Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, United Kingdom.
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London, United Kingdom.
Elife. 2019 Feb 18;8:e41927. doi: 10.7554/eLife.41927.
Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (, and ), implicating genetic mechanisms that act in across the two genomes. We replicate ~21% of associations with independent tissue-matched datasets and find genetic variants linked to these nuclear loci that are associated with cardio-metabolic phenotypes and Vitiligo, supporting a potential role for variable mitochondrial-encoded gene expression in complex disease.
线粒体在细胞过程和疾病中发挥着重要作用，但人们对线粒体基因组的转录调控如何在个体和组织之间变化知之甚少。通过分析超过 11000 个横跨 36 种组织/细胞类型的 RNA 测序文库，我们发现线粒体编码基因在整个线粒体转录组中的表达存在相当大的变化，跨越组织和个体，突出了细胞类型特异性和转录后过程在塑造线粒体编码 RNA 水平方面的重要性。利用全基因组遗传数据，我们鉴定出 64 个与线粒体基因组中 14 个基因表达水平相关的核基因座，包括参与线粒体功能的基因（MT-ND1、MT-ND2 和 MT-TF）内的错义变异，提示存在跨两个基因组起作用的遗传机制。我们在具有独立组织匹配数据集的情况下复制了约 21%的关联，并发现与这些核基因座相关的遗传变异与心血管代谢表型和白癜风相关，支持可变线粒体编码基因表达在复杂疾病中的潜在作用。
