应性进化 趋同进化
学位专业	遗传学
中文摘要	具有回声定位能力的动物利用回声定位导航和搜索食物，这种特殊的感觉系统对它们的生存和繁殖是非常重要的。尽管人们已经对回声定位的动物行为学和生理学等方面进行了大量研究，但是对其产生的分子机制却知之甚少。本研究采用进化生物学的理论和分析方法，并结合功能实验对蝙蝠回声定位的分子机制进行了深入地探讨。我们选取听力基因作为研究回声定位分子机制的切入点，因为回声定位动物必须通过发出高频声音进行回声定位，它们对高频声音的敏感度比不具有回声定位能力的动物要强得多。首先，我们通过进化分析及功能实验表明，听力基因prestin的进化历程跟脊椎动物的高频听力的产生密切相关。prestin编码的马达蛋白是哺乳动物耳蜗放大机制的分子基础，该放大机制的产生使哺乳动物具有了最高的听觉敏感性和频率选择性。然而，在脊椎动物中，不同物种对高频声音的感知能力具有巨大的差异。特别是从鱼类到四足动物以及从原始的哺乳动物到较高等的哺乳动物，高频听觉能力呈现出显著提高的趋势。基于这一进化现象，我们提出听力基因prestin可能会在这些关键的进化阶段受到正选择的作用，使生物具有了不同的高频声音感知能力，从而更好地适应其所处的环境的假说。为验证该假说，我们比较分析了脊椎动物不同类群的prestin直系同源基因，分别在四足动物的共同祖先、哺乳动物共同祖先、真兽亚纲祖先以及胎盘哺乳动物祖先检测到了正选择的信号，并且通过功能实验进一步验证了该假说。其次，我们发现了第一个与回声定位相关的基因—prestin。我们分别从海豚和蝙蝠中获得了prestin的核苷酸序列，经过进化分析发现在基于该基因的氨基酸序列构建的系统发育关系树上，具有回声定位能力的海豚和具有回声定位能力的食虫蝙蝠聚到了一起；而用同义突变位点构建系统发育关系树时，其拓扑结构又与物种系统发育关系树的拓扑结构一致，说明是该基因的功能性氨基酸位点而不是其进化历史导致了这两类回声定位动物聚在一起。进一步的进化分析表明，prestin在回声定位海豚和蝙蝠中受到了平行进化的作用,并且鉴别出11个受到平行进化的位点。通过功能实验，我们进一步确认了回声定位动物prestin的功能趋同性，并且阐明了导致prestin功能趋同的氨基酸位点正是我们鉴别出受到平行进化的位点。第三，利用比较基因组学的手段，我们发现与prestin共同在哺乳动物耳蜗外毛细胞表达的基因KCNQ4在回声定位蝙蝠中是平行进化的，从而鉴别出了第二个可能与蝙蝠回声定位相关的基因。通过构建高频听力基因KCNQ4的祖先序列，我们发现高频听力在回声定位蝙蝠中可能是独立起源的。该基因的发现进一步加深了我们对蝙蝠回声定位分子机制的理解。综上所述，本论文结合进化生物学和实验生物学的方法和理论，以蝙蝠为模式探索了哺乳动物回声定位产生的分子机制，为揭示基因型和复杂表型之间的相互作用关系提供了新的研究思路。
英文摘要	Echolocating animals use echolocation to navigate and to forage. This special sensory system is essential for their survival and reproduction. Although many behavioral and physiological studies exist on animal echolocation, little is known about the underlying molecular mechanisms. This study employs theoretical and analytical evolutionary methods and combines functional experiments to explore the molecular mechanisms of echolocation in bats. Hearing genes are paramount because echolocating animals must emit the high-frequency sounds to echolocate. Their sensitivity for high-frequency sounds is much higher than that of non-echolocating animals. First, evolutionary analyses and functional experiments determine that the hearing gene prestin is involved in vertebrate high-frequency hearing. Motor proteins encoded by prestin form the molecular basis of cochlear amplification in mammals, which is responsible for the highest hearing sensitivity and frequency selectivity. The ability to detect high-frequency sounds varies enormously among different species. From fishes to tetrapods, and from lower mammals to higher mammals, the detection of high-frequency sounds improves. Based on this evolutionary phenomenon, we hypothesized that prestin might be under positive selection for the detection of sound signals to adapt their surroundings. To test this hypothesis, we compare and analyze the orthologs of prestin from different groups of vertebrates. Signals of positive selection occur in the most recent common ancestor (MRCA) of tetrapods, mammals, therians, and placentals, respectively. Functional experiments fail to refute this hypothesis and reveal the functional divergence of voltage-dependent nonlinear capacitance of prestin. Second, we identify the first echolocating gene—prestin. We obtain coding sequences of prestin from the dolphin and bats to conduct the evolutionary analyses. Phylogenetic reconstructions based on the amino acid sequences of prestin cluster dolphins and echolocating bats. However, when we use synonymous sites to re-construct the phylogenetic tree, the topology is consistent with that of species phylogeny, which suggests that the functional amino acids and not the evolutionary history of prestin cause these two types of echolocating mammals to cluster together. Evolutionary analyses further show that prestin experienced parallel evolution in dolphin and echolocating bats and we identify 11 parallel-evolved amino acids. We verify functional convergence of prestin between the dolphin and echolocating bats, and by using experiments determine that parallel sites drive functional convergence. Finally, using methods of comparative genomics, we find the hearing gene KCNQ4, a gene that co-expresses with prestin in the outer hair cells of mammalian cochlea, also experienced parallel evolution in echolocating bats. Thus, it may be the second gene related to bat echolocation. The evolutionary trajectories of the parallel sites suggest independent gains of higher frequency hearing in echolocating bats. The identification of KCNQ4 further deepens our understanding of the molecular mechanisms of bat echolocation. In summary, we explore the molecular mechanisms of echolocation in bats by applying theories and methods of evolutionary and experimental biology to provide new insight for investigating the relationships between genotypes and complex phenotypes.
语种	中文
公开日期	2012-12-10
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/7130]
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	刘振. 哺乳动物回声定位的分子机制[D]. 北京. 中国科学院研究生院. 2012.

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