The evolution of the immune system over 10,000 years

Scientists at the Institut Pasteur, Université Paris Cité, the CNRS and Collège de France used paleogenomics to trace the evolution
of the human immune system over 10,000 years.
They analyzed the genomes
of more than 2,800 people who have lived in Europe over the past 10,000 years.
They were able to determine that most of the increased frequency of mutations that favored warding off pathogens occurred after
the Bronze Age, 4500 years ago.
The scientists also observed that mutations with a higher risk of inflammatory diseases have become more frequent
over the past 10,000 years.
These illuminating results on the effects of natural selection on immune genes were published in the January 13, 2023 issue of Cell Genomics
.

In the 50s of the 20th century, geneticist J.
B.
S.
Haldane will cause the maintenance or persistence of mutations common in red blood cells in Africa to attribute these abnormalities to providing protection
against malaria.
Malaria is an endemic infection that kills millions
.
This theory suggests that pathogens are one of
the strongest selection pressures humans face.
Several subsequent population genetics studies confirmed this theory
.
But major questions remain, particularly regarding the specific periods when pathogens exert the strongest selective pressure on human populations and their impact
on the current risk of developing inflammatory or autoimmune diseases.

To address these issues, scientists from the Institut Pasteur, Université Paris Cité, the French National Centre for Scientific Research and the Collège de France, in collaboration with the Institut Imagine and the Rockefeller University (USA), adopted an approach
based on paleogenomics.
The discipline, which studies DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as demonstrated
by the decision to award the 2022 Nobel Prize in Physiology or Medicine to paleogeneticist Svante Pääbo.
The study, led by the Institut Pasteur, analyzed genomic variation in more than 2,800 people living in Europe over the past 10,000 years, covering the Neolithic, Bronze, Iron Age, Middle Ages and the present
.

By reconstructing the evolution of hundreds of thousands of genetic mutations over time, the scientists initially identified mutations that increased rapidly in frequency in Europe, suggesting that they were favorable
.
These mutations, which evolved under "aggressive" natural selection, were mainly located in 89 functionally rich genes involved in innate immune responses, specifically immune response genes, OAS genes responsible for antiviral activity, and genes
responsible for the ABO blood group system.
Surprisingly, these positive selection events, as evidenced by genetic adaptations to pathogenic environments, most began recently, beginning in the Bronze Age, some 4500 years ago
.
Scientists explain this "acceleration" of adaptation as the growth of human populations during this period and/or the strong selective pressure exerted by Bronze Age pathogens, which may be linked to
the spread of serious infectious diseases such as plague.

At the same time, scientists also observed the opposite, in other words, the frequency of mutations has decreased
significantly over the past 10,000 years.
These mutations can be influenced by "negative" choices because they increase the risk of
disease.
Again, they point out that these selection events mainly began in the Bronze Age
.
Many of these adverse mutations are also located in genes associated with innate immune responses, such as TYK2, LPB, TLR3, and IL23R, and have been demonstrated in experimental studies to have harmful effects
in terms of infectious disease risk.
The findings highlight the value of
an evolutionary approach in the study of genetic susceptibility to infectious diseases.

Finally, the scientists explored the theory that the selection of past pathogens gave an advantage to alleles with the ability to resist infectious diseases, but in turn, these alleles increased the risk of
current autoimmune or inflammatory diseases.
They looked at thousands of known mutations, first increasing susceptibility to tuberculosis, hepatitis, HIV or COVID-19, followed by susceptibility to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease
.
By watching these mutations evolve over time, they observed that those associated with an increased risk of inflammatory diseases, including Crohn's disease, had become more frequent over the past 10,000 years, while the frequency of mutations associated with the risk of contracting the disease had decreased
。 "These results show that the risk of inflammatory diseases has increased in Europeans since the Neolithic period, due to the increased resistance to infectious diseases by the active selection of mutations," explains
Lluis Quintana-Murci, director of the study and head of the Human Evolutionary Genetics Unit (Institut Pasteur/French Centre for Scientific Research Evolutionary Genomics Modeling and Health/Université Paris Cité).

The study, which harnessed the enormous potential of paleogenomics, showed that over the past 10,000 years, natural selection has targeted human immune genes in Europe, particularly since the beginning of the Bronze Age, and has led to differences
in the risk of infectious and inflammatory diseases today.

Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe