Mitochondrial Genetic Variation Across Human Tissues

项目摘要 编码氧化磷酸化(OXPHOS)复合体的线粒体基因缺陷导致 人类疾病的范围，从严重的儿科综合征到与衰老有关的疾病。这个 OXPHOS复合体I和III-IV的催化亚基由线粒体基因组(MtDNA)编码， 每个线粒体有6-10个拷贝。由于细胞中存在多个线粒体， 不同的线粒体通常共存于组织内的单个线粒体或细胞群中， 这种情况称为异质性，导致组织嵌合体。线粒体疾病出现在 成年期通常是携带致病变体的线粒体DNA在受影响的人体内积累的结果 组织。不同组织中是否存在不同的线粒体异质性遗传变异 一般人群中的身体尚不清楚。我们假设线粒体DNA的变种和水平(变种 等位基因频率、异质线粒体DNA变异体总数)在人体组织中各不相同 反映了它们的生殖层起源。我们还假设，体内异质性变异的积累 一种特定的组织与年龄有关。我们将利用之前的全基因组测序和RNAseq数据 作为基因类型-组织表达项目的一部分收集的数据集，包括跨越以下范围的测序数据 964名身体上的54个组织部位是死后收集的。我们将创建一条管道来识别 来自全基因组测序和RNAseq读取的mtDNA变体将被用于识别组织- 特定的同质和异质mtDNA变体，我们将在 出版。我们将比较来自同一组织的同质和异质变体 个体识别组织特异性变异(目标1A)，并按胚层分层(内胚层、中胚层、 外胚层)形成组织(目标1B)。我们将评估年龄(死亡时)与 每个组织的线粒体DNA异质变负荷(异质变总数，VAF)(目标2)。 我们的研究将有助于深入了解组织特异性mtDNA变异的可能来源，以及这些变异 改变线粒体功能，这可能与该组织中疾病的发展有关。如果没有一个 了解组织特异性mtDNA变异在普通人群中的存在程度，描绘 与人类疾病相关的良性和致病性mtDNA变异之间的区别将继续是一个挑战。

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.