After a decade of research, the University of Toulouse and the University of Papua New Guinea started the Papuan Past project in 2015 to collect the data.

"The project now brings together researchers from France, Papua New Guinea, and Estonia, who explore the biological, cultural, and technological developments since human settlement in Papua New Guinea 50,000 years ago," explained Mathilde André, who joined the project in 2019 at the University of Tartu.

Striking differences in the populations of Papua New Guinea

The highlanders and lowlanders of Papua New Guinea are facing very different environmental stresses. While the highlanders face low oxygen availability due to altitude, the lowlanders are exposed to specific pathogens not found in the highlands, such as malaria.

The new study analyzed the specific adaptations of these populations, which have been overlooked until now. Their findings are based on new whole genome sequences from highlanders and lowlanders.

"The kind of adaptation we are talking about in this paper happens after many generations (thousands of years) of exposure to the same environmental pressures. Papua New Guinean highlanders have probably been exposed to this oxygen deficiency for at least 20,000 years, since they settled at high altitude," André, a co-author of the study, explained.

"The case of the lowlanders is a bit more complex, as we have suggested that the selective pressure to which they were exposed may have been malaria, but the temporal extent of the selective pressure imposed by malaria in Papua New Guinea is currently unknown. It may have been there for at least a few thousand years," she said.

The project examined the newly sequenced whole genomes of 54 highlanders and 74 lowlanders. The scientists suggest that the genomes of the two populations have been shaped differently to mitigate these effects of their respective environments.

The genetic variants found in the study show associations with blood-related phenotypes, André said.

"Some of the genetic variants we found under selection in highlanders and lowlanders might affect the composition of the blood of these populations," she said.

"In the case of the highlanders, they could affect the number of red blood cells, which play a role in oxygen transport, and in the case of the lowlanders, the number of white blood cells, which play a role in immunity," André went on.

"This supports the idea that hypoxia might have been the main driving force of selection that has acted on Papua New Guinean highlanders," she added.

Non-human origins detected

Denisova is one of the archaic hominin populations that lived in Asia before modern humans arrived in Papua New Guinea about 50,000 years ago.

Although the Denisova quickly became extinct at that time, they interbred with Papua New Guinean ancestors and left their legacy in the genome of modern populations.

Mayukh Mondal, a co-leader of the project at the University of Tartu, explained that one of the top candidates for selection in the lowlanders is of non-human origin, suggesting that a genetic mutation in Denisova has been passed directly to Papua New Guinean genomes.

"It looks like the altered protein is beneficial for the lowlanders to survive in their environment. Although we do not know the exact cause of this selection, this mutation might help the lowlanders overcome malaria," he said.

European biobanks and beyond

So far, such methods have been used in European populations where more samples are available thanks to biobanks, most notably the U.K. national biobank and the Estonian biobank.

"Thanks to their larger sample size, these large biobanks allow for more powerful analyses than those we performed in this project," André said.

"The [European population-scale] biobanks have data for thousands of individuals, while in our case, our sampling size was 'only' 142. However, these biobanks only include the genetic diversity present in Europeans, which is only a fraction of humans' global diversity, and there is still a need to explore other populations as well, i.e. to identify the role of genetic variants that are not present in Europeans. Both kinds of approaches are, of course, necessary," she said.

The new study is published in April 2024 in Nature Communications.

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