Polygenic basis of cardiac function in Drosophila melanogaster

描述（由申请人提供）：本提案涉及果蝇作为器官衰竭病因学多基因基础遗传解剖模型的实用性。具体来说，我们将测试的假设，隔离变异的基因，调节生理学，内分泌学和心脏的形态有助于年龄依赖性的成年苍蝇的心脏功能丧失。在这个过程中，我们希望能发现影响心脏病发作的新基因。复杂疾病的遗传决定有两类不同的模型，即“常见疾病-常见变异”和“主要效应的罕见等位基因优势”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不一致的复制与复杂疾病的关联正在挑战其适用性。另一方面，显然需要新的方法来检测导致多基因疾病的罕见等位基因。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。仔细观察近交野生型品系的心脏功能表明，存在表现出一系列异常的极端基因型。在详细评估了年轻和年老果蝇中心力衰竭和心律失常的发生率升高或降低后，我们将进行定量遗传分析，目的是（i）评估遗传背景改变疾病促进等位基因组合的遗传率和表达率的能力;（ii）记录影响心脏性能的不同方面的天然存在的等位基因彼此互补和/或相互作用的能力;和（iii）定位和克隆十个左右罕见的主要影响心脏病易感性等位基因。还将进行转录和代谢分析，以开发心脏生物标志物。 项目叙述：该提案使用一种模式生物来研究老年人的心脏性能如何受到罕见突变的影响。它结合了经典的遗传分析与群体遗传学，以寻找新的基因参与心功能不全的各个方面，并询问是否有可能与基因组工具检测到的易感性的共同特征。

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.