Luo Lintao, Wang Mengge, Liu Yunhui, Li Jianbo, Bu Fengxiao, Yuan Huijun, Tang Renkuan, Liu Chao, He Guanglin
Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China.
Sci China Life Sci. 2025 Jan 21. doi: 10.1007/s11427-024-2736-7.
Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging, neurodegenerative diseases, and complex muscle disorders. Due to its uniparental and haploid inheritance, mtDNA captures matrilineal evolutionary trajectories, playing a crucial role in population and medical genetics. However, critical questions about the genomic diversity patterns, inheritance models, and evolutionary and medical functions of mtDNA remain unresolved or underexplored, particularly in the transition from traditional genotyping to large-scale genomic analyses. This review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health, disease, and evolution. We propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational technologies. Haplotype-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs, reduce diagnostic inaccuracies, and provide clearer insights into heteroplasmy patterns and the authenticity of paternal inheritance. This review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms, the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility, and the detailed functions of NUMTs.
人类线粒体DNA（mtDNA）携带与衰老、神经退行性疾病和复杂肌肉疾病相关的重要突变。由于其单亲本和单倍体遗传方式，mtDNA记录了母系进化轨迹，在群体遗传学和医学遗传学中发挥着关键作用。然而，关于mtDNA的基因组多样性模式、遗传模型以及进化和医学功能等关键问题仍未得到解决或未被充分探索，尤其是在从传统基因分型向大规模基因组分析的转变过程中。本综述总结了数据驱动的基因组研究和技术创新方面的最新进展，这些进展解决了上述问题，并阐明了核线粒体片段（NUMTs）和mtDNA变异对人类健康、疾病和进化的生物学影响。我们提出了一个简化流程，利用先进的测序和计算技术全面鉴定mtDNA和NUMT的基因组多样性。单倍型解析的mtDNA测序和组装能够区分真实的mtDNA变异与NUMTs，减少诊断误差，并更清晰地洞察异质性模式和父系遗传的真实性。本综述强调需要整合多组学方法和新兴的长读长测序技术，以深入了解突变机制、异质性和父系遗传对mtDNA多样性和疾病易感性的影响，以及NUMTs的详细功能。
