From association to causation: pinpointing the genetic and molecular determinants underlying natural behavioral variations

项目总结 破译自然遗传变异如何影响复杂的表型特征是人类的一个中心目标 遗传学和进化生物学。在过去的几十年里，模型系统中的经验研究在概念上 提高了对生理和形态性状自然变异的遗传理解。相比之下， 如何从改变神经功能的基因变化中产生自然行为变化仍然是一个基本的问题 神秘感。尽管遗传变异和行为变异之间的众多相关性一直是 确定了包括人类在内的广泛物种的身份和偶然基因的功能性质 变革在很大程度上遥不可及。近缘果蝇物种求偶歌曲的进化提供了 这是建立这种因果联系的难得机会，通过提供非凡的行为多样性和无与伦比的 遗传、神经和行为的可控性。这项提议的首要目标是利用这一强大的 系统，并利用我们的创新平台来识别导致基因和分子变化的原因 神经系统和行为的进化。我们的研究将在两个独立但互补的地方进行 方向。首先，通过结合有针对性的基因图谱方法和自动行为量化 以前所未有的吞吐量，我们将对已定义的与特征相关的基因组进行基因解析解剖 描述特定物种求爱歌曲特征背后的因果基因和突变的区域。第二, 基于我们在求爱歌曲进化中相关神经元的知识和我们在遗传学上的专业知识 标记这些跨物种的神经元，我们将利用可能的适应性变化的神经部位作为一个入口 使用单细胞转录本来探测基因表达的变化，特别是顺式调节的变化，即 负责物种特有的神经功能和行为。重要的是，对于每个方向，我们都会检查 候选基因和分子变化的表型效应使用综合方法，如 明确的遗传测试和神经元特异性基因沉默。这两个方向在连接 在生物组织的不同水平上的进化变化之间的点。这项研究将带来丰富的 了解进化如何作用于基因和神经系统以产生适应行为 特征，这将允许我们推导出可跨物种推广的主要机制，并反过来，告知 人类行为障碍和精神疾病的病因状况。

PROJECT SUMMARY Deciphering how natural genetic variations influence complex phenotypic traits is a central goal in human genetics and evolutionary biology. Over the past decades, empirical studies in model systems have conceptually advanced the genetic understanding of natural variations in physiological and morphological traits. In contrast, how natural behavioral variations arise from genetic changes altering neural functions remains a fundamental mystery. Although numerous correlations between genetic variations and behavioral variations have been identified across a wide range of species including human, the identity and functional nature of casual genetic changes are largely out of reach. The evolution of courtship song in closely related Drosophila species provides a rare opportunity to establish such causal links, by offering extraordinary behavioral diversity and unparalleled genetic, neuronal and behavioral tractability. The overarching goal of this proposal is to leverage this powerful system and employ our innovative platforms to identify causal genetic and molecular changes that mediate the evolution of the nervous system and behaviors. Our research will proceed in two independent but complementary directions. First, by combining a targeted genetic mapping approach and automated behavioral quantification with unprecedented throughput, we will perform a gene-resolution dissection of defined trait-associated genomic regions to delineate the causal genes and mutations underlying a species-specific courtship song trait. Second, building on our knowledge of relevant neurons in courtship song evolution and our expertise in genetically labeling these neurons across species, we will exploit possible neural sites of adaptive changes as an entry and use single-cell transcriptomes to probe gene expression changes, especially cis-regulatory changes, that are responsible for species-specific neural functions and behaviors. Importantly, for each direction, we will examine the phenotypic effects of candidate genetic and molecular changes using integrative approaches such as definitive genetic tests and neuron-specific gene silencing. The two directions are synergistic in connecting the dots between evolutionary changes at different levels of biological organization. This study will lead to a rich understanding of how evolution operates on the genes and the nervous system to yield adaptive behavioral traits, which will allow us to derive principal mechanisms generalizable across species, and in turn, inform the etiological conditions of behavioral disorders and mental disease in human.