Novel biological insights by utilizing mitochondrial genome information from HuBMAP resources

项目摘要 尽管典型的scRNA-seq或scATAC-seq数据包含5-25%的定位到线粒体DNA的读段， 在线粒体DNA（mtDNA）基因组中，这样的mtDNA映射读段在下游分析期间经常被过滤掉或忽略。的 线粒体产生超过90%的细胞能量，是健康和疾病的核心。mtDNA突变 直接导致线粒体疾病此外，随机的体细胞mtDNA突变随着年龄的增长而积累， 与一系列与衰老有关的疾病有关，如免疫系统紊乱、心血管疾病、 和神经退化然而，很少有人知道特定mtDNA变异的积累是否 在不同的细胞类型、器官、年龄、性别和种族中，衰老的发生率相同。这样的见解 将大大提高我们对mtDNA突变如何导致各种人类疾病的理解。 因此，单细胞生物学领域的重大知识缺口包括缺乏稳健的mtDNA 分析工具，以及如何利用丰富的mtDNA信息往往被忽视在不断增加的数据集， 获得新的生物学见解。我们建议通过以下方式来填补这些知识空白：（1）开发鲁棒的mtDNA 与HuBMAP Portal集成的分析工作流程和工具;（2）系统地分析来自单个 由HuBMAP和其他资源生成的细胞数据集;（3）确定人类是否以及如何流行 mtDNA变异影响线粒体和细胞功能。

PROJECT SUMMARY Although typical scRNA-seq or scATAC-seq data contain 5-25% of reads that map to the mitochondrial DNA (mtDNA) genome, such mtDNA mapped reads are often filtered out or ignored during downstream analysis. The mitochondria generate over 90% of the cellular energy and are central to health and disease. mtDNA mutations directly cause mitochondrial disease. In addition, random somatic mtDNA mutations accumulate with age and are associated with a broad range of aging-related diseases such as immune disorders, cardiovascular disease and neurodegeneration. However, little is understood about whether accumulation of specific mtDNA variants during aging occurs at the same rate across different cell types, organs, age, gender and race. Such insights would substantially improve our understanding of how mtDNA mutations contribute to various human diseases. Accordingly, significant gaps of knowledge in the single-cell biology field include the lack of robust mtDNA analysis tools and how to utilize the rich mtDNA information often neglected in the ever-increasing datasets to obtain new biological insights. We propose to address these knowledge gaps by: (1) develop robust mtDNA analysis workflows and tools integrated with the HuBMAP Portal; (2) systemically analyze mtDNA from single- cell datasets generated by HuBMAP and other resources; (3) determine whether and how prevalent human mtDNA variants impact mitochondrial and cellular function.