Rarely Common: Uncovering the dominant role of rare variants in the genetic architecture of complex human traits.

罕见：揭示罕见变异在复杂人类特征的遗传结构中的主导作用。

• 批准号: 10366074
• 负责人: Ryan D. Hernandez
• 金额: $ 54.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366074
• 关键词: Alleles; Bioinformatics; Biological; Biological Assay; Biology; Communities; Complex; DNA; Data; Data Analyses; Development; Disease; Enhancers; Exhibits; Feedback; Frequencies; Gene Expression; Gene Expression Profile; Gene Frequency; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Variation; Genetic study; Genome; Genome engineering; Genomics; Genotype-Tissue Expression Project; Goals; Growth; Heritability; Human; Human Genetics; Human body; Iceberg; Learning; Mendelian disorder; Methods; Minor; Minority Groups; Modeling; Mutation; Phenotype; Play; Population; Population Genetics; Population Heterogeneity; Recording of previous events; Reporter; Research; Research Personnel; Role; Sampling; Science; Statistical Models; Technology; Testing; Time; Tissues; Trans-Omics for Precision Medicine; Transcriptional Regulation; Validation; Variant; Work; bioinformatics tool; causal variant; environmental change; exome; experience; genetic architecture; genome sequencing; genome wide association study; human disease; human tissue; improved; insight; large datasets; pathogen; precision medicine; rare variant; reproductive; success; tool; trait; transcriptome sequencing; whole genome

ABSTRACT: The vast majority of human mutations have minor allele frequencies (MAF) under 1%, with the plurality observed only once (i.e., “singletons”). While Mendelian diseases are predominantly caused by rare alleles, the cumulative contribution of rare variants to complex phenotypes remains hotly debated. In our recent work, we demonstrated that ultrarare variants (MAF<0.01%) make a substantial contribution to the genetic architecture of human transcriptional regulation (an intermediate between genetic variation and complex disease)1, and low frequency variants constitute nearly half the heritability of several complex traits (on average)2. In this study, we will functionally validate the role that ultrarare variants play in human gene expression using massively parallel reporter assays (MPRAs). MPRA have revolutionized the way enhancers can be assayed for activity. We will utilize MPRAs to functionally validate our finding that ultrarare variants dominate the genetic architecture of human gene expression. We will use insights from this technology to drive statistical and bioinformatic improvements in the way genetic variation data are analyzed. We will then expand our analysis to quantify the genetic architecture of gene expression across tissues. All tissues in the human body derive from essentially the same DNA but exhibit remarkably different patterns of gene expression. We will extend our Haseman-Elston (HE) regression approach for modeling the genetic architecture of gene expression to multiple traits to uncover cross-tissue and tissue-specific genetic effects using WGS and multi-tissue RNA-sequencing data from the GTEx project5. Finally, we will improve genomic-based precision medicine efforts for all by characterizing the population-specific genetic architecture of complex traits. Every human population has experienced a different evolutionary history in the recent past (different pathogens, different limits on reproductive growth, etc). Each population therefore has a different distribution of genetic variation. As a consequence, different populations likely have different genetic architectures for complex traits. Further, many understudied populations are admixed (with ancestry deriving from multiple populations). We will extend our HE regression approach to model shared and population-specific genetic effects using >140 thousand samples from multiple populations with whole genome sequencing data and complex trait data from the TOPMed Project6.

抽象的： 绝大多数人突变的等位基因频率（MAF）低于1％，其多数 仅观察到一次（即“单例”）。虽然孟德尔疾病主要由稀有等位基因引起，但 稀有变体对复杂表型的累积贡献仍然是激烈的争论。在我们的最新消息中 工作，我们证明了Ultrarare变体（MAF <0.01％）为遗传做出了重大贡献 人类转录调控的结构（遗传变异与复杂之间的中间体 疾病）1，低频变体几乎构成了几个复杂特征的一半（on 平均）2。在这项研究中，我们将在功能上验证超大变体在人类基因中起的作用 使用大量平行的报告基因测定（MPRA）表达。 MPRA彻底改变了方式 可以分配增强剂进行活动。我们将利用MPRA来验证我们的发现 Ultrarare变体主导着人类基因表达的遗传结构。我们将使用来自 这项技术可推动统计和生物信息学改进遗传变异数据的方法 分析。然后，我们将扩展我们的分析，以量化基因表达的遗传结构 组织。人体中的所有组织均来自基本上相同的DNA，但暴露了明显不同 基因表达的模式。我们将扩展我们的Haseman-Elston（HE）回归方法 基因表达对多种特征的遗传结构，以发现跨组织和组织特异性 使用WGS和来自GTEX Project5的多组织RNA测序数据的遗传效应。最后，我们会的 通过表征特定人群的通用性来改善基于基因组的精确医学努力 复杂特征的建筑。每个人口在 最近的过去（不同的病原体，对复制生长的不同限制等）。因此，每个人口 具有不同的遗传变异分布。结果，不同的人群可能有不同 复杂性状的遗传体系结构。此外，许多理解的人群都被混合了（祖先 来自多个人群）。我们将将我们的HE回归方法扩展到模型共享和 人群特定的遗传效应使用来自多个人群的1.4万样本 来自顶级项目的基因组测序数据和复杂性状数据6。