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Indigenous groups in the Amazon evolved resistance to deadly Chagas

Humans have evolved to have some remarkable superpowers. People can thrive at high altitudes, dive for long periods underwater, and even tolerate a glass of lactose-rich milk well into adulthood. Now, a new study of Indigenous peoples from the Amazon rainforest reveals one more such adaptation: a genetic resistance to the endemic parasite responsible for deadly Chagas disease. The study’s findings could help scientists develop desperately needed new therapies for the disease, which infects roughly 6 million people in Latin America and is a leading cause of death in the region.

“This paper is very important,” says Putira Sacuena, a bioanthropologist at the Federal University of Pará, Belém, who was not involved in this study. “It’s the first evidence of natural selection because of a pathogen in the Americas.”

Tábita Hünemeier, a population geneticist at the University of São Paulo’s main campus and Pompeu Fabra University, studies how certain populations’ genomes adapt to the unique challenges of their environments. Her research previously found, for instance, three genes in people living in the Andes mountains that could explain why they appear to thrive more at high altitudes than at sea level.

Inspired by the renewed attention to infectious diseases and tropical forests that the COVID-19 pandemic brought, Hünemeier wondered whether past pandemics had left a mark in the genomes of Indigenous peoples who live in the Amazon rainforest. It’s a phenomenon with historical precedent: Last year, researchers found some survivors of the bubonic plague during the Middle Ages escaped the disease because they possessed a gene variant that made them more resistant to catching the plague-causing bacterium. As a result of this natural selection, the proportion of people carrying that gene variant jumped following the Black Death.

To see whether any diseases had left a similar genetic mark in Amazonian communities, Hünemeier and colleagues turned to genomes housed within the Human Genome Diversity Project, a database of more than 1000 individuals from 52 different ethnic groups. The team compared the genomes of 118 individuals belonging to 19 different Native communities in the Amazon—including the Xikrin, Kayapo, and Parakanã peoples—with the genomes of 35 individuals from closely related Native cultures in Mexico and Central America, as well as genomes from 231 more distantly related East Asian individuals. In these genomes, they looked for patterns suggesting certain genes had been influenced by natural selection.

After statistically accounting for more recent causes of population bottlenecks—including the genocide of Indigenous people during Portuguese colonization—the scientists found that in Indigenous groups from the Amazon, natural selection was responsible for a handful of genes related to cardiovascular functions and metabolism. But three genes stood out: PPP3CA and DYNC1I1, which are associated with an immune response against Trypanosoma cruzi, the protozoan that causes Chagas disease; and NOS1AP, which is a gene that affects how the body reacts to mosquito bites.

It wasn’t until Hünemeier saw these genes that she realized that Chagas, despite being endemic in Brazil, is somehow rare among the people living in the Amazon. This is despite the fact that triatomine insects, or kissing bugs, which transmit T. cruzi, are commonly found in the communities where these people live. That suggests, the researchers report today in Science Advances, that these gene variants likely evolved to protect Amazonian populations against Chagas disease.

To bolster its case, the team overlaid a map of Latin American regions where Chagas is endemic—from Argentina to Mexico—and where the people with the PPP3CA variant live, and it turns out there’s very little geographical overlap. “It’s almost a match,” Hünemeier says of the neat divide (see map, below). “At first, I didn’t believe it because it’s so perfect.”

Distribution of Chagas disease and the parasite-resistant gene variant

(Graphic) D. An-Pham/Science; (Data) C. Couto-Silva et al., SCIENCE ADVANCES, DOI: 10.1126/sciadv.abo0234

To confirm that PPP3CA is related to susceptibility to Chagas infection, researchers infected cultured human heart cells with T. cruzi. Some of the heart cells had normal variants of PPP3CA, whereas others were engineered to reduce the gene’s expression. They found that, on average, 25% fewer parasites infected the cells with lowered expression of the gene, suggesting the gene indeed plays some role in the parasite’s ability to enter the cell. This is the first experimental evidence that this gene is involved with Chagas disease, Hünemeier says. It’s not yet clear, however, exactly how the Amazonian variant wards off the protozoan invader.

Hünemeier estimates that positive selection of the variant the team found in Amazonian tribes of PPP3CA began roughly 7500 years ago, when Chagas likely affected Indigenous groups in the Amazon. That’s consistent with archaeological findings from the region. The oldest sign of T. cruzi infection in South America was found in 9000-year-old mummies from northern Chile and southern Peru. Scientists have also found 7000-year-old human remains from Brazil that were infected with the parasite. 

“I think it’s fantastic to have studies focused on these populations and that are done with care,” says Andrés Moreno-Estrada, a population geneticist at Mexico’s National Laboratory of Genomics for Biodiversity, who was not involved in the new study. That’s especially true because genomes of Indigenous peoples in the country are still underrepresented in databases, he says.

“We realize the importance of these results because our elders always talked about the disease,” Sacuena, who is a member of the Beré people, an Indigenous group from the Amazon. At the same time, she adds, “we need genetics, epidemiology, and anthropology to reinforce all the knowledge of our ancestral sciences that exist in our territories within the Amazon.”

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