Polygenic basis of cardiac function in Drosophila melanogaster

描述(由申请人提供)：这项建议解决了果蝇作为器官衰竭病因的多基因基础的遗传解剖的模型的用途。具体地说，我们将测试这一假设，即调节心脏生理、内分泌和形态发生的基因的分离变异导致成年果蝇心脏功能的年龄相关性丧失。在这个过程中，我们希望发现影响心脏病发病的新基因。复杂疾病的遗传决定有两类截然不同的模型，即“常见疾病-共同变异”模型和“稀有主效等位基因优势”模型。前者一直是占主导地位的范式，但许多连锁研究的失败和与复杂疾病的关联的不一致复制正在挑战其适用性。另一方面，显然需要新的方法学方法来检测导致多基因疾病的稀有等位基因。我们认为，果蝇心脏功能障碍，表现为起搏引起的心力衰竭和心律失常，是一个理想的模型。对近交系野生型心脏功能的仔细观察表明，存在表现出一系列异常的极端基因类型。在详细评估了年轻果蝇和老年果蝇心力衰竭和心律失常的发生率后，我们将进行定量遗传分析，以(I)评估遗传背景改变致病等位基因组合的外显率和表达能力的能力；(Ii)记录影响心脏性能不同方面的自然发生的等位基因相互补充和/或相互作用的能力；以及(Iii)定位和克隆10个左右罕见的主要影响心脏病易感基因的能力。还将进行转录和代谢分析，以开发心脏生物标记物。 项目简介：这项建议使用一个模型生物体来研究罕见的突变如何影响老年的心脏表现。它将经典遗传分析与群体遗传学相结合，寻找涉及心脏功能障碍各个方面的新基因，并询问是否存在可用基因组工具检测到的共同易感性特征。

DESCRIPTION (provided by applicant): This proposal addresses the utility of Drosophila as a model for the genetic dissection of the polygenic basis for the etiology of organ failure. Specifically, we will test the hypothesis that segregating variants in genes that regulate the physiology, endocrinology, and morphogenesis of the heart contribute to age-dependent loss of heart function in adult flies. In the process, we expect to identify novel genes that affect the onset of heart disease. There are two distinct classes of models for the genetic determination of complex diseases, namely the "common disease-common variant" and "preponderance of rare alleles of major effect" models. The former has been the dominant paradigm, but failure of many linkage studies and inconsistent replication of association with complex diseases is challenging its suitability. On the other hand, there is a clear need for new methodological approaches to the detection of rare alleles that contribute to polygenic disease. We propose here that dysfunction of the Drosophila heart, manifested as pacing-induced heart failure and arrhythmia is an ideal model. Careful visualization of heart function in inbred wild-type lines indicates that there are extreme genotypes that exhibit a range of abnormalities. After detailed assessment of the incidence of elevated or reduced heart failure and of arrhythmias in young and old flies we will carry out quantitative genetic analyses designed to (i) assess the capacity of the genetic background to modify the penetrance and expressivity of disease-promoting allelic combinations; (ii) document the capacity of naturally occurring alleles that affect different aspects of heart performance to complement and/or interact with one another; and (iii) map and clone ten or so rare major-effect heart disease susceptibility alleles. Transcriptional and metabolic profiling will also be performed to develop cardiac biomarkers. Project Narrative: This proposal uses a model organism to study how heart performance in old age may be affected by rare mutations. It combines classical genetic analysis with population genetics to find new genes involved in various aspects of cardiac dysfunction, and asks whether there are common features of susceptibility that might be detected with genomic tools.