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

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. NUMTs record mitochondrial‑to‑nuclear DNA transfer, but their diversity is not well defined. Here, the authors create a pangenome‑based NUMT map, revealing hundreds of fixed and polymorphic events, regulatory activity, lineage‑specific dynamics and NUMT‑derived tandem repeats.