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

基本信息

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
项目类别：
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

项目摘要

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性状，但确定因果变异、目标基因和负责的生物机制此外，基于单核苷酸多态性的标准 GWAS 已被证明具有挑战性。（SNP）由于未能解释大多数研究性状的大部分遗传力以及无法解释而受到限制。捕获多等位基因变异，例如拷贝数变异 (CNV) 和未用 SNP 标记的重复序列。我们重点关注基因组重复区域的遗传变异的作用，具体而言，我们考虑。两种重复类型：短串联重复序列 (STR)，由 1-6bp 和可变数量的重复基序组成；串联重复序列（VNTR），具有 7+bp 的基序，我们将 STR 和 VNTR 统称为串联重复序列。 (TR) 包含约 200 万个基因座，占基因组的 3% 以上。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 是遗传变异的最大来源之一。可能是 GWAS 的“遗传性缺失”的一部分，但是，由于生物信息学和实验的原因。尽管重复研究面临着挑战，但 TR 在人类性状中的全基因组作用仍未得到探索。我们发现 TR 变异是复杂性状的关键驱动因素，我们最近发现了数千种。预测会因果调节基因表达的 STR（称为表达 STR 或 eSTR）并揭示 eSTR 可能通过多种机制发挥作用，包括调节核小体定位和 DNA 我们还鉴定了可能发布的 GWAS 信号背后的特定 eSTR。此外，其他研究小组最近发现TRs是身高和精神分裂症的因果驱动因素。复杂的特征，包括疟疾抵抗力、癌症风险和双相情感障碍。虽然这些发现提供了有趣的证据，表明数以千计的 TR 有助于人类表型，它们有一些局限性，其中包括：可以从下一步准确地进行基因分型的 TR 范围。世代测序 (NGS)；缺乏足够大的 NGS 数据集来进行关联分析；对 TR 参与基因调控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 基因分型工具和 (ii) 我们发布的单倍型面板，允许将 TR 归入可用的 SNP 阵列数据集中，以系统地评估 TR 对基因的贡献我们将首先生成与人类相关的 TR 的综合目录。基因调控（目标 1）并建立使用大规模并行报告基因验证 TR 效应的框架然后，我们将把超过 200 万个 TR 归入现有的大型 GWAS 中。数据集并进行精细映射，以识别与一系列复杂特征相关的 TR 描述了预测为 GWAS 信号因果驱动因素的几个 TR（目标 3）。我们对复杂性状遗传结构的认识存在重大差距。