Dissertation Research: Molecular Evolution of the Nuclear Receptor Superfamily

DeSalle 9870055基因突变在进化过程中产生了新的生化功能。这项研究阐述了这些变化是如何利用核受体蛋白发生的。核受体蛋白超家族包括50多个相关的转录因子，调节从水母到人类的各种动物的生殖、发育、变态和维持动态平衡。这个超家族包括类固醇和甲状腺激素(包括雌激素和睾酮)、维甲酸、维生素D和昆虫蜕皮激素的受体，以及大量的孤儿受体，这些配体的受体未知或可能不存在。尽管关于核受体功能的信息很多，但这组重要的生理基因的进化史却鲜为人知。本研究项目旨在阐明这一历史，具体目的如下：1)利用现有分子序列数据的简约分析重建核受体之间的系统发育关系；2)生成几种七鳃鳗类固醇受体序列的分子序列信息，以确定特定蛋白质何时通过复制和分歧事件进化，并为类固醇受体蛋白序列进化的比较分析提供数据；以及3)通过在系统发育的背景下分析分子和功能特征的相关进化、分歧率和基因组组织模式，来表征遗传变化在类固醇受体中产生新功能的机制和动力学。

DeSalle 9870055 Genetic changes have produced novel biochemical functions during the course of evolution. This study addresses the way in which these changes have occurred using nuclear receptor proteins. The superfamily of nuclear receptor proteins comprises over 50 related transcription factors that regulate reproduction, development, metamorphosis, and the maintenance of homeostasis in a broad range of animal taxa from jellyfish to humans. The superfamily includes receptors for steroid and thyroid hormones (including estrogen and testosterone), retinoic acids, vitamin D, and insect ecdysteroids, as well as a large number of orphan receptors, the ligands for which receptors are unknown or may not exist. Despite extensive information on nuclear receptor function, the evolutionary history of this group of physiologically important genes is obscure. This research project seeks to elucidate the history with the following specific aims: 1) reconstruction of the phylogenetic relationships among the nuclear receptors using parsimony-based analysis of existing molecular sequence data; 2) generation of molecular sequence information for steroid receptor sequences from several species of lamprey, the most ancient extant vertebrate lineage, in order to specify when specific proteins evolved through duplication and divergence events, and to provide data for a comparative analysis of the evolution of steroid receptor protein sequences; and 3) characterization of the mechanisms and dynamics by which genetic change has produced novel functions among the steroid receptors, by analyzing in a phylogenetic context the correlated evolution of molecular and functional characters, the rate of divergence, and the patterns of genomic organization in this important and well-studied class of proteins.