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

导致小鼠和大鼠成瘾行为的串联重复和结构变异的表征

• 批准号: 10392381
• 负责人: Melissa Gymrek
• 金额: $ 65.28万
• 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 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392381
• 关键词: Addictive Behavior; Address; Animal Model; Behavioral; Bioinformatics; Bipolar Disorder; Catalogs; Communities; Complex; Computing Methodologies; Data; Data Set; Drug abuse; Gene Expression; Genetic; Genetic Polymorphism; Genetic Variation; Genetic study; Genotype; Height; Heritability; Human; Human Genetics; Human Genome; Hybrids; Inbred Mouse; Inbred Strain; Inbred Strains Rats; Inbreeding; Leadership; Malignant Neoplasms; Methods; Molecular Genetics; Mouse Strains; Mus; Mutation; Phenotype; Play; Population; Population Study; Public Health; Publishing; Rattus; Recombinant Inbred Strain; Resources; Risk; Rodent; Role; Schizophrenia; Signal Transduction; Single Nucleotide Polymorphism; Source; Surveys; Tandem Repeat Sequences; Technology; Variant; addiction; autism spectrum disorder; behavioral phenotyping; causal variant; cohort; computerized tools; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic locus; mouse genome; nanopore; novel sequencing technology; rat genome; rodent genome; single molecule; trait; whole genome

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.

项目摘要 在模式生物如小鼠和大鼠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基因位点，但确定了成瘾行为的因果关系。 基因仍然具有挑战性。单核苷酸多态性（SNP）可能无法充分标记其他类别 变异体，如具有较高突变率的结构和重复变异体。因此， 近交品系和远交群体将不能鉴定基因座和致病等位基因的子集。我们 建议通过使用尖端方法来发现和基因分型， 结构变体（SV）和串联重复序列（TR）。因为它们在技术上很难分析， SV和TR尚未在啮齿动物中进行充分调查。然而，已经有广泛的 有证据表明SV和TR在小鼠和大鼠中普遍存在，并且它们具有重要的功能， 后果我们的提案汇集了人类遗传学和生物信息学方面的互补专业知识 分析SV（Sebat）和重复变异（Gymrek），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的影响的大规模资源。我们使用 这一资源，以检查基因表达和行为性状的近交系小鼠（BXD重组近交系 品系、杂交小鼠多样性小组（HMDP）、多样性远交（DO）小鼠、杂交大鼠 多样性面板（HRDP）和异质性股票（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。最后在 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。我们将 确定SV和TR基因型对基因表达和行为的表型后果， 性状我们将SV和TR输入远交系小鼠和大鼠，然后使用大量的 小鼠和大鼠种群已有的基因表达和行为数据 在这个项目中研究。该项目的完成将表征小鼠中的SV和TR景观， 大鼠，阐明它们在基因表达和与成瘾相关的复杂行为特征中的作用， 一个社区资源，将加强许多正在进行的小鼠和大鼠遗传研究。