Denisovan DNA Continues to Shape Human Immunity and Skeletal Development, Yale-Led Study Reveals
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A Yale-led study sequenced genomes of 177 individuals from 12 Near Oceanic populations, filling a major gap in genomics research historically focused on European ancestry.
Researchers identified over 3,100 Denisovan (search)-inherited genetic variants that actively alter gene expression, with many affecting the interferon-gamma immune signaling pathway.
The study found that ancestors of Near Oceanic populations interbred with at least three distinct Denisovan (search)-related groups, revealing unprecedented detail about ancient human adaptation.
A comprehensive new study led by Yale University (search) has delivered one of the most detailed analyses to date of genetic variation in Oceanic populations, revealing how DNA inherited from extinct Denisovan (search) hominins continues to actively regulate human immunity and skeletal development tens of thousands of years after interbreeding occurred.
Published June 11 in the journal Science, the research sequenced the genomes of 177 individuals across 12 distinct populations in Near Oceania—the southwestern Pacific region encompassing Papua New Guinea, the Bismarck Archipelago, and the Solomon Islands—and analyzed them alongside 1,284 previously published genomes from individuals worldwide.
"The drastic underrepresentation of Oceanians limits our understanding of human evolution and could exacerbate health inequalities as genomic research is used to develop novel medical treatments," said lead author Serena Tucci, assistant professor of anthropology in Yale's Faculty of Arts and Sciences and principal investigator of the Yale Human Evolutionary Genomics Laboratory. "To fill that gap, my research team embarked on a large-scale project to expand what is known about human genetic variation, including genetic variants inherited from extinct hominins."
Multiple Denisovan (search) Groups Shaped the Pacific's Earliest Pioneers
By tracing the deep history of the Pacific's earliest migrants, who arrived in the region at least 45,000 years ago, the researchers uncovered that ancestors of Near Oceanic populations mated with at least three distinct groups related to Denisovans—the enigmatic hominin group initially discovered from fossil fragments in Siberia. This finding substantially expands the known complexity of archaic human admixture in the region.
"Previous studies showed that DNA inherited from extinct hominins, such as Neanderthals and Denisovans, survives, scattered, in the genomes of present-day human populations," Tucci said. "With this study we have moved beyond simply 'resurrecting' this DNA to showing how it actively turns genes on and off, which is game-changing. This DNA is not just a remnant of ancient liaisons; it continues to influence our biology today."
Over 3,100 Functional Variants Identified
Using an advanced functional genomic technique known as a massively parallel reporter assay, the research team physically tested the functional consequences of inherited genetic variants and identified more than 3,100 that alter gene expression. This analysis provides some of the largest-scale evidence for how specific, adaptive genetic variants inherited from Denisovans function inside humans today.
A substantial proportion of these adaptive and functional variants affected the interferon-gamma signaling pathway, a vital component of the human immune system that defends against infectious pathogens.
"DNA from extinct hominins—Denisovans and Neanderthals—helped facilitate human adaptation to diverse environments that people encountered as they migrated into this region of the world," said Patrick Reilly, first author of the study and associate research scientist in the Yale Human Evolutionary Genomics Laboratory. "Pathogens are one of the strongest selective pressures—environmental factors that affect our ability to survive—throughout human evolution. We find evidence that genes inherited from Denisovans bolstered immunity to viruses and bacteria ancient humans encountered in Near Oceania."
Skeletal Development and Convergent Evolution
The study also revealed that Denisovan (search) DNA influences skeletal development. Researchers discovered adaptive variants inherited from Denisovans in a specific gene called TRPS1 (search). Notably, this same gene has been under strong positive selection in central African rainforest hunter-gatherers and highland populations in Ecuador, illustrating how evolution can result in recurrent local adaptations in different regions of the world.
Steven Reilly, assistant professor of genetics at Yale School of Medicine and co-author of the study, emphasized the enduring biological impact of archaic DNA. "We found thousands of archaic variants that tune genes up or down, concentrated in immune and antiviral pathways," he said. "Neanderthals and Denisovans had adapted to life outside Africa over hundreds of thousands of years, and we inherited some of those genetic programs and co-opted them. Tens of thousands of years later, this DNA may still shape how these populations fight viruses—or their risk for autoimmune disease (search)."
"While Denisovans vanished from the Earth thousands of years ago, this research proves that our histories remain deeply intertwined," Tucci said.
The research was supported by the National Institute of General Medical Sciences and the National Human Genome Research Institute of the National Institutes of Health. Additional coauthors include Daniela Tejada-Martinez, Samantha L. Miller, Audrey Tjahjadi, Chang Liu, and Alysa Pomer of the Yale Human Evolutionary Genomics Laboratory; Stephen Rong, Jared Akers, and Margaret E. Prentice of Yale School of Medicine; D. Andrew Merriwether of Binghamton University; Françoise R. Friedlaender and Jonathan S. Friedlaender of Temple University; and George Koki of Papua New Guinea Institute for Medical Research.