Characterization of Tandem Repeat and Structural Variants Contributing to Addictive Behaviors in Mice and Rats

项目总结 在小鼠和大鼠等模式生物中进行的全基因组关联研究(GWAS) 确定了数百个与成瘾行为相关的遗传基因座，但确定了原因 基因仍然具有挑战性。单核苷酸多态(SNPs)可能不足以标记其他类别 具有较高突变率的变异，如结构和重复变异。因此，两个小组的 近交系和异交群体将无法识别出基因座和因果等位基因的子集。我们是 建议通过使用尖端方法发现和基因分型来解决这一严重限制 结构变异(SVS)和串联重复序列(TRs)。因为它们在技术上很难分析， 在啮齿动物中，SVS和TRS还没有得到充分的调查。然而，已经有了广泛的 证据表明SVS和TRS在小鼠和大鼠中普遍存在，并且它们具有重要的功能 后果。我们的计划结合了人类遗传学和生物信息学方面的互补专业知识 SVS(SEBAT)和重复变异(Gymrek)的分析在阐明 模式生物行为表型的遗传基础(Palmer)。这项研究将产生第一个 用于分析复杂变异对小鼠和大鼠表型影响的大规模资源。我们用 本资源用于检测近交系小鼠(BXD重组近交系)的基因表达和行为特征 品系，杂交小鼠多样性小组(HMDP)，多样性杂交(DO)小鼠，杂交大鼠 多样性小组(HRDP)和异种系(HS)杂交大鼠。 在特定的目标1中，我们将用单分子来表征近交系和近交系小鼠和大鼠的SVS 测序。在具体目标2中，我们将对近交系和近交系小鼠和大鼠进行tr基因分型。最后，在 具体目标3，我们将使用SV和TR对基因表达和行为特征进行GWA。我们会 确定SV和TR型对基因表达和行为的表型影响 特征。我们将把SVS和TRS注入杂交的小鼠和大鼠中，然后利用丰富的 可用于小鼠和大鼠种群的预先存在的基因表达和行为数据 在本项目中进行了研究。该项目的完成将描述MICE和 大鼠，阐明它们在与成瘾相关的基因表达和复杂行为特征中的作用，并创造 这是一个社区资源，将加强许多正在进行的小鼠和大鼠基因研究。

PROJECT SUMMARY Genome-wide association studies (GWAS) in model organisms such as mice and rats have identified hundreds of genetic loci that are associated with addictive behaviors, but determining the causal genes remains challenging. Single nucleotide polymorphisms (SNPs) may not adequately tag other classes of variants such as structural and repetitive variants that have higher mutation rates. Thus, both panels of inbred strains and outbred populations will fail to identify a subset of loci and causal alleles. We are proposing to address this serious limitation by using cutting-edge methods to discover and genotype structural variants (SVs) and tandem repeats (TRs). Because they are technically challenging to analyze, SVs and TRs have not yet been adequately surveyed in rodents. However, there is already extensive evidence that SVs and TRs are prevalent in mice and rats, and that they have important functional consequences. Our proposal brings together complementary expertise in human genetics and bioinformatic analysis of SVs (Sebat) and repetitive variation (Gymrek) with established leadership in elucidating the genetic basis of behavioral phenotypes in model organisms (Palmer). This study will generate the first large-scale resource for analyzing the effects of complex variation on mouse and rat phenotypes. We use this resource to examine gene expression and behavioral traits in inbred mice (BXD recombinant inbred strains, the Hybrid Mouse Diversity Panel (HMDP), the Diversity Outbred (DO) mice, the Hybrid Rat Diversity Panel (HRDP) and the Heterogeneous Stock (HS) outbred rats. In Specific Aim 1 we will characterize SVs in inbred and outbred mice and rats by single-molecule sequencing. In Specific Aim 2 we will genotype TR in inbred and outbred mice and rats. Finally, in Specific Aim 3 we will perform GWAS using SV and TR for gene expression and behavioral traits. We will determine the phenotypic consequences of the SV and TR genotypes on gene expression and behavioral traits. We will impute SVs and TRs into outbred mice and rats and then perform GWAS using the wealth of preexisting gene expression and behavioral data that are available for the mouse and rat populations studied in this project. Completion of this project will characterize the SV and TR landscape in mice and rats, elucidate their role in gene expression and complex behavioral traits relevant to addiction, and create a community resource that will enhance numerous ongoing mouse and rat genetic studies.