The role of structural variants and tandem repeats in substance abuse-related behavioral traits

项目摘要 在小鼠和大鼠等模式生物中进行的全基因组关联研究(GWAS)已经确定 数百个与成瘾行为相关的遗传基因，但决定原因的基因仍然存在 很有挑战性。单核苷酸多态(SNPs)可能不足以标记其他类型的变体，如 具有较高突变率的结构和重复变异。因此，近交系和近交系的两组 群体将无法识别基因座和因果等位基因的子集。我们提议认真解决这一问题 使用尖端方法发现结构变异(SVS)和串联重复序列并对其进行基因分型的局限性 (TRS)。由于在技术上难以分析，因此尚未对SVS和TRS进行充分调查 在啮齿动物身上。然而，已经有广泛的证据表明，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。我们的建议汇集了以下方面的互补专业知识 已建立的SVS(Sebat)和重复变异(Gymrek)的人类遗传学和生物信息学分析 在阐明模式生物行为表型的遗传基础方面的领导作用(帕尔默)。本研究 将产生第一个大规模资源，用于分析复杂变异对小鼠和大鼠的影响 表型。我们利用这个资源来检测近交系小鼠(BXD)的基因表达和行为特征 重组近交系，杂交小鼠多样性小组(HMDP)，多样性外交系(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，在具体目标上 3我们将使用SV和TR对基因表达和行为特征进行GWAS。我们将确定 Sv和tr基因对基因表达和行为特征的表型影响。我们将归因于 将SVS和TRS导入近交系小鼠和大鼠，然后利用先前存在的丰富的基因表达进行GWA 以及该项目中研究的小鼠和大鼠种群的行为数据。完成 该项目将描述小鼠和大鼠的SV和TR景观，阐明它们在基因表达中的作用 和与上瘾相关的复杂行为特征，并创建一个社区资源，将增强众多 正在进行的小鼠和大鼠基因研究。 在这项补充申请中，我们延长了由家长资助的课程，以寻求新的 使用目标1和目标2产生的数据集进行遗传分析。具体地说，我们将计算多基因 来自GWAS汇总统计数据的风险分数(PR)，并确定PR是否修改了破坏性较大 影响父奖助金发现的SV和RR。

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. In this supplement request, we are extending on the studies funded by the parent grant to pursue a new line of genetic analysis using the datasets produced by Aims 1 and 2. Specifically, we will calculate polygenic risk scores (PRS) from GWAS summary statistics and determine if PRS modifies the effects of damaging large effect SVs and TRs that are discovered by the parent grant.