Evolution of sodium channel genes

描述（由申请人提供）：电压依赖性钠通道基因突变导致神经系统、肌肉和心脏疾病。虽然对钠通道的功能已经了解很多，但仍有很多需要了解的。钠通道是一个大分子，了解其许多氨基酸中的哪一种对其功能很重要是一项艰巨的任务。确定蛋白质中潜在重要氨基酸的一种方法是将来自许多不同生物体的相同蛋白质的序列进行比对，以找出哪些氨基酸在进化过程中不会发生变化。我们在这里采用的另一种较少使用的策略是包括来自生物体的序列，其中该分子处于强大的选择压力下进化。在这种情况下，我们寻找在进化过程中确实发生变化的氨基酸变化。弱电鱼产生电器官放电（EOD）用于通信和感知对象。EODs是由钠通道产生的，电鱼的钠通道在通道的关键区域的氨基酸的物种特异性变化经历了强烈的选择。使用上述方法，我们已经发现了钠通道的一个新的功能域。我们将继续研究这两个独立进化的电鱼群体中钠通道基因的进化过程，以发现通道的其他功能重要区域。使用生物信息学方法比较两组电鱼，非电鱼和其他脊椎动物（包括人类）的氨基酸和核苷酸序列，我们将检测电鱼钠通道中可能处于正选择下的氨基酸位点。然后，我们将通过将我们在电鱼钠通道中观察到的氨基酸变化引入人类肌肉钠通道（以及匡威），并确定这些变化是否改变了表达的钠通道的生物物理特性，来测试这些特定的氨基酸是否对通道功能真正重要。除了提供对进化过程的见解，这项工作将有助于我们对钠通道功能的基本理解，钠通道是临床上重要的离子通道家族。 项目叙述：钠通道基因突变导致神经系统、肌肉和心脏疾病。使用生物信息学的方法，我们将确定可能是重要的钠通道的功能的氨基酸。然后，我们将测试这些特定的氨基酸是否是真正重要的通道功能，通过干扰这些氨基酸在人类肌肉钠通道基因，并观察这些是否改变钠通道的生物物理特性。这项工作将是医学上重要的了解钠通道，一个临床上重要的家庭离子通道的功能。

DESCRIPTION (provided by applicant): Mutations in voltage-dependent sodium channel genes cause neurological, muscular, and cardiac diseases. Although much is known about sodium channel function, there is still much to learn. The sodium channel is a large molecule and understanding which of its many amino acids is important to its function is a daunting task. One method to pinpoint potentially important amino acids in a protein is to align the sequences of the same protein from a number of different organisms to find out which amino acids do NOT change over the course of evolution. Another lesser-used strategy that we employ here is to include sequences from organisms in which that molecule is under strong selection pressure to evolve. In this case, we look for amino acid changes that DO change over the course of evolution. Weakly electric fish generate electric organ discharges (EODs) for communication and sensing objects. EODs are generated by sodium channels and the sodium channels of electric fish have undergone strong selection for species-specific changes in amino acids in critical regions of the channel. Using the approach described above, we have already discovered a novel functional domain of sodium channels. We will continue to study the process of evolution of sodium channel genes in the two independently evolved groups of electric fish in order to discover other functionally important regions of the channel. Using bioinformatics approaches to compare amino acid and nucleotide sequences in the two groups of electric fish, non-electric fish, and other vertebrates, including humans, we will detect amino acids sites that are likely under positive selection in the electric fish's sodium channels. We will then test whether these particular amino acids are truly important to channel function by introducing the amino acid changes that we observe in electric fish sodium channels into a human muscle sodium channel (as well as the converse) and determining whether these alter the biophysical properties of expressed sodium channels. Besides providing insights into the evolutionary processes, this work will aid our basic understanding of the functioning of sodium channels, a clinically important family of ion channels. Project Narrative: Mutations in sodium channel genes cause neurological, muscular, and cardiac diseases. Using bioinformatics approaches we will identify amino acids that are likely to be important to the function of the sodium channel. We will then test whether these particular amino acids are truly important to channel function by perturbing these amino acid in a human muscle sodium channel gene and observing whether these alter the biophysical properties of the sodium channels. This work will be medically important to understand the function of sodium channels, a clinically important family of ion channels.