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

从关联到因果关系：查明自然行为变异背后的遗传和分子决定因素

基本信息

批准号：
10864416
负责人：
Yun Ding
金额：
$ 25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-05-31
项目状态：
未结题

项目摘要

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.

项目概要破译自然遗传变异如何影响复杂的表型特征是人类的中心目标遗传学和进化生物学。在过去的几十年里，模型系统的实证研究已经在概念上促进了对生理和形态特征自然变异的遗传学理解。相比之下，遗传变化如何引起自然行为变异改变神经功能仍然是一个基本问题神秘。尽管遗传变异和行为变异之间存在许多相关性在包括人类在内的广泛物种中发现了偶然遗传的身份和功能性质改变在很大程度上是遥不可及的。密切相关的果蝇物种求偶歌曲的进化提供了通过提供非凡的行为多样性和无与伦比的方式来建立这种因果联系的难得机会遗传、神经元和行为的易处理性。该提案的总体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介导的因果遗传和分子变化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领域进行方向。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通量，我们将对定义的性状相关基因组进行基因分辨率解剖区域来描述物种特异性求爱歌曲特征背后的因果基因和突变。第二，建立在我们对求爱歌曲进化中相关神经元的了解以及我们在遗传方面的专业知识的基础上跨物种标记这些神经元，我们将利用适应性变化的可能神经位点作为入口和使用单细胞转录组来探测基因表达变化，特别是顺式调控变化，即负责物种特定的神经功能和行为。重要的是，对于每个方向，我们都会检查使用综合方法，例如候选遗传和分子变化的表型效应明确的基因测试和神经元特异性基因沉默。这两个方向在连接上具有协同作用生物组织不同层次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性行为特征，这将使我们能够推导出跨物种可推广的主要机制，并反过来告知人类行为障碍和精神疾病的病因条件。