Structural, functional genomics olfactory receptor genes

描述(申请人提供)：哺乳动物的鼻子能够检测数百万种不同的气味，是外部环境的精致传感器。对于大多数动物来说，嗅觉对于定位食物、避免伤害、导航和个体之间的交流是必不可少的。负责气味分子识别的嗅觉受体(ORs)家族因其大小、多样性、基因组分布、进化动力学和不寻常的调控而引人注目。OR‘亚基因组’拥有1000多个基因，约占核DNA的1%，为研究塑造基因组的进化过程提供了一个独特而具有挑战性的机会。这个项目的总体目标是了解这些过程如何参与OR基因家族的进化，最终使动物能够适应不断变化的嗅觉景观。为了实现这一目标，我们将计算和实验方法相结合，以全面描述OR基因的进化、变异和调控。在目标1中，我们研究了在多个物种中影响OR进化的选择压力。气味识别和神经元连接的互补功能研究将进一步加深我们对OR基因序列的保守和变异如何转化为嗅觉的理解。在目标2中，我们研究了复制和基因转换如何导致OR家族的扩大和多样化，并有助于物种内和物种间的基因变异。在目标3中，我们使用微阵列技术来表征ORs的表达谱，识别在其中表达ORs的其他组织，以及在发育、衰老以及不同的环境和生理条件下表达模式是如何变化的。最后，在目标4中，我们将小鼠遗传学和基因组分析结合起来，以获得对决定嗅觉感觉神经元如何从整个OR谱系中选择单个基因进行表达的调节机制的新见解。总之，这些相互关联和互补的研究解决了嗅觉和神经生物学领域的基本问题，同时也对基因家族进化、转录调控以及复杂基因组结构的起源和后果做出了重大贡献。

DESCRIPTION (provided by applicant): The mammalian nose, with its capacity to detect millions of different odors, is an exquisite sensor of the external environment. For most animals, the sense of smell is essential for locating food, avoiding harm, navigating, and communicating between individuals. The family of olfactory receptors (ORs) responsible for the molecular recognition of odors is remarkable for its size, diversity, genomic distribution, evolutionary dynamics, and unusual regulatory control. With well over 1000 genes and occupying approximately 1% of nuclear DNA, the OR 'subgenome' provides a unique and challenging opportunity to study the evolutionary processes that shape genomes. The overall goal of this project is to understand how these processes participate in the evolution of the OR gene family, ultimately allowing animals to adapt to changing olfactory landscapes. Towards that goal, we combine computational and experimental approaches in order to globally characterize OR gene evolution, variation, and regulation. In Aim 1, we examine the selective pressures that have influenced OR evolution in multiple species. Complementary functional studies of odor recognition and neuronal wiring will further our understanding of how conservation and variation in OR gene sequences translate into olfactory perception. In Aim 2, we examine how duplication and gene conversion have led to expansion and diversification of the OR family and contribute to genotypic variation within and between species. In Aim 3, we use microarray technology to characterize the expressed repertoire of ORs, identifying additional tissues in which ORs are expressed, and how expression patterns change during development, aging, and under different environmental and physiological conditions. Finally, in Aim 4, we combine mouse genetics and genome analyses to gain new insights into the regulatory mechanisms that determine how olfactory sensory neurons select a single gene from the entire OR repertoire for expression. Together, these interrelated and complementary studies address fundamental questions in the fields of olfaction and neurobiology, while also contributing significantly to the areas of gene-family evolution, transcriptional regulation, and the origin and consequences of complex genome architectures.