Infectious diseases are considered one of the strongest factors driving human evolution. This is perhaps unsurprising: if a particular infectious disease can be fatal, those individuals who are better adapted to survive it are more likely to produce offspring and pass on these favourable genes, causing a shift in the gene pool. It has long been assumed that the considerable impact that Yersinia pestis – the bacterium responsible for the Black Death – had on the medieval populations of Europe and North Africa (causing the deaths of 30-50% of the population during the 14th century) must have also had an impact on our genetic makeup. Before now, though, the specific genes that might have been positively selected for were unknown. In this month’s ‘Science Notes’, we explore a new study – carried out by an international team of researchers and recently published in Nature (https://doi.org/10.1038/s41586-022-05349-x) – that has sought to change this and identify the particular genes that might have been selected for in the wake of the Black Death.
To identify these genes, the team had to find an appropriate sample of individuals who lived just prior to the start of the Black Death as well as those who lived immediately afterwards. This is easier said than done, though, as the samples had to be securely dated in order to make sure that it was the Black Death that was effecting any observed changes and not any other factor, such as tuberculosis or famine. The extensive human remains stored within collections at the Museum of London proved to be perfect for this purpose.
After sampling 318 skeletons from the London assemblages, 143 were deemed to have sufficient endogenous DNA to pass very strict inclusion criteria in the analyses. The team then searched for alleles that were most likely to have been selected for in response to Y. pestis by assessing which had the largest degree of differentiation between the pre- and post-Black Death samples. The team reasoned that the variants that were most likely to have conferred protection against Y. pestis should have increased among the population following the Black Death, while those associated with susceptibility should have decreased. Looking at the genes that fit this pattern, the team were able to identify 35 loci of interest. These results were then compared with data from pre- and post-Black Death human remains recovered from various sites across Denmark. Through this, they were able to identify four loci that showed similar patterns in both populations.
Most studies of positive selection identify signals, but rarely are able to test the actions of these alleles in vivo (that is, in living organisms). In this work, however, collaborators working at the Pasteur Institute were able to determine whether any of these loci were involved in response to a Y. pestis infection. By infecting macrophages (specialised white blood cells that engulf and destroy foreign materials) with a heat-killed version of the bacteria, they ascertained that, in particular, the rs2549794 variant was associated with the production of a full-length ERAP2 protein. This protein, in its full-length form, probably increased Yersinia-derived antigens and may have triggered an immune response to the bacteria. Because of this, individuals with two copies of this variant may have been about 40% more likely to have survived the Black Death than those with no copies. While this variant appears to be the strongest candidate for an allele that was positively selected for in response to the Black Death, additional data may be able to identify more.
Overall, this would seem to reflect evolution at its finest: the positive selection of an allele to make humans better at fighting off a disease likely to kill them. In some instances, though, an adaption that proves to be advantageous in one way can be disadvantageous in another. This is perhaps most clearly apparent in the case of sickle-cell disease. If a person inherits an abnormal copy of the ß-globin gene (HBB), they are more likely to be able to survive malaria – a powerful benefit in areas of equatorial Africa where the disease is widespread. If a person inherits two abnormal copies of the gene, however, they develop sickle-cell disease, which can be life-limiting.
This dichotomy appears to be the case for the rs2549794 allele. Although people with this variant would have been better able to survive a Y. pestis infection, it overlaps with alleles that are associated with an increased risk of developing an autoimmune disease, particularly Crohn’s disease. So, while this variant may have helped save our ancestors from being victims of the Black Death 700 years ago, its continued presence in the gene pool could now be contributing to the prevalence of other illnesses, which is why the allele did not sweep to a frequency of 100%. This is a great example of balancing selection in action. While two full-length proteins provided a strong immune response to infection in a landscape riddled with pathogens, the reduced bacterial burden of Western society today would select against a hyperactive immune response, thereby balancing out the auto-immune burden that comes from two copies of the rs2549794 allele and other alleles selected for by the Black Death.