Genetic and Developmental Mechanisms of Evolutionary Innovations

描述（由申请人提供）：人类和其他灵长类动物之间的形态、生理和行为差异部分归因于人类谱系中出现的进化创新。了解这些创新如何以及为何进化是对黑猩猩和其他灵长类动物基因组进行测序的核心动机。解释数量快速增长的比较序列和基因表达数据将需要一个连接分子和表型进化的综合概念框架。在该项目中，此类框架将在果蝇模型中开发，该模型允许将基因组和群体遗传数据与遗传杂交以及基因调控和功能的实验分析相结合。最近在果蝇进化中起源并多样化的性别特异性形态结构将提供一个强大的实验模型。该项目的首要目标是确定 DNA 序列变化和群体遗传力，这些变化和群体遗传力是控制该结构发育的基因之间调控相互作用的起源和丧失的原因。为了实现这一目标，将结合生化、遗传学和比较方法来重建控制性别特异性分化的关键基因调控区域中转录因子结合位点的进化，并检查自然选择对这些位点的序列和亲和力的影响。第二个目标是确定在微进化时间尺度上重塑性别特异性发育途径的遗传和分子变化。基因表达的比较分析将与遗传杂交和转基因测定相结合，以了解基因调控的进化变化如何影响细胞分化并产生塑造成体形态的新形态发生途径。然后，这些方法将扩展到更广泛的模型，以阐明导致新的性别特异性器官起源的遗传和发育变化，并测试不同进化谱系中趋同的形态变化是否是由相似的发育变化引起的。该项目的最终目标是确定导致独特性别特异性感觉系统最近起源的基因和 DNA 序列变化。这将为理解行为进化变化的分子遗传和神经生物学机制开辟道路。公共卫生相关性：包括人类在内的所有动物都遵循性发育的基本原则，即性别特异性调节器通过调节其他发育途径的输出来发挥作用。阐明性别分化的分子机制和进化的模型系统研究将有助于更好地了解人类性别特异性特征的起源和发展，为设计针对男性或女性特异性发育途径的药物和预防性治疗开辟道路。

DESCRIPTION (provided by applicant): Morphological, physiological, and behavioral differences between humans and other primates are partly due to evolutionary innovations that arose in the human lineage. Understanding how and why these innovations evolved is a central motivation for sequencing the chimpanzee and other primate genomes. Interpreting the rapidly growing amounts of comparative sequence and gene expression data will require an integrated conceptual framework that connects molecular and phenotypic evolution. In this project, such framework will be developed in a Drosophila model, which allows genomic and population-genetic data to be combined with genetic crosses and experimental analyses of gene regulation and function. A powerful experimental model will be provided by a sex-specific morphological structure that originated and diversified recently in Drosophila evolution. The first goal of this project is to identify DNA sequence changes and population-genetic forces responsible for the origin and loss of regulatory interactions between genes that control the development of this structure. To accomplish this, biochemical, genetic, and comparative approaches will be combined to reconstruct the evolution of transcription factor binding sites in the regulatory region of a key gene that controls sex-specific differentiation, and examine the effects of natural selection on the sequence and affinity of these sites. The second goal is to identify the genetic and molecular changes responsible for the remodeling of a sex-specific developmental pathway on microevolutionary timescales. Comparative analysis of gene expression will be combined with genetic crosses and transgenic assays to understand how evolutionary changes in gene regulation affect cell differentiation and generate new morphogenetic pathways that shape adult morphology. These approaches will then be extended to a wider range of models to elucidate the genetic and developmental changes responsible for the origin of a novel sex-specific organ, and to test whether convergent morphological changes in different evolutionary lineages were caused by similar changes in development. The final goal of this project is to identify the genes and DNA sequence changes responsible for the recent origin of a unique sex-specific sensory system. This will open the way for understanding the molecular-genetic and neurobiological mechanisms of evolutionary changes in behavior. PUBLIC HEALTH RELEVANCE: The fundamental principle of sexual development - that sex-specific regulators act by modulating the output of other developmental pathways - is shared by all animals, including humans. Model system research that elucidates the molecular mechanisms and evolution of sexual differentiation will lead to a better understanding of the origin and development of sex-specific traits in humans, opening the way for designing drugs and prophylactic treatments that target male- or female-specific developmental pathways.