Mapping the gene regulatory landscape of archaic hominin introgression in modern Papuans

Abstract

28 Interbreeding between anatomically modern humans and archaic hominins has 29 contributed to the genomes of present-day human populations. 30 understanding of the specific gene regulatory consequences of Neanderthal, and 31 particularly, Denisovan introgression is limited. 32 reporter assay to investigate the regulatory effects of 25,869 high-confidence introgressed 33 SNPs segregating in present-day individuals of Papuan genetic ancestry in immune cell 34 types. Overall, 8.22% of Denisovan and 8.58% of Neanderthal sequences showed active 35 regulatory activity, and 9.22% of these displayed differential activity between alleles. 36 We examined the properties of active and differentially active sequences, and found no 37 impact of introgressed allele frequency on the probability of activity, but do observe 38 an association with distance to the nearest transcription start site. Differential activity 39 was also associated with differential transcription factor binding. Genes predicted to 40 be regulated by differentially active sequences included IFIH1 and TNFAIP3, key immune 41 genes and known examples of archaic introgression. Overall, this work provides insight 42 into the regulatory activity of archaic variants in Papuan populations and, more broadly, 43 the contribution of archaic introgression in shaping modern human genetic diversity. 44 Denisovan | archaic hominin introgression | massively parallel reporter assay | TNFAIP3 | Papuan genetic ancestry Comerford et al. | Mapping gene regulation in modern Papuans However, our Here, we used a massively parallel | 2 bioRxiv preprint doi: https://doi.org/10.1101/2025.05.04.652069; this version posted May 4, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. 45