Polygenic basis of cardiac function in Drosophila melanogaster

这项建议致力于利用果蝇作为遗传解剖的模型 器官衰竭病因的多基因基础。具体地说，我们将检验这一假设 分离基因中调节生理、内分泌和形态发生的变异 心脏是成年果蝇心脏功能随年龄增长而丧失的原因。在这个过程中，我们 期待发现影响心脏病发病的新基因。有两个截然不同的 复杂疾病的遗传决定模型的类别，即常见的 疾病-常见的变异；和罕见的等位基因优势的主要影响模型。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 与复杂疾病相关的研究正在挑战其适宜性。另一方面，还有一个 显然需要新的方法学方法来检测有助于 多基因疾病。我们在这里提出，果蝇心脏功能障碍，表现为 起搏诱发的心力衰竭和心律失常，是一种理想的模型。对心脏的仔细观察 在近交系野生型中的功能表明，存在表现出一定范围的极端基因类型 异常的情况下。在详细评估心力衰竭的发生率升高或降低后 对于幼龄和老年果蝇的心律失常，我们将进行设计的定量遗传分析 以(I)评估遗传背景改变外显性和表现力的能力 致病等位基因组合；(Ii)记录自然发生的等位基因的能力 影响心脏功能的不同方面，以补充和/或与之相互作用 另一个；以及(Iii)定位和克隆10个左右罕见的重大心脏病易感等位基因。 还将进行转录和代谢分析，以开发心脏生物标记物。

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.