Denisovan introgression has shaped the immune system of present-day Papuans

Abstract

Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.

Long-range regulatory effects of Neandertal DNA in modern humans

“…Many of the phenotype-associated archaic variants have been associated with transcriptional regulatory effects as well, including several instances of Neandertal DNA with additional evidence for local adaptation ( Gittelman et al 2016 ). In general, it has been demonstrated that both Neandertal and Denisovan DNA have significantly shaped the transcriptomic landscape in people today ( Vespasiani et al . 2022 ; Quach et al 2016 ; Dannemann et al 2017 ; McCoy et al 2017 ; Silvert et al 2019 ; Gokhman et al 2020 ).…”

Functional archaic DNA regulates molecular variation and is associated with disease risk across global populations

“…These population-specific alleles showed a comparable pattern to those for which we did not perform this filtering (S1 Fig). It has been reported that Denisovan DNA is not present in the contemporary European population [22] which would appear to contradict these results. However, those alleles annotated here as being Denisovan in origin are segregating at a significantly reduced allele frequency in Europe (median ratio 0.6, Mann-Whitney p < 2.2x10 -16 ).…”

“…The consequences of these introgression events for the modern human genome have been the focus of much investigation. Both Neanderthal and Denisovan DNA is largely found outside protein-coding regions but enriched within transcriptional regulatory sites including enhancers [21,22]. These observations suggest that, similar to sequences that have undergone changes throughout mammalian evolution, this introgressed archaic DNA is likely to have played a prominent role in rewiring our gene regulatory architecture.…”

“…The Denisovan genome has been sequenced to a much greater coverage (31-fold vs 1.3-fold for the Neanderthal Genome [25]) and this resulted in a much greater ability to detect genuine Denisovan variants. As in a recent study [22], we further required that these variants were not observed within the African population to remove variants that had been segregating prior to the emergence of archaic species such as Neanderthals and Denisovans. This resulted in a high-quality set of 13,191 and 442,873 Neanderthal and Denisovan variants, respectively, that we considered in subsequent analyses.…”

Ancient DNA as a tool for medical research

“…There is also growing evidence to suggest that Denisovan variants introgressed into modern human genomes have affected mainly immunity-related functions 17,18 . However, unlike Neanderthal ancestry, which is homogeneously distributed between non-African populations, the Denisovan heritage is highly variable across modern human populations, being especially prevalent in populations from the Asia-Pacific region.…”