Infectious Diseases and its Significance as a Selective Pressure

Infectious diseases have been a major driving force in the evolution of humans and other species, acting as one of the most significant selective pressures. Evidence has shown numerous instances of positive selection for immune response genes in specific populations, which supports the idea that adaptation has been triggered by exposure to new or reoccurring pathogens. However, it can be difficult to determine the precise connection between signatures of natural selection and their underlying pathogens unless the genetic loci involved are still linked to susceptibility to the same pathogen in contemporary populations. For example, evidence has linked the evolution of immune response genes with the Black Death, the devastating pandemic that swept Europe during the 14th century. The Black Death, caused by the bacterium Yersinia pestis, claimed the lives of about 30-50% of Europe, the Middle East, and Nothern Africa's population. In this study, Jennifer Klunk et al. aim to determine the impact of the Black Death on the evolution of immune genes and provide insights into the relationship between pandemics, host immunity, and human evolution. 

The researchers started the experiment by characterizing genetic variation from ancient DNA extracts derived from individuals who died between, before, or after the time frame of the Black Death in London and areas in Denmark. They did this by performing a series of analytical tests, including PCR assay, on the remains to identify any presence of human DNA. In addition, they used hybridization capture to target immune-related genes selectively and genome-wide association study (GWAS) loci previously linked to immune disorders. The hybridization step was essential because it differentiated signatures due to Y. pestis from those associated with other infectious/immune diseases and overcame the challenge of low endogenous DNA content in their poorly preserved samples. As a result, they identified four loci that were strongly differentiated before and after the Black Death pandemic in London, and they saw the same results in the Danish cohort. 

Of the four loci, the loci ERAP2 demonstrated the strongest evidence of selection from a genetic and functional viewpoint, with a calculated selection coefficient of 0.4. This estimation implies that individuals with two copies of the protective allele, also known as homozygous, were 40% more likely to survive the Black Death than those with two copies of the harmful variant. The protective allele is associated with increased ERAP2 expression and the production of the recognized full-length ERAP2 protein. Furthermore, this protein is suggested to enhance the display of Yersinia-derived antigens to CD8+ T cells, promoting a defensive immune response against Y. pestis. Additionally, they demonstrated that macrophages from individuals carrying the selected ERAP2 allele exhibit a distinctive cytokine response upon Y. pestis infection and are more effective at controlling Y. pestis replication in vitro.

Another observation they discovered was individuals carrying more copies of the selectively favorable haplotype demonstrated a reduced cytokine response to infection but rather a superior ability to control bacterial growth. For example, IL-1β levels, a significant pro-inflammatory cytokine frequently correlated with pyroptotic cell death, were three times lower in individuals homozygous for the beneficial ERAP2 genotype compared to those homozygous for the potentially harmful variant. Hence, it provides more evidence that individuals with the favored haplotype are more capable of controlling internalized bacteria and resisting Y. pestis-induced cell death than those with the harmful haplotype, which could help minimize background tissue damage during infection.

The study provided evidence that supports the hypothesis that ERAP2 is highly responsive to stimulation by various pathogens and highlights its crucial role in regulating immune responses. The data presented in this paper also suggest that selection caused by Y. pestis on ERAP2 may impact the immune response to other pathogenic traits or diseases. In support of this hypothesis, evidence has shown that the selectively favorable ERAP2 variant has been linked to Crohn's disease and other infectious diseases. This observation suggests that the selection of defense mechanisms against pathogens such as Y. pestis may have been balanced against the risk of immune disorders. Additionally, another top candidate loci, rs11571319 near CTLA4, is associated with an increased risk of rheumatoid arthritis and systemic lupus erythematosus. This suggests individuals having the presumably favorable allele during the Black Death had an increased risk for autoimmune diseases in the present day. 

In conclusion, understanding the processes that have shaped the human immune system is crucial for comprehending historical diseases' impact on disease susceptibility in the present day. Unfortunately, most evidence connecting risk alleles for autoimmune diseases with adaptation to previous infectious diseases is not direct, largely due to the unknown selection causes. However, with more ancient genomic and functional analysis, there can be a more prominent link to the impact of past pandemics on current susceptibility to disease.