Modern humans have inherited as much as 8% of their genome from extinct hominins, with the highest frequencies of Neanderthal and Denisovan DNA today found in the Pacific region1,2. This ‘archaic’ DNA is enriched within immune pathway regulatory elements3, and clusters non-randomly across the genome4 in a pattern characteristic of the co-associating domains that form during 3D folding of DNA in the nucleus. Yet how archaic DNA interacts in 3D space and thus influences gene expression remains poorly understood.
To address this knowledge gap, we employ a multi-faceted approach: (i) we identify archaic DNA regions in the genomes of 12 individuals from Papuan New Guinea; (ii) subsequently, we empirically determine how archaic DNA aligns in the three-dimensional space of living immune cells from these individuals through Hi-C experiments; (iii) we then explore how this 3D structure influences DNA accessibility and gene expression by integrating ATAC-seq and RNAseq data from the same cells. Finally, (iv) we compare the results to data from 6 African samples, which have no archaic introgression, and 6 European samples, which carry only Neanderthal introgression. This study contributes to a deeper understanding of our genetic inheritance from archaic hominins by shedding light on the complex interplay between archaic DNA, three-dimensional genomic organization, and gene regulation in immune cells.