A Genomic Analysis of Sexual Trait Variation Within and Between Species

描述(由申请人提供)：复杂的疾病，如糖尿病、阿尔茨海默氏症和其他疾病，由大量潜在的相互作用的遗传和环境因素控制。如果导致疾病风险变异的基因位点能够被解决，可能会提出新的治疗方案和促进定制疾病治疗的基因测试。然而，我们还远远没有确定影响任何复杂疾病易感性变异的致病部位目录，或者实际上是任何数量性状的变异。作为副产品，我们仍然对形成复杂疾病背后的分离变异的进化力量一无所知。可能相关的多态是由突变不断产生的，但它们的危害性太强了，以至于它们在达到高频之前就从种群中迅速消除了。或者，可以通过各种形式的平衡选择将多态积极地维持在中频。例如，在不同的环境条件下，交替的等位基因可能是有利的，导致在一个群体中保持多个等位基因。为了深入了解复杂性状的遗传变异模式，我们必须了解罕见的有害突变和常见的选择性维持的多态的相对作用。实验测试最好是在模型遗传系统中进行，采用经过选择的性状，在大型半自然实验室小组和自然种群中剖析性状变异。我们在这里关注的特征，后叶，是一种雄性限制的果蝇生殖特征，在密切相关的物种之间显示出显著的形态差异。快速进化是动物雄性生殖器的普遍特征，后叶也表现出显著的物种内变异。这项建议的主要目标是描述导致模式生物黑腹丝虫形态变异的遗传因素。为了实现这一点，我们将在一项跨越两个大型、独立的图谱小组的重复研究中利用一种新的遗传图谱方法。我们使用的方法在提供定位的QTL的群体频率估计方面是独一无二的，因此可以区分试图解释变异维持的理论模型。此外，我们的框架提供了一种从QTL到所涉及的精确核苷酸的简化方法。我们将验证这些位点，并通过后续的关联测试在多个野生来源的种群中识别可复制的致病变异。最后，为了阐明导致物种间后叶形态显著差异的过程，我们将比较种内性状变异的遗传结构和物种间杂交中看到的遗传结构。我们对数千个重组杂交个体的使用将提供阐明这种关系所需的高分辨率数据。 与公共健康相关：多年来，生物学家一直在争论进化过程，这些过程塑造了与生态和医学相关的复杂特征的自然遗传变异。为了检验已经提出的各种假说，我们首先必须能够详细描述复杂特征的遗传结构--这是一个在遗传易处理的模型系统中比在人类中简单得多的研究程序。在这项建议中，我们将对果蝇中一对男性受限的性特征进行基因特征描述，并通过这样做来洞察可能影响人类疾病遗传变异模式的选择过程。

DESCRIPTION (provided by applicant): Complex diseases, such as diabetes, Alzheimer's, and others are controlled by a large number of potentially interacting genetic and environmental factors. If the genetic loci contributing to variation in disease risk can be resolved, novel therapeutic regimens, and genetic tests that facilitate tailored disease treatments may be suggested. However, we are far from identifying the catalog of causative sites that influence variation in susceptibility to any complex disease, or indeed variation in any quantitative trait. As a byproduct, we remain ignorant of the evolutionary forces that shape segregating variation underlying complex disease. It may be that relevant polymorphisms are continually created by mutation, but are so strongly deleterious that they are rapidly eliminated from the population before they attain high frequency. Alternatively, polymorphisms may be actively maintained at intermediate-frequency by various forms of balancing selection. For instance, alternate alleles may be favored under different environmental conditions, leading to the maintenance of multiple alleles in a population. To gain insight into the pattern of genetic variation for complex traits, we must understand the relative roles of rare deleterious mutations and common selectively-maintained polymorphisms. Experimental tests can best be carried out in model genetic systems, employing traits that are subject to selection, dissecting trait variation both in large semi-natural laboratory panels and in natural populations. The trait we focus on here, the posterior lobe, is a male-limited Drosophila genital trait that shows striking morphological differentiation among closely-related species. Rapid evolution is a general feature of male genitalia in animals, and the posterior lobe also exhibits significant within-species variation. The primary goal of this proposal is to characterize the genetic factors that contribute to morphological variation within the model organism D. melanogaster. To achieve this we will utilize a novel genetic mapping approach in a replicated study across two large, independent mapping panels. The method we employ is unique in providing an estimate of the population frequency of mapped QTL, and thus can distinguish between theoretical models that seek to explain the maintenance of variation. In addition, our framework offers a streamlined approach to move from QTL to the precise nucleotides involved. We will validate these sites, and identify replicable causative variants by follow-up association tests in multiple wild-derived populations. Finally, to elucidate the processes that led to the dramatic divergence in posterior lobe morphology among species, we will compare the genetic architecture of intraspecific trait variation to that seen in between-species crosses. Our use of thousands of recombinant hybrid individuals will provide the high resolution data required to articulate this relationship. PUBLIC HEALTH RELEVANCE: For many years, biologists have debated about the evolutionary processes that shape natural genetic variation for ecologically- and medically-relevant complex traits. To test the various hypotheses that have been put forward, it is essential that we first be able to describe in detail the genetic architecture for complex traits - a research program that is much simpler in genetically-tractable model systems than it is in humans. In this proposal we will genetically characterize a pair of male-limited sexual traits in Drosophila, and in so doing gain insight into the selective processes than can influence patterns of genetic variation for human disease.