Characterizing variation and adaptation in the immune response to plague (Y. pestis) through single-cell sequencing and ancient genomics

PROJECT SUMMARY Pathogens have been one of the strongest selective pressures in human evolution. Migrating out of Africa, modern humans encountered novel pathogens along with new environments. These populations likely adapted to these pathogens, leading to population-specific adaptations. Consistent with this hypothesis, some of the most

compelling signatures of local adaptation in the human genome overlap genes involved in immunity and host defense. Importantly, these regions also overlap genetic loci which are associated with infectious, autoimmune, and inflammatory disease risk in modern humans. Thus, understanding adaptation to pathogens throughout

history is important for understanding modern human health. The Black Plague was likely one of the strongest selective events in recent human history. Exposure to Yersinia pestis (the causative agent of plague) therefore likely drove adaptations in the human immune system which continue to shape modern immune variation. Importantly, because the plague ravaged Eurasia while

leaving sub-Saharan Africa relatively untouched, adaptation to plague likely occurred in European but not African populations. However, it is not known whether human populations differ in their immune response to plague as a consequence of prior evolutionary history. Addressing this gap is not only important for understanding the

recent evolution of the human immune system, but may also help reveal the molecular basis of ancestry-related differences in susceptibility to infectious disease, chronic inflammation, and autoimmune disorders. The basic research questions driving this proposal are: What was the impact of Y. pestis to the functional

differentiation of immune responses between African- and European-ancestry individuals? To which extent natural selection has favored the increase in frequency of protective alleles in Europeans, a population with increased exposure to Y. pestis? What cell types and immunological pathways show the most divergence in

response to Y. pestis between populations? To answer this questions, I will experimentally infected peripheral blood cells in culture to characterize the immune response to plague. Using single-cell RNA sequencing I will be able to analyze variation in the immune response across cell types, but also characterize differences in the

proportion of cells responding to infection and the strength of that response. Using this data, I will identify genes and pathways which are regulated differently in individuals of European and African ancestry, and identify genetic variants which contribute to these differences. I will then use a combination of ancient and

modern genomics to test whether loci underlying variation in the immune response to Y. pestis also experienced position selection during the Black Plague. Thus, this project is a novel integration of functional and population genetic approaches to study adaptation to a deadly human pathogen. At its conclusion, this study will reveal how

Europeans adapted to Y. pestis exposure during the plague, and identify highly-promising genetic candidates which may contribute to disease susceptibility in modern human populations.