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是由大量潜在的相互作用的遗传和环境因素控制的。如果能解决导致疾病风险变化的遗传位点，就可能提出新的治疗方案和基因检测，以促进定制的疾病治疗。然而，我们还远远没有确定影响任何复杂疾病易感性变化的致病位点目录，或者任何数量性状的变化。作为副产品，我们仍然不知道形成复杂疾病下的分离变异的进化力量。相关的多态性可能是由突变不断产生的，但它们是如此强烈地有害，以至于它们在达到高频率之前就被迅速地从群体中消除了。或者，多态性可以通过各种形式的平衡选择主动维持在中频。例如，在不同的环境条件下，交替的等位基因可能是有利的，从而导致在群体中维持多个等位基因。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多态性的相对作用。实验测试最好在模型遗传系统中进行，采用受选择的性状，在大型半自然实验室小组和自然群体中剖析性状变异。我们在这里关注的特征，后叶，是一个雄性限制的果蝇生殖器特征，在密切相关的物种中显示出惊人的形态分化。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种内变异。本建议的主要目标是描述模式生物D中导致形态变异的遗传因素。黑腹菌为了实现这一目标，我们将利用一种新的遗传作图方法，在两个大型独立的作图小组中进行重复研究。我们采用的方法是独特的，在提供一个估计的群体频率映射QTL，从而可以区分理论模型，试图解释变异的维持。此外，我们的框架提供了一种简化的方法，从QTL移动到所涉及的精确核苷酸。我们将验证这些网站，并确定可复制的致病变异的后续关联测试在多个野生衍生的人群。最后，为了阐明导致物种间后叶形态显著分化的过程，我们将比较种内性状变异的遗传结构与种间杂交的遗传结构。我们使用数千个重组杂交个体将提供阐明这种关系所需的高分辨率数据。

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.