Brown University researchers find genetic marker that helped the first Americans survive

Extinct human relatives left a genetic gift that helped people thrive in the Americas

By Kevin Stacey, Senior Writer for the Physical Sciences, Brown University

A new study provides fresh evidence that ancient interbreeding with archaic human species may have provided modern humans with a genetic variant that helped them adapt to new environments as they dispersed across the globe.

The study, published in Science, focused on a gene known as MUC19, which is involved in the production of proteins that form saliva and mucosal barriers in the respiratory and digestive tracts. 

The researchers show that a variant of that gene derived from Denisovans, an enigmatic species of archaic humans, is present in modern Latin Americans with Indigenous American ancestry, as well as in DNA collected from individuals excavated at archeological sites across North and South America. 

The frequency at which the gene appears in modern human populations suggests the gene was under significant natural selection, meaning it provided a survival or reproductive advantage to those who carried it. It’s not clear exactly what that advantage might have been — but given the gene’s involvement in immune processes, it may have helped populations fight off pathogens encountered as they migrated into the Americas thousands of years ago.

“From an evolutionary standpoint, this finding shows how ancient interbreeding can have effects that we still see today,” said study author Emilia Huerta-Sánchez, a professor of ecology, evolution and organismal biology at Brown University. “From a biological standpoint, we identify a gene that appears to be adaptive, but whose function hasn’t yet been characterized. We hope that leads to additional study of what this gene is actually doing.”

Not much is known about the Denisovans, who lived in Asia between 300,000 and 30,000 years ago, aside from a few small fossils from Denisova cave in Siberia, two jaw bones found in Tibet and Taiwan, and a nearly complete skull from China found this year. A finger fossil from Siberia contained ancient DNA, which has enabled scientists to look for common genes between Denisovans and modern humans. Prior research led by Huerta-Sánchez found that a version of a gene called EPAS1 acquired from Denisovans may have helped Sherpas and other Tibetans to adapt to high altitudes. 

For this study, the researchers compared Denisovan DNA with modern genomes collected through the 1,000 Genomes Project, a survey of worldwide genetic variation. The researchers found that the Denisovan-derived MUC19 gene is present in high frequencies in Latino populations who harbor Indigenous American genetic ancestry. The researchers also looked for the gene in the DNA of 23 individuals collected from archeological sites in Alaska, California, Mexico and elsewhere in the Americas. The Denisovan-derived variant was present at high frequency in these ancient individuals as well. 

The team used several independent statistical tests to show that the Denisovan MUC19 gene variant rose to unusually high frequencies in ancient Indigenous American populations and present-day people of Indigenous descent, and that the gene sits on an unusually long stretch of archaic DNA — both signs that natural selection had boosted its prevalence. The research also revealed that the gene was likely passed through interbreeding from Denisovans to another archaic population, the Neanderthals, who then interbred with modern humans. 

Huerta-Sánchez said the findings demonstrate the importance that interbreeding had in introducing new and potentially useful genetic variation in the human lineage. 

“Typically, genetic novelty is generated through a very slow process,” Huerta-Sánchez said. “But these interbreeding events were a sudden way to introduce a lot of new variation.”

In this case, she said, that “new reservoir of genetic variation” appears to have helped modern humans as they migrated into the Americas, perhaps providing a boost to the immune system.

“Something about this gene was clearly useful for these populations — and maybe still is or will be in the future,” Huerta-Sánchez said. 

She’s hopeful that the recognition of the gene’s importance will spur new research into its function to reveal novel biological mechanisms, especially since it involves coding genetic variants that alter the protein sequence.

Huerta-Sánchez co-authored the study with Fernando Villanea, a former postdoctoral researcher at Brown who is now at University of Colorado, Boulder; David Peede, a graduate student at Brown; and an international team of collaborators. The research was supported by the Leakey Foundation; the National Institutes of Health (1R35GM128946- 01, T32 GM128596, R35GM142978, R01NS122766); the Alfred P. Sloan Foundation; the Blavatnik Family Graduate Fellowship in Biology and Medicine; the Brown University Predoctoral Training Program in Biological Data Science (NIH T32 GM128596); the Burroughs Wellcome Fund; and the Human Frontier Science Program.