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<p>Nuclear-embedded mitochondrial DNA segments (NUMT) preserve a record of ongoing mitochondrial-to-nuclear DNA transfer during evolution, with important implications for disease mechanisms and genome organization. Here, we develop a pangenome graph-based NUMT detection approach, achieving a 2.52-fold improvement in sensitivity and generating a high-resolution human NUMT map comprising 774 fixed and 280 polymorphic events, alongside 74 superpopulation-stratified loci. Notably, NUMTs derived from the 3’-end of mtDNA D-loop are less frequently fixed and exhibit <i>cis</i>-regulatory activity, revealing selective pressures shaping their genomic landscape. We also identify seven NUMTs associated with gene expression or splicing, suggesting their potential modulatory functions. Comparative analysis of complete primate genomes reveals lineage-specific NUMT dynamics, with particularly high rates in the <i>Pan</i> lineage. Furthermore, we uncover two NUMT-derived tandem repeats, establishing them as a novel source of complex variants. In summary, the integrated analysis enhances understanding of NUMT genomic architecture, population dynamics, and evolutionary implications, establishing them as dynamic genomic components of biomedical relevance.</p>

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A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月15日

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  • Lianting Fu,
  • Jieyi Chen,
  • Da Lian,
  • Siyuan Du,
  • Dongya Wu,
  • Chentao Yang,
  • Ziyi Wang,
  • Hongyi Ma,
  • Zhengtong Li,
  • Nicole J. Lake,
  • Xiangyu Yang,
  • Yongyong Shi,
  • Guojie Zhang,
  • Kaiyue Ma,
  • Yafei Mao

摘要

Nuclear-embedded mitochondrial DNA segments (NUMT) preserve a record of ongoing mitochondrial-to-nuclear DNA transfer during evolution, with important implications for disease mechanisms and genome organization. Here, we develop a pangenome graph-based NUMT detection approach, achieving a 2.52-fold improvement in sensitivity and generating a high-resolution human NUMT map comprising 774 fixed and 280 polymorphic events, alongside 74 superpopulation-stratified loci. Notably, NUMTs derived from the 3’-end of mtDNA D-loop are less frequently fixed and exhibit cis-regulatory activity, revealing selective pressures shaping their genomic landscape. We also identify seven NUMTs associated with gene expression or splicing, suggesting their potential modulatory functions. Comparative analysis of complete primate genomes reveals lineage-specific NUMT dynamics, with particularly high rates in the Pan lineage. Furthermore, we uncover two NUMT-derived tandem repeats, establishing them as a novel source of complex variants. In summary, the integrated analysis enhances understanding of NUMT genomic architecture, population dynamics, and evolutionary implications, establishing them as dynamic genomic components of biomedical relevance.