Resource development for a new model of social threat response

描述(由申请人提供)：社会行为变异的潜在遗传基础引起了人们的强烈兴趣，但只有少数基因与脊椎动物的特定社会行为有关。因此，迫切需要确定在基因和社会行为之间存在明显联系的人群，无论是人类还是其他人群。在拟议的项目中，将开发资源，以利用一种独特的适合模型--白喉麻雀。这种丰富的北美鸣禽的雄性和雌性以两种不同的羽毛形态出现，其存在的染色体重排(ZAL2m)预测了对社会威胁的反应。白条纹(WS)羽型鸟类(ZAL2m/ZAL2)对领土入侵的反应是声音攻击水平高，而棕色条纹(TS)鸟类(ZAL2/ZAL2)对领土入侵的反应相对较少或没有声音攻击。在社会依恋的形成和父母供给率方面，形态也不同；因此，表型的特征是一套具有离散遗传基础的相关复杂特征。这项研究计划的长期目标是充分利用这种独特的模式生物，它在许多社会行为方面与人类相似，以前所未有的方式将基因表达和复杂行为联系起来。ZAL2和ZAL2m单倍型之间有限的基因流动导致重排染色体区域的遗传分化，导致单核苷酸多态积累等变化。这一建议的主要目的是评估这些遗传力对基因组和脑转录组的影响，从而为在未来的研究中确定行为失调的分子机制奠定基础。我们将结合两个PI的经验：一个是野生麻雀行为神经内分泌学的专业知识，另一个是基因组进化方面的专业知识。在目标1中，我们将识别和评估这两个单倍型之间的序列差异，这将揭示大量潜在的功能多态，然后可以进行实验探索。在目标2中，我们将使用下一代技术对自然环境中反应性攻击性被量化的个体的总mRNA进行测序。然后，我们将使用加权基因共表达网络分析(WGCNA)的映射和量化的阅读，以确定高度相关的基因模块与变形和反应性攻击。这两个目标加在一起，将揭示社交战略背后的候选机制。这个探索性的项目将专注于对社会威胁的反应，这是在自然主义环境下很难在人类身上研究的。所有的行为操作和测量都将在动物的自然栖息地进行，这使得这个项目具有很高的创新性。这个项目意义重大，因为 许多精神障碍--包括自闭症、抑郁症、双相情感障碍和精神分裂症--的特征是对社会威胁的反应失调，因为反应性攻击往往与冒险、药物滥用和犯罪行为并存。因此，了解应对社会威胁的潜在机制对人类健康非常重要。

DESCRIPTION (provided by applicant): The underlying genetic basis of variation in social behavior is of intense interest, yet only a handful of genes have been linked to specific social behaviors in vertebrates. Thus, there is a strong need to identify populations, human or otherwise, in which there is clear linkage between genes and social behavior. In the proposed project, resources will be developed to take advantage of a uniquely suited model, the white-throated sparrow. Males and females of this abundant North American songbird occur in two plumage morphs that differ with respect to the presence of a chromosomal rearrangement (ZAL2m) that predicts responses to social threat. Birds of the white-striped (WS) plumage morph (ZAL2m/ZAL2) respond to a territorial intrusion with high levels of vocal aggression, whereas birds of the tan-striped (TS) morph (ZAL2/ZAL2) respond with relatively little or no vocal aggression. The morphs also differ with respect to the formation of social attachments and parental provisioning rates; the phenotypes are thus characterized by a suite of correlated complex traits with a discrete genetic basis. The long-term goal of this research program is to fully exploit this unique model organism, which resembles humans with respect to many aspects of social behavior, to link gene expression and complex behavior in ways never before possible. Limited gene flow between the ZAL2 and ZAL2m haplotypes has led to the genetic differentiation of the rearranged chromosomal region, resulting in the accumulation of single nucleotide polymorphisms and other changes. The primary objective of this proposal is to assess the impact of these genetic forces on the genome and brain transcriptome, thus laying the groundwork to identify molecular mechanisms of behavioral dysregulation in future studies. We will combine the experience of two PIs: one with expertise in the behavioral neuroendocrinology of wild sparrows and the other in genome evolution. In Aim 1, we will identify and evaluate sequence differences between the two haplotypes, which will reveal a large number of potential functional polymorphisms that can then be explored experimentally. In Aim 2, we will use Next Generation techniques to sequence total mRNA from individuals for whom reactive aggression was quantified in a natural setting. We will then use weighted gene coexpression network analysis (WGCNA) of the mapped and quantified reads to identify modules of highly correlated genes associated with morph and reactive aggression. Together, the two aims will reveal candidate mechanisms underlying social strategies. This exploratory project will focus on responses to social threat, which are difficult to study in humans in a naturalistic setting. All behavioral manipulations and measurement will be conducted in the animals' natural habitat, making this project highly innovative. The project is significant because many mental disorders-including autism, depression, bipolar disorder and schizophrenia are characterized by dysregulated responses to social threat and because reactive aggression is often comorbid with risk-taking, substance abuse, and criminal behavior. Thus an understanding of the mechanisms underlying response to social threat is important for human health.