Regulatory modifiers of coding variant penetrance via haplotype epistasis in human populations and diseases

通过人类群体和疾病中的单倍型上位性对编码变异外显率的调节调节

• 批准号: 9926898
• 负责人: Tuuli Lappalainen
• 金额: $ 37.36万
• 依托单位: NEW YORK GENOME CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926898
• 关键词: Affect; Alleles; Clinical; Code; Collection; Data; Data Set; Disease; Evolution; Exons; Family; Future; Gene Expression; Gene Expression Regulation; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Epistasis; Genetic Models; Genetic Risk; Genetic Variation; Genetic study; Genome; Genotype-Tissue Expression Project; Haplotypes; Heritability; Human; Human Cell Line; Human Genetics; Individual; Light; Linkage Disequilibrium; Malignant Neoplasms; Maps; Mendelian disorder; Methods; Modeling; Mutation; Natural Selections; Outcome; Pattern; Penetrance; Phase; Phenotype; Population; Population Genetics; Prevalence; Proxy; RET gene; RNA Splicing; Risk; Role; Severities; Shapes; Signal Transduction; Tissues; Tumor Suppressor Genes; Variant; Work; autism spectrum disorder; base; biobank; disorder risk; driver mutation; exome; exome sequencing; functional genomics; gene function; genetic analysis; genetic architecture; genetic variant; genome editing; genome sequencing; genome wide association study; human disease; improved; insight; novel; rare variant; trait; transcriptome sequencing; whole genome

PROJECT ABSTRACT Variable penetrance is a phenomenon where the severity of the effect of a genetic variant differs among individuals who carry it. We propose to study a specific type of modified penetrance caused by genetic interaction or epistasis in humans, where a regulatory variant in cis modifies the penetrance of coding variants of the target gene. We call this phenomenon haplotype epistasis. We will study this phenomenon using genetic data of the general human population and of diseases with different genetic architectures. First, we will study signals of purifying selection against specific haplotype combinations as a proxy of phenotypically relevant epistatic effects. This will shed light on the modes and prevalence of haplotype epistasis, and the role of epistatic selection in shaping the spectrum of genetic variation in humans. Second, haplotype epistasis has been shown to affect genetic disease risk in some specific examples, but this mechanism is rarely considered in genetic studies that typically analyze genetic variants one-by-one. We aim to characterize haplotype epistasis as a potentially important phenomenon in rare variants contributing to autism risk, common variants predisposing to diverse traits mapped by genome-wide association studies, and germline modifiers of somatic cancer driver mutations. Furthermore, we will validate 5-10 examples of epistasis by genome editing of human cell lines, followed by cellular phenotyping. In summary, our study integrates many domains in human genetics that are usually studied in isolation. It is the first systematic characterization of haplotype epistasis and has potential to bring forward an important paradigm of epistatic functional effects of genetic variants.

项目摘要 变异遗传是一种现象，其中遗传变异的影响的严重性在不同的人之间不同。 我们建议研究一种由遗传引起的特定类型的修饰性染色体畸变， 相互作用或上位性，其中顺式中的调节变体修改编码变体的顺式 的靶基因。我们称这种现象为单倍型上位性。我们将使用遗传学方法来研究这种现象。 一般人群和不同遗传结构疾病的数据。首先，我们将研究 针对特定单倍型组合的纯化选择信号作为表型相关性的代理 上位效应这将揭示单倍型上位性的模式和流行，以及 上位选择在人类遗传变异谱形成中的作用。第二，单倍型上位性 在一些具体的例子中，已经显示出影响遗传疾病的风险，但这种机制很少被考虑 在遗传学研究中，通常一个接一个地分析遗传变异。我们的目标是描述单倍型 上位性作为一个潜在的重要现象，在罕见的变异有助于自闭症的风险，常见的变异 易受全基因组关联研究绘制的不同性状的影响，以及体细胞遗传学的种系修饰因子。 癌症驱动突变。此外，我们将通过人类基因组编辑验证5 - 10个上位性的例子。 细胞系，然后进行细胞表型分析。总之，我们的研究整合了人类遗传学的许多领域 通常被孤立地研究。这是单倍型上位性的首次系统表征， 潜在的提出一个重要的范例上位功能效应的遗传变异。