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

结构变异和串联重复在药物滥用相关行为特征中的作用

• 批准号: 10838864
• 负责人: Melissa Gymrek
• 金额: $ 5.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838864
• 关键词: Addictive Behavior; Address; Behavioral; Bioinformatics; Catalogs; Communities; Complex; Data; Data Set; Disease; Drug abuse; Funding; Gene Expression; Genetic; Genetic Variation; Genetic study; Genotype; Human Genetics; Hybrids; Inbred Mouse; Inbred Strain; Inbreeding; Leadership; Methods; Molecular Genetics; Mus; Mutation; Phenotype; Population; Population Study; Postdoctoral Fellow; Public Health; Rattus; Recombinant Inbred Strain; Resources; Risk; Rodent; Role; Single Nucleotide Polymorphism; Source; Substance abuse problem; Surveys; Tandem Repeat Sequences; Variant; addiction; behavioral phenotyping; causal variant; genetic analysis; genetic variant; genome wide association study; genomic locus; model organism; parent grant; polygenic risk score; single molecule; statistics; trait

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.

项目摘要 在模式生物如小鼠和大鼠中的全基因组关联研究（GWAS）已经确定了 数百个与成瘾行为相关的基因位点，但确定因果基因仍然存在。 挑战性单核苷酸多态性（SNP）可能无法充分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，两组近交系和远交系 群体将无法识别基因座和致病等位基因的子集。我们建议解决这一严重的 通过使用尖端方法发现和基因型结构变异（SV）和串联重复序列的限制 （TRs）。由于分析SV和TR在技术上具有挑战性，因此尚未对其进行充分调查 在啮齿类动物中。然而，已经有大量证据表明SV和TR在小鼠和大鼠中普遍存在， 它们具有重要的功能性后果。我们的建议汇集了互补的专业知识， SV（Sebat）和重复变异（Gymrek）的人类遗传学和生物信息学分析， 领导阐明模式生物行为表型的遗传基础（帕尔默）。本研究 将产生第一个用于分析复杂变异对小鼠和大鼠影响的大规模资源 表型我们利用这一资源来研究近交系小鼠（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）、多样性远交（DO）小鼠、 杂交大鼠多样性小组（HRDP）和异质性原种（HS）远交大鼠。 在具体目标1中，我们将通过单分子生物学方法表征近交系和远交系小鼠和大鼠中的SV 测序在特定目标2中，我们将在近交系和远交系小鼠和大鼠中对TR进行基因分型。最后，具体目标 3.我们将使用SV和TR进行GWAS，用于基因表达和行为特征。康贝特人将以 SV和TR基因型对基因表达和行为性状的表型影响。我们将归咎于 SV和TR植入远交系小鼠和大鼠，然后使用大量预先存在的基因表达进行GWAS 以及本项目中研究的小鼠和大鼠种群的行为数据。完成 这个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， 以及与成瘾相关的复杂行为特征，并创建一个社区资源， 正在进行的小鼠和大鼠遗传研究。 在这项补充申请中，我们正在扩大由家长补助金资助的研究，以寻求一个新的 使用目标1和2产生的数据集进行遗传分析。具体来说，我们将计算多基因 GWAS汇总统计的风险评分（PRS），并确定PRS是否修改了损害性大 影响由父授权发现的SV和TR。