Elucidating the effects of structural variation on cis-regulation in stickleback

描述(由申请者提供)：是什么决定了一个人独特的一系列特征，如发色、心率，甚至发展成疾病的可能性？健康生物体的大多数特征是遗传遗传因素与环境条件(如饮食或压力水平)相互作用的组合。当这些相互作用出错时，结果往往是某些人群成员处于疾病状态。通常，疾病的源头是有害的基因的分离变异，它可以扰乱一个基因或一组基因的正常调控或转录。单字母变化，即所谓的单核苷酸多态(SNPs)，长期以来一直被认为是一种重要的遗传变异。最近，随着更多高通量基因组技术的出现，结构变异的流行--例如大段DNA的倒位、缺失或易位--越来越受到重视。重要的是，初步研究表明，这些结构变异可能与血友病和亨特综合征等许多人类疾病有关。结构变异可以通过基因拷贝数的变化影响基因组和表型，并通过基因缺失暴露隐性等位基因。然而，这种基因组水平的差异如何转化为生物特征的差异仍不清楚。一种假设是，结构变异可能会改变基因的调节，改变特定基因在每个细胞中产生的时间、地点和数量。研究结构和表型变异之间的机制关系在人类中是困难的，但可以在模式脊椎动物生物中完成，如老鼠，或者在我们的案例中，自然种群的小鱼。这项研究的主要目标是记录自然种群中结构变异的基因组分布，并检验基因组水平的结构变异通过基因表达的变化而导致表型变异的假说。这项研究将主要集中在三刺背上，这是一种剖析数量性状表型变异遗传基础的新兴模型，既适用于自然群体的筛选，也适用于实验室的操纵研究。我们将使用几种全基因组分析和下一代测序技术的新合成来实现以下目标。首先，我们将确定结构变异在祖先和衍生三刺鱼种群内和种群之间的分布，其次，我们将通过eQTL分析来定位结构变异对基因表达的影响，以推断顺式调控变化。为了使我们的分析技术广泛应用于其他模式生物，我们将创建一套公共的、基于网络的计算资源，用于识别结构变化与基因表达的关联。 与公共卫生相关：最近的研究表明，遗传结构变异--如倒位、易位或大段DNA缺失--与某些人类疾病有关。导致这种相关性的机制尚不清楚，他们在人类身上的研究也很困难。通过观察结构变异在刺鱼自然种群中的流行情况，并阐明结构变异是如何改变基因表达的，我们将更好地了解构成人类一类重要疾病的基本遗传机制。

DESCRIPTION (provided by applicant): What produces an individual's unique set of traits, such as hair color, heart rate, or even probability of developing a disease? Most traits of healthy organisms are a combination of inherited genetic factors interacting with environmental conditions such as diet or stress levels. When these interactions go awry, the outcome is often a disease state in certain members of the population. Often, the source of the disease is a segregating variant of a gene that is harmful and which can disrupt the normal regulation or transcription of a gene or set of genes. Single letter changes, so-called Single Nucleotide Polymorphisms (SNPs), have long been recognized as an important category of genetic variation. Recently, with the advent of more high throughput genomic techniques, the prevalence of structural variation - such as inversions, deletions, or translocations of large blocks of DNA - has become increasingly appreciated. Importantly, initial studies have indicated that these structural variants can be associated with human diseases such as hemophilia and Hunter syndrome among many others. Structural variation can affect genomes and phenotypes by creating variation in gene copy number, and by exposing recessive alleles through gene deletions. However, the way that this genomic level variation can translate to differences in organismal traits is still unclear. A hypothesis is that structural variants may alter the regulation of genes, changing when, where and how much of a particular gene is made in each cell. Studying the mechanistic relationship between structural and phenotypic variation is difficult in humans, but can be accomplished in model vertebrate organisms such as mice or in our case natural populations of small fish. The primary goal of this research project is to document the genomic distribution of structural variants in natural populations and to test the hypothesis that genome level structural variation contributes to phenotypic variation through changes in gene expression. The research will focus primarily on threespine stickleback, an emerging model for dissecting the genetic basis of phenotypic variation in quantitative traits, and is amenable to both screens in natural populations and manipulative studies in the laboratory. We will use a novel synthesis of several whole-genome analysis and next generation sequencing techniques to accomplish the following aims. First, we will identify the distribution of structural variants within and among populations of ancestral and derived threespine stickleback fish, and second, we will genetically map the effects of structural variation on gene expression to infer cis-regulatory changes through an eQTL analysis. To make our analysis techniques widely available for use in other model organisms, we will create a set of public, web-based computational resources for identifying associating structural variation with gene expression. PUBLIC HEALTH RELEVANCE: Recent research has shown that variation in genetic structural variants - such inversions, translocations, or deletions of large blocks of DNA - is correlated with some human diseases. The mechanisms causing this correlation are unclear, their study is difficult in humans. By observing the prevalence of structural variants in natural populations of stickleback fish, and elucidating how structural variants change gene expression, we will better understand the fundamental genetic mechanisms that underlie an important class of human diseases.