Every time a virus invades a person, it collides with thousands of years of human history.
A study led by researchers at the USC Dornsife College of Letters, Arts and Sciences and Howard University suggests that some of the genes involved in the body's immune response today bear the marks of ancient battles with infectious diseases.
The research also identified rare genetic variants that may help explain why some people developed more severe COVID-19 than others. The findings connect two fields that are rarely studied together: human evolution and infectious disease. By bringing them together, the scientists uncovered clues that may have been missed by studying either field alone.
The study traced the evolutionary history of four immune system genes, which were previously linked to respiratory or inflammatory diseases, across populations around the world. The research team then examined whether changes in those genes were linked to severe COVID-19 in nearly 4,000 people in Italy, using data from the Italian GEN-COVID study.
For Michael Campbell , associate professor of biological sciences at USC Dornsife and the study's senior author, understanding how evolution shaped the immune system over thousands of years offers a new way to think about why people respond differently to disease today.
"SARS-CoV-2, the coronavirus that causes COVID-19, may be new, but the immune system it encountered isn't," Campbell said. "Our immune genes have been shaped by thousands of generations of encounters with pathogens. Understanding the evolutionary history of immune genes can provide insights into why people respond differently to infectious diseases today."
How have ancient diseases shaped the human immune system?
To explore that history, the scientists at USC Dornsife and Howard collaborated with colleagues at Yale and Columbia universities to analyze four genes that help regulate the body's immune response — IL-4, TLR2, CCL2 and SLC11A1. Using genetic data from more than 2,000 people representing populations from Africa, Europe and Asia, they searched for signs that evolution had favored particular versions of these genes over time, leaving lasting marks in the human genome.
The team found evidence that all four genes had been shaped by natural selection, but not in the same way everywhere. Different versions of the genes were more common in different populations, suggesting infectious diseases and other environmental pressures may have shaped human evolution differently around the world.
Some of those gene variants were also found in the DNA of Neanderthals or Denisovans, extinct human relatives that lived tens of thousands of years ago. In some cases, the similarities likely reflect inherited DNA from a shared ancestor. In others, they point to ancient interbreeding between early modern humans and these extinct relatives.
Importantly, Campbell said, these evolutionary changes almost certainly happened long before the coronavirus emerged. "The signals we found weren't created by COVID-19," he said. "They reflect much older evolutionary pressures, probably from infectious diseases our ancestors faced over thousands of years."
Rare gene variants linked to severe COVID-19
The researchers then turned to a different question: Could some of these immune genes also help explain severe COVID-19?
Using genetic and clinical information from nearly 4,000 people in Italy who tested positive for COVID-19, the researchers identified two rare changes in the TLR2 gene. One was found more often in COVID-19 patients who had previously received an organ transplant than in other COVID-19 patients. The second was associated with more severe forms of COVID-19, suggesting it may contribute to differences in how seriously ill some people become.
Unlike the common gene variants shaped by evolution over thousands of years, these TLR2 variants were rare and appear to be much more recent genetic mutations.
Because organ transplant recipients are already known to face a higher risk of severe COVID-19, the finding suggests a TLR2 variant could be one factor influencing that increased risk. The researchers say, however, that more research is needed to determine if that's the case.
The researchers also caution that the COVID-19 findings overall should be interpreted carefully. The genetic associations will need to be confirmed in larger, independent populations and validated through laboratory studies. They also note the need to include more genetically diverse populations in future studies to better understand disease risk worldwide.
Why evolution still matters today
By identifying immune genes shaped by ancient infectious diseases, such as TLR2, scientists may gain new clues about the biological basis of infectious disease susceptibility.
"The pathogens our ancestors encountered thousands of years ago helped shape the immune system we carry today," Campbell said. "By tracing that evolutionary history, we can better understand why people respond differently to infectious diseases today and identify biological pathways that may inform new strategies for disease prevention and treatment."
About the study
In addition to Campbell, study authors include Alessandro Lisi and Marisol Fermin Flores of USC Dornsife; Thomas Heinbockel and Kareem Washington of Howard University; Christopher N. Cross of Howard University and Yale University; and Faith C. Simmonds of Columbia University.
The study was supported by the National Institutes of Health (P30AI117970), the National Science Foundation (IOS-1355034, BCS-2221924, and BCS-2221920), and the National Geographic Society (HJ-116ER-17), as well as fellowships from the Gordon and Betty Moore Foundation and the Chancellor's Doctoral Incentive Program.
