Using paleogenomics to illustrate 10,000 years of evolution of the immune system

Scientists from the Institut Pasteur, Université Paris City, CNRS and Collège de France have used paleobiology to trace 10,000 years of the evolution of the human immune system. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past 10,000 years.

They were able to date the increase in the frequency of most mutations beneficial in defense against pathogens to post-Bronze Age, 4,500 years ago. The scientists also note that mutations that confer a higher risk of inflammatory disorders have become more frequent over the past 10,000 years. These enlightening findings about the effects of natural selection on immunity genes are published in the journal Cell genomics On January 13, 2023.

In the 1950s, geneticist JBS Haldane attributed the persistence or persistence of the mutation responsible for red blood cell anomalies commonly observed in Africa to the protection these anomalies afforded against malaria, an endemic infection that kills millions. This theory proposed that pathogens are among the strongest selective pressures that humans face. Several population genetics studies have subsequently confirmed this theory. But major questions remained, particularly regarding the specific epochs in which selective pressures exerted by pathogens on humans were strongest and their impact on the current risk of developing inflammatory or autoimmune disorders.

To answer these questions, scientists from the Pasteur Institute, Paris City University, CNRS and Collège de France, in collaboration with the Imagine Institute and Rockefeller University (USA), have adopted an approach based on paleobiology. This discipline, which studies DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as evidenced by the decision to award the 2022 Nobel Prize in Physiology or Medicine to paleontologist Svante Pääbo. The study was led by the Pasteur Institute and published Jan. 13 in the journal Journal Cell genomicsScientists analyzed the diversity of the genomes of more than 2,800 individuals who lived in Europe over the past 10,000 years—a period spanning the Neolithic Age, Bronze Age, Iron Age, Middle Ages, and the present.

By recreating evolution over time for hundreds of thousands of genetic mutations, the scientists first identified mutations that rapidly increased in frequency in Europe, suggesting they were beneficial. These mutations that have arisen under “positive” natural selection are mainly located in 89 genes rich in functions related to the innate immune response, including in particular: OAS Genes – responsible for antiviral activity – and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which show genetic adaptation to the pathogenic environment, began as recently as the beginning of the Bronze Age, about 4,500 years ago. Scientists explain this “acceleration” of adaptation by growth in population during this period and/or strong selective pressures exerted by Bronze Age pathogens, likely related to the spread of severe infectious diseases such as the plague.

At the same time, scientists also looked at the opposite situation, in other words, mutations whose frequency has decreased significantly over the past ten thousand years. These mutations are likely to be subject to “negative” selection because they increase disease risk. Note again that these selection events mainly began in the Bronze Age. Many of these unfavorable mutations are also found in genes associated with the innate immune response, such as TYK2And lpbAnd TLR3, And IL23RIt has been confirmed in empirical research that it has a detrimental effect in terms of infectious disease risk. The results underscore the value of adopting an evolutionary approach in researching genetic susceptibility to infectious diseases.

Finally, scientists explored the theory that selection exerted by pathogens in the past gave an advantage to alleles that confer resistance to infectious disease, but that in turn increased the risk of autoimmune or inflammatory disorders. They investigated a few thousand mutations known to increase susceptibility to tuberculosis, hepatitis, HIV or COVID-19, and secondarily to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they note that those associated with an increased risk of inflammatory disorders — including Crohn’s disease — have become more frequent over the past 10,000 years, while the frequency of those associated with the risk of infectious diseases has decreased. explains Lluis Quintana-Murci, study director and head of the Human Evolutionary Genetics Unit (Institut Pasteur / CNRS Evolutionary Genome, Modeling, and Health Unit / University of Paris City).

The results of the study, which harnessed the vast potential of paleobiology, show that natural selection has targeted human immunity genes over the past thousands of years in Europe, especially since the beginning of the Bronze Age, and has contributed to the current disparities in terms of the risk of infectious and inflammatory diseases.

In addition to the institutions listed above, this research was supported by the French Foundation for Medical Research (FRM), the Allianz-Institut de France, and the Fondation de France.

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