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Denisovan DNA Detected in Papuan Immune Gene Regulatory Regions

NEW YORK – Remnants of archaic DNA stemming from ancient dalliances with Denisovans appear to be overrepresented in regulatory regions with roles in immune cells in contemporary Papuan populations, according to new research by a University of Melbourne-led research team.

"Some of the Denisovan DNA that has persisted in Papuan individuals until today plays a role in regulating genes involved in the immune system," senior and corresponding author Irene Gallego Romero, an integrative genomics researcher at the University of Melbourne and the University of Tartu, said in a statement.

As they reported in PLOS Genetics on Thursday, she and her colleagues scrutinized whole-genome sequences for 56 present-day Papuan participants from New Guinea, using genotype, introgression inference, allele frequency, recombination clues, and other data to assess nearly 7.8 million SNPs across the genome in the context of non-archaic, Denisovan, or Neanderthal haplotypes.

"Our study is the first to comprehensively shed light on the functional legacy of Denisovan DNA in the genomes of present-day humans," Gallego Romero noted.

In the process, she and her colleagues narrowed in on more than 1.1 million informative SNPs originating from non-archaic ancestry, along with 140,916 Denisovan variants and 88,625 Neanderthal variants.

Consistent with past findings in populations descended from Neanderthal admixture, the researchers found that common and high-frequency archaic variants tended to turn up at transcribed sequences and enhancer element sequences described in the Roadmap Epigenomics Project, which represents 15 chromatin states in more than 100 cell types. Conversely, the archaic variants were found at lower-than-usual levels across other sequences, including transcription start site and promoter sequences.

More than 16,000 Denisovan high-confidence variants and 10,032 Neanderthal variants were found at cis-regulatory elements expected to alter binding by one or more transcription factors. A similar pattern of cis-regulatory element overrepresentation turned up when the team analyzed more than 11.4 million Neanderthal variants in 75 Simons Genome Diversity Project participants of western Eurasian ancestry.

Even so, the distribution of the archaic variants differed depending on their source: The Denisovan archaic variants appeared to be enriched in regulatory elements with known activity in blood and immune cells, while the Neanderthal variants seemed to influence a range of biological processes.

"In Papuans, Denisovan DNA, but not Neanderthal, strongly and consistently affects immune cells and immune-related processes of potential evolutionary relevance," the authors wrote, noting that "[v]ariation in gene expression might be key to understanding the consequences of admixture between modern humans and archaic hominins, as has been observed with Neanderthal DNA in other human populations."

The researchers found further evidence for archaic Denisovan variants influencing immune gene expression in their follow-up plasmid reporter assay and quantitative PCR experiments. Their results flagged at least two variants passed down from Denisovans that corresponded to lower-than-usual expression of certain innate immune response genes in lymphoblastoid cell lines generated from Papuan donors.

"Denisovan cis-regulatory variants were predicted to regulate genes such as TNFAIP3, OAS2, and OAS3, all of which have been repeatedly identified as harboring archaic hominin contribution that impact immune responses to pathogens," the authors explained.

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