Mitochondrial Genetic Variation Across Human Tissues

人体组织的线粒体遗传变异

• 批准号: 10741135
• 负责人: Jessica L Fetterman
• 金额: $ 8.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741135
• 关键词: Adult; Affect; Age; Aging; Autopsy; Benign; Biogenesis; Biology; Biopsy; Blood specimen; Brain; Cardiovascular Diseases; Catalytic Domain; Cell Cycle; Cell Differentiation process; Cells; Cessation of life; Childhood; Complex; Data; Data Set; Defect; Development; Diagnosis; Diagnostic; Disease; Ectoderm; Endoderm; Enzymes; Exclusion; Future; Gene Frequency; General Population; Genes; Genetic; Genetic Variation; Genome; Genotype-Tissue Expression Project; Germ Layers; Heart; Hematopoietic; Human; Human Genome; Individual; Inherited; Life; Mesoderm; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mutation; Neurodegenerative Disorders; Nuclear; Oxidative Phosphorylation; Pathogenicity; Patients; Phase; Phenotype; Population; Publications; RNA Folding; Site; Skeletal Muscle; Syndrome; Time; Tissues; Variant; cell type; genetic epidemiology; genetic variant; genome sequencing; heteroplasmy; human disease; human tissue; induced pluripotent stem cell; insight; mitochondrial DNA mutation; mitochondrial genome; precursor cell; tissue mosaicism; transcriptome sequencing; transmission process; whole genome

Project Summary Defects in mitochondrial genes encoding the oxidative phosphorylation (OXPHOS) complexes result in a spectrum of disease in humans, ranging from severe pediatric syndromes to aging-related diseases. The catalytic subunits of OXPHOS complexes I and III-IV are encoded by the mitochondrial genome (mtDNA), which is present in 6-10 copies per mitochondrion. Due to the presence of multiple mitochondria in a cell, different mtDNAs often co-exist within an individual mitochondrion or population of cells within a tissue, a condition termed heteroplasmy, resulting in tissue mosaicism. Mitochondrial diseases that present in adulthood are often the result of the accumulation of mtDNAs carrying a pathogenic variant in the affected tissue. Whether different heteroplasmic mitochondrial genetic variants exist in different tissues of the body within the general population is not known. We hypothesize that mtDNA variants and levels (variant allele frequency, total number of heteroplasmic mtDNA variants) differ across the tissues of the human body reflective of their germ layer origin. We also hypothesize that the accumulation of heteroplasmic variants within a given tissue is associated with age. We will utilize whole genome sequencing and RNAseq data previously collected as part of the Genotype-Tissue Expression project, a dataset consisting of sequencing data spanning 54 tissue sites across the body of 964 individuals collected postmortem. We will create a pipeline to identify mtDNA variants from both whole genome sequencing and RNAseq reads that will be used to identify tissue- specific homoplasmic and heteroplasmic mtDNA variants, which we will make publicly available upon publication. We will compare homoplasmic and heteroplasmic variants across the tissues from the same individual to identify tissue-specific variants (Aim 1A), and stratify by the germ layer (endoderm, mesoderm, ectoderm) that gave rise to the tissues (Aim 1B). We will evaluate the association of age (at time of death) with mtDNA heteroplasmic variant burden (total number of heteroplasmic variants, VAF) for each tissue (Aim 2). Our study will lend insight into the possible origins of tissue-specific mtDNA variants and whether such variants alter mitochondrial function, which may be relevant to the development of disease in that tissue. Without an understanding of the extent to which tissue-specific mtDNA variants exist in the general population, delineating between benign and pathogenic mtDNA variants in relation to human disease will continue to be a challenge.

项目摘要 编码氧化磷酸化（OXPHOS）复合物的线粒体基因的缺陷导致线粒体内的蛋白质合成。 人类疾病谱，从严重的儿科综合征到与衰老相关的疾病。的 OXPHOS复合物I和III-IV的催化亚基由线粒体基因组（mtDNA）编码， 其以每个拷贝6-10份存在。由于细胞中存在多个线粒体， 不同的mtDNA通常共存于组织内的单个细胞或细胞群中， 这种情况称为异质性，导致组织镶嵌。线粒体疾病存在于 成年期的疾病通常是携带致病变异的mtDNA在受影响的人中积累的结果。 组织.不同的异质性线粒体遗传变异是否存在于不同的组织中， 一般人群中的身体是未知的。我们假设mtDNA变异和水平（变异 等位基因频率，异质性mtDNA变体的总数）在人体的组织中不同 反映了它们的胚层起源。我们还假设，异质性变异的积累， 给定的组织与年龄相关。我们将利用全基因组测序和RNAseq数据， 作为基因型-组织表达项目的一部分收集，该数据集由测序数据组成， 在964个个体的尸体上收集了54个组织部位。我们将建立一个管道， 来自全基因组测序和RNAseq读数的mtDNA变体将用于识别组织- 特定的同质和异质线粒体DNA变体，我们将公开这些变体 出版物我们将比较来自相同组织的同质和异质变体， 个体以鉴定组织特异性变体（Aim 1A），并通过胚层（内胚层，中胚层， 外胚层），产生组织（目的1B）。我们将评估年龄（死亡时）与 每个组织的mtDNA异质变体负荷（异质变体总数，VAF）（目标2）。 我们的研究将有助于深入了解组织特异性mtDNA变异的可能起源，以及这些变异是否 改变线粒体功能，这可能与该组织中疾病的发展有关。没有 了解组织特异性mtDNA变异在一般人群中存在的程度， 良性和致病性mtDNA变异与人类疾病之间的关系将继续是一个挑战。