A new Yale-led study provides one of the most detailed and comprehensive analyses to date of genetic variation in human populations in Oceania, filling a major gap in representation in genomics research.

Despite harboring remarkable diversity, populations in this vast region in the South Pacific historically have been overlooked in global human genetic studies, which have often focused largely on peoples of European descent, researchers say.

“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 the lead author Serena Tucci, assistant professor of anthropology in Yale’s Faculty of Arts and Sciences and the 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.”

The study, published on June 11 in the journal Science, shows how the genes that ancient humans acquired after mating with extinct hominins continue to shape the biology, health, and survival of our species today.

For the study, the research team sequenced the genomes of 177 individuals across 12 distinct populations in different parts of Near Oceania — the southwestern portion of the Pacific region that includes Papua New Guinea, the Bismarck Archipelago, and the Solomon Islands — and analyzed them alongside a massive dataset of 1,284 previously published genomes from individuals worldwide.

By tracing the deep history of the Pacific’s earliest pioneers, who migrated to the region by at least 45,000 years ago, the researchers uncovered unprecedented insights into human evolutionary history and adaptation. For example, they discovered that ancestors of Near Oceanic populations mated with at least three distinct groups related to Denisovans — an enigmatic hominin group initially discovered from fossil fragments in Siberia.

“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.”

Mating between ancient humans and Denisovans left a legacy of many genetic variants, including some that contribute to functions in present-day humans, the researcher said.

For the new study, the researchers used an advanced functional genomic technique known as a “massively parallel reporter assay” to physically test the functional consequences of these genetic variants and identified over 3,100 that alter gene expression. This analysis provided some of the largest-scale evidence for how specific, adaptive genetic variants inherited from Denisovans function inside humans today, the researchers say.

They found that 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 in the Department of Anthropology. “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.”

The study also revealed that Denisovan DNA influences skeletal development. The researchers discovered adaptive variants inherited from Denisovans in a specific gene called TRPS1. This same gene has been under strong positive selection in central African rainforest hunter-gatherers and highland populations in Ecuador, showing how evolution can result in recurrent local adaptations in different regions of the world.

“While Denisovans vanished from the Earth thousands of years ago, this research proves that our histories remain deeply intertwined,” Tucci said.

Coauthors of the study 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, Margaret E. Prentice, and Steven K. Reilly 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.

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.