ABOVE: The parasite Trypanosoma cruzi (green) readily infected stem cell–derived heart cells (left) but struggled when the cells were engineered to lack the PPP3CA gene (right). COUTO-SILVA ET AL., SCIENCE ADVANCES

Diseases have the potential to shape human evolution, leaving an indelible mark on the genetic code of generations to come. And that’s exactly what happened in South America, finds a study published March 8 in Science Advances. Based on genome datasets spanning two decades, researchers concluded that Chagas disease, a deadly tropical disease caused by a parasite, drove a strong pulse of natural selection in the Amazon roughly seven thousand years ago—the first documented example of pathogen-driven natural selection in the Americas. As a result, many Amazonian Indigenous people alive today carry mutations that protect them from Chagas disease.

“I think this is a fascinating paper,” John Lindo, an anthropologist at Emory College in Georgia, writes in an email to The Scientist. “The findings make tremendous sense, since there is a high mortality rate associated with the Chagas disease, thereby causing a very strong selection pressure.”

Tábita Hünemeier, a population geneticist at the University of Saõ Paulo and the Institute of Evolutionary Biology, didn’t set out to find the impact of Chagas. Rather, she says she wondered how the Amazonian environment may have shaped the evolution of the people who live there. Hot, humid, and lush, the Amazon is a hub for vector-driven diseases. “It’s an extreme environment,” she explains—and one that she has spent her career working in.

She has been working with Indigenous groups in Mesoamerica and South America ever since obtaining her PhD at the Federal University of Rio Grande do Sul in 2010. In previous work, her group found that people living in the Andes mountains have genes that help them survive at high altitudes. For the past 15 years, she’s been studying Amazonian populations in southern Brazil and Argentina specifically. “These populations are neglected in genetic studies,” she says. This is especially true in Brazil, where many groups are linguistically and geographically isolated.

To look for disease-driven natural selection, Hünemeier and colleagues analyzed genome data from 118 individuals belonging to 19 Indigenous groups throughout the Amazon stored in the Human Genome Diversity Project database. But before the team could find evidence of natural selection, they first had to rule out allele frequency shifts stemming from genetic drift: random changes in allelic frequency that are more pronounced in small populations like the groups involved in the study. Using modern East Asian and Mesoamerican populations as a starting point, the researchers created a model to predict what happened to alleles during the region’s historical population bottlenecks, like the genocide of Indigenous people during European colonization.

After accounting for genetic drift, natural selection appeared to be influencing a handful of genes related to cardiovascular function and metabolism. But three gene variants stood out as being present in higher- or lower-than-expected frequencies in all of the Indigenous populations: PPP3CA, DYNC1I1, and NOS1AP. Previous work has associated PPP3CA and DYNC1I1 with the immune response to Chagas disease and NOS1AP to the body’s reaction to a mosquito bite.

Hünemeier says she was surprised to find genes linked to Chagas disease. Initially, she says she expected to see evidence that viral or bacterial pandemics were the primary drivers of evolutionary change, as that’s what has been observed for human populations in Europe and Africa. “As a geneticist and biologist, I always think about viruses or bacteria. I never thought about [parasitic infections like] Chagas disease.”

Not that the disease isn’t noteworthy enough. Chagas disease is a leading cause of death in Latin America. It’s caused by the parasite Trypanosoma cruzi, which is transmitted to animals and people by insect vectors called triatomine bugs or kissing bugs due to their tendency to bite their unsuspecting host’s face while they sleep. The bugs carry the parasites in their feces and can infect hosts after a bite. Thirty percent of those infected develop congestive heart failure as the parasites make their way into the heart.

And archaeological finds by other groups support the new genetic data: Mummies and other human remains in the region show evidence of T. cruzi infection going back more than 7,000 years ago.

Still, before Hünemeier would be convinced the correlations weren’t spurious, she needed to see evidence that the genes function in slowing T. cruzi infection. So, she collaborated with researchers at Harvard Medical School to employ an in vitro approach to test if the selected alleles conferred protection from the parasite. The team focused on PPP3CA, as it had the strongest signal of selection. They disrupted the gene’s expression in human pluripotent stem cell–derived heart cells and found that T. cruzi had a harder time infecting the cells. Further experiments suggested that the PPP3CA variant found in Indigenous populations may lead to a reduction in the expression of PPP3CA in atrial cells of the heart, thus protecting these cells from infection.

Lindo says the combination of computationally sound genetic findings and functional relevance makes the conclusion robust. The one line of evidence missing, however, is epidemiological data showing that these genes do in fact confer resistance to parasitic infection, but he admits that “these studies would be hard to do.”

Hünemeier is confident in the findings: “We now know that there is a genetic component” to Chagas, she says. And that knowledge could prove clinically useful, as it remains a mystery why some people develop heart failure while others don’t. The genes identified in the study could help researchers predict which people will have severe reactions to T. cruzi, or maybe even hint at ways prevent severe disease from developing.

Any clues to improving treatments are desperately needed, she says, as Chagas is “a tough pathogen” with “no cure,” and it’s spreading not only in the Americas but also in Europe.

Hünemeier is also working with Brazilian Indigenous authorities and schools to create and distribute educational materials about her findings. In the future, she wants to continue studying how pandemics both pre-and post-European contact shaped the genetic evolution of Indigenous populations. “It’s also related . . . to genocidal history [of European colonization]. In fact, 98 percent of the Indigenous population died in the contact with Europeans. We have to know what [the consequences] of this were.”