Polygenic basis of cardiac function in Drosophila melanogaster

描述（由申请人提供）：该提案解决了果蝇作为器官衰竭病因多基因基础的遗传解剖模型的效用。具体来说，我们将验证这样一个假设，即在成年果蝇中，调节心脏生理、内分泌和形态发生的基因的分离变异导致了年龄依赖性的心脏功能丧失。在这个过程中，我们希望能发现影响心脏病发病的新基因。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“主要作用的罕见等位基因优势”模型。前者一直是主导范式，但许多连锁研究的失败和与复杂疾病关联的不一致的复制正在挑战其适用性。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。我们在此提出，果蝇心脏功能障碍，表现为起搏性心力衰竭和心律失常是一个理想的模型。在自交系野生型系中仔细观察心脏功能表明，存在表现出一系列异常的极端基因型。在详细评估幼龄和老年果蝇心力衰竭和心律失常发生率升高或降低后，我们将进行定量遗传分析，旨在(i)评估遗传背景改变促病等位基因组合外显率和表达的能力；（ii）记录影响心脏功能不同方面的天然等位基因相互补充和/或相互作用的能力；（三）绘制和克隆10个左右罕见的主要影响心脏病的易感等位基因。转录和代谢分析也将用于开发心脏生物标志物。

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.