Systematic characterization of tandem repeat variants contributing to complex traits

导致复杂性状的串联重复变异的系统表征

• 批准号: 10052847
• 负责人: Alon Goren
• 金额: $ 70.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10052847
• 关键词: Automobile Driving; Bioinformatics; Biological; Biological Assay; Bipolar Disorder; Blood; Catalogs; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Copy Number Polymorphism; DNA; Data Set; Exhibits; Failure; Gene Expression; Gene Expression Regulation; Genes; Genetic Variation; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Haplotypes; Height; Heritability; Human; Human Genetics; In Situ; Individual; Knowledge; Length; Malaria; Medical; Minisatellite Repeats; Molecular Biology; Mutation; Non-linear Models; Nucleosomes; Phenotype; Population; Positioning Attribute; Publishing; RNA; RNA Splicing; Repetitive Sequence; Reporter; Resistance; Resources; Role; SNP array; Sampling; Schizophrenia; Short Tandem Repeat; Signal Transduction; Single Nucleotide Polymorphism; Source; Structure; Tandem Repeat Sequences; Techniques; Testing; Tissues; Transcript; Variant; base; cancer risk; causal variant; experience; genetic architecture; genetic variant; genome editing; genome wide association study; genome-wide; genomic locus; molecular phenotype; next generation sequencing; novel; predictive test; statistics; technology development; tool; trait; web app; Automobile Driving; Bioinformatics; Biological; Biological Assay; Bipolar Disorder; Blood; Catalogs; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Copy Number Polymorphism; DNA; Data Set; Exhibits; Failure; Gene Expression; Gene Expression Regulation; Genes; Genetic Variation; Genome; Genomics; Genotype; Genotype-Tissue Expression Project; Haplotypes; Height; Heritability; Human; Human Genetics; In Situ; Individual; Knowledge; Length; Malaria; Medical; Minisatellite Repeats; Molecular Biology; Mutation; Non-linear Models; Nucleosomes; Phenotype; Population; Positioning Attribute; Publishing; RNA; RNA Splicing; Repetitive Sequence; Reporter; Resistance; Resources; Role; SNP array; Sampling; Schizophrenia; Short Tandem Repeat; Signal Transduction; Single Nucleotide Polymorphism; Source; Structure; Tandem Repeat Sequences; Techniques; Testing; Tissues; Transcript; Variant; base; cancer risk; causal variant; experience; genetic architecture; genetic variant; genome editing; genome wide association study; genome-wide; genomic locus; molecular phenotype; next generation sequencing; novel; predictive test; statistics; technology development; tool; trait; web app

