Introgressed mitochondrial fragments from archaic hominins alter nuclear genome function in modern humans

TL;DR

Ancient human DNA fragments from mitochondria can influence modern human genome function, affecting gene regulation and chromatin structure.

Contribution

Identifies archaic mitochondrial DNA segments in modern humans that modulate gene expression and chromatin structure.

Findings

Introgressed NUMTs modulate gene expression, including up-regulating the immune-related gene RASGRP3.

NUMTs reshape three-dimensional chromatin structure at loci such as SCD5 and HNRNPD.

Five NUMTs were identified as introduced into modern humans via archaic hominin introgression.

Abstract

Archaic introgression introduced functionally relevant variants into modern humans, yet small-scale insertions remain understudied. Here, we leverage 2519 modern human genomes and four high-coverage archaic hominin genomes to systematically characterize nuclear mitochondrial DNA segments (NUMTs). We uncover 483 polymorphic NUMTs across globally diverse human populations and 10 in archaic genomes. By combining overlap with Neanderthal-derived and Denisovan-derived haplotypes, phylogenetic analyses, insertion time estimates, and haplotype colocalization, we identify five NUMTs introduced into modern humans via archaic hominin introgression. Functional analyses reveal that introgressed NUMTs can modulate gene expression, including allele-specific up-regulation of the immune-related gene RASGRP3, and reshape three-dimensional chromatin structure at loci such as SCD5 and HNRNPD. These findings highlight an underappreciated mechanism by which archaic mitochondrial fragments shape nuclear genome function and evolution. Our study reframes NUMTs not as passive genomic fossils but as dynamic elements influencing modern human diversity and adaptation.

Nuclear mitochondrial DNA from archaic hominins is uncovered in humans and shown to affect gene regulation and genome structure.

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