Thus natural selection operated on our immune system

Ever since Haldane linked the spread of mutations responsible for sickle cell anemia in Africa to the protection provided by these anomalies against malaria, an endemic infection that kills millions of people, in the 1950s, it has been suggested that the selection pressure exerted by pathogens is among the most important evolutionary forces still active on humans.

Since then, a host of studies have confirmed the predictions of this theory, but it is these days a global study that, in a very elegant way, has managed to give an overview of how and when selection has operated on our immune system.

The experimental approach used by an international group of researchers, based on paleogenomics, has in fact made it possible to demonstrate that the events of strong selection all occurred simultaneously and in limited periods of time, in parallel with important moments in our social evolution. Paleogenomics is the discipline that studies the DNA of ancient living beings; for the contributions made to the study of fossil and ancient DNA, Svante Pääbo received the Nobel Prize for Medicine in 2022.

In the study just published in the journal Cell Genomics, the scientists analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia, a period that spans the Neolithic, the Bronze Age, the Iron Age, the Classical Age, the Middle Ages and then comes down to us.

By reconstructing the evolution of hundreds of thousands of genetic mutations over time, the researchers identified mutations that rapidly increased in frequency in Europe, indicating that they were beneficial. These mutations that have evolved under natural selection called “positive” are found mainly in 89 genes, in which functions related to the innate immune response are particularly represented. In other words, when important and rapid selection effects occurred on the genetic heritage of European populations, the bulk of the affected genes turned out to be genes linked to that part of the immune response which defends us on a broad spectrum and not specifically against a large variety of pathogens.

Among these above all, selected genes of a group called Oas are results which, in the presence of a viral infection with an RNA virus, is activated to produce molecules capable of selectively inducing the degradation of the viral genome, and the gene that determines the ABO blood group, linked for some time to susceptibility to certain types of infection . Surprisingly, most of these positive selection events, demonstrating genetic adaptation to environmental pathogens, started very recently, at the beginning of the Bronze Age, about 4,500 years ago. In the same period the human population began a strong growth, and pathogens such as the plague began to give rise to widespread epidemics, exerting a selective pressure that was hardly possible in the previous human populations, more dispersed and smaller in size.

There have also been other gene variants whose frequency has decreased significantly over the past ten millennia. Again, these selection events started in the Bronze Age. Many of these detrimental variants eliminated or declining in population after the Bronze Age are also found in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and previous experimental research had already shown that they have a deleterious effect in terms of the risk of infectious diseases.

Finally, the researchers went in search of effects similar to those originally described by Haldane, i.e. effects of selection of gene variants that have been selected because, although they may predispose to other pathologies, they are still protective against infectious agents and parasites.

By studying the few thousand mutations known to increase susceptibility to firstly tuberculosis, hepatitis, HIV or Covid-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease, they observed 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 a risk of developing infectious diseases has decreased. These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period due to positive selection for mutations that enhance resistance to infectious diseases.

The results obtained therefore demonstrate that our propensity for pathological inflammatory conditions has increased over the last 10,000 years, in a substantial part as a price to pay to obtain better protection from parasites; the evolutionary “leaps” occurred in a short time, especially in correspondence with the Bronze Age and the events of social reorganization and increase in the human population connected to that era, which favored the spread of old and new infections on a previously unknown scale .

Even today, we know that some genetic variants influence the risk of developing severe Covid-19; and even today parasites, and first of all viruses, can spread like never before in a human population that has undergone a rapid increase in its size and connectivity.

This is why, looking at what happened in the past as well, we shouldn’t be surprised if we have to face a new, important phase of epidemics different from the previous ones, having however the hope that thanks to science and technology, a selective population event, such as the one documented in the Bronze Age, will not occur again from the study discussed here.