SUMMARY ABSTRACT Genome-wide association studies (GWAS) have identified thousands of genetic loci associated with complex traits, but determining the causal variants, target genes, and biological mechanisms responsible for each signal has proven challenging. Furthermore, standard GWAS based on single nucleotide polymorphisms (SNPs) have been limited by failure to explain the majority of heritability for most traits studied and an inability to capture multi-allelic variants such as copy number variants (CNVs) and repeats not tagged by SNPs. We focus on the role of genetic variation at repetitive regions of the genome. Specifically, we consider two repeat types: short tandem repeats (STRs), consisting of repeated motifs of 1-6bp; and variable number tandem repeats (VNTRs), with motifs of 7+bp. We collectively refer to STRs and VNTRs as tandem repeats (TRs). TRs encompass approximately 2 million loci comprising over 3% of the genome. They exhibit rapid mutation rates and are one of the largest sources of genetic variation. Growing evidence suggests that TRs are likely to account for part of the “missing heritability” of GWAS. However, due to bioinformatic and experimental challenges in studying repeats, the genome-wide role of TRs in human traits remains mostly unexplored. We hypothesize that TR variants are key drivers of complex traits. We recently identified thousands of STRs predicted to causally regulate gene expression (termed expression STRs, or eSTRs) and revealed that eSTRs potentially act through a variety of mechanisms including modulating nucleosome positioning and DNA or RNA secondary structure. We additionally identified specific eSTRs likely underlying published GWAS signals for height and schizophrenia. Furthermore, other groups have recently discovered TRs as causal drivers of complex traits including malaria resistance, cancer risk, and bipolar disorder. While these findings offer intriguing evidence that thousands of TRs contribute to human phenotypes, they have several limitations. These include: the range of TRs that can be accurately genotyped from next- generation sequencing (NGS); a lack of sufficiently large NGS datasets for most traits for performing association analyses; and limited understanding of the potential mechanisms by which TRs participate in gene regulation. Here, we leverage (i) our recently developed TR genotyping tools and (ii) our published haplotype panel allowing imputation of TRs into available SNP-array datasets, to systematically evaluate the contribution of TRs to gene regulation and complex traits in humans. We will first generate a comprehensive catalog of TRs associated with gene regulation (Aim 1) and establish a framework for validating TR effects using massively parallel reporter assays and genome editing (Aim 2). We will then impute more than 2 million TRs into large existing GWAS datasets and perform fine-mapping to identify TRs associated with a range of complex traits and deeply characterize several TRs predicted to be causal drivers of GWAS signals (Aim 3). This project will fill an important gap in our knowledge of the genetic architecture of complex traits.

摘要摘要 全基因组关联研究（GWAS）已经确定了数千个与 复杂的特征，但确定了负责的因果变异，靶基因和生物学机制 每个信号都有经过证明的挑战。此外，基于单个核苷酸多态性的标准GWA （SNP）受到未能解释大多数特征的遗传力的限制，并且无法解释 捕获多相关变体，例如拷贝数变体（CNV），并重复SNP标记。 我们关注遗传变异在基因组重复区域的作用。具体来说，我们考虑 两种重复类型：短串联重复序（STR），由1-6bp的重复基序组成；和变量数 串联重复（VNTR），基序为7+bp。我们共同将Strs和VNTR称为串联重复 （TR）。 TRS包括大约200万个基因座，占基因组的3％以上。他们表现出迅速的表现 突变率，是遗传变异的最大来源之一。越来越多的证据表明TR是 可能是GWAS的“缺失遗传力”的一部分。但是，由于生物信息学和实验性 在研究重复方面的挑战，TR在人类特征中的全基因组作用仍然大多是出乎意料的。 我们假设TR变体是复杂性状的关键驱动力。我们最近确定了数千个 预测的因果体调节基因表达（称为表达strs或Entrs）的StR，并揭示了这一点 ESTR可能通过多种机制作用，包括调节核小体定位和DNA 或RNA二级结构。我们还确定了可能出版的GWAS信号潜在的特定偏心 高度和精神分裂症。此外，其他团体最近发现TRS是 复杂性状，包括疟疾抗性，癌症风险和躁郁症。 尽管这些发现提供了有趣的证据，表明成千上万的TR有助于人类表型，但 他们有几个局限性。其中包括：可以从下一 生成测序（NGS）;对于大多数特征，缺乏足够大的NGS数据集用于执行关联 分析；对TRS参与基因调节的潜在机制的了解有限。 在这里，我们利用（i）我们最近开发的TR基因分型工具，以及（ii）我们已发布的单倍型面板允许 将TRS插入可用的SNP阵列数据集中，以系统地评估TRS对基因的贡献 人类的调节和复杂特征。我们将首先生成与与之相关的TRS的全面目录 基因调节（AIM 1）并建立一个框架，用于使用大量平行报告基因验证TR效应 测定和基因组编辑（AIM 2）。然后，我们将将超过200万TR算成大型现有GWAS 数据集并执行精细映射以识别与一系列复杂性状相关的TR和深层 描述几个被预测为GWAS信号的因果驱动因素（AIM 3）。这个项目将填补 我们对复杂性状遗传结构的了解的重要差距。