Quantifying Adaptive Evolution of the Human Immune Cell Landscape

The human immune system is under constant evolutionary pressure, primarily through its role as first line of defence against pathogens. Accordingly, population genomics studies have shown that immune-related genes have a high rate of adaptive evolution. These studies, however, are mainly based on protein-coding genes without cellular context, leaving the adaptive role of cell types and states uncharted. Inferring the rate of protein-coding genes adaptation in developing and adult immune cells at cellular resolution, we found cell types from both the lymphoid and myeloid compartments to harbour significantly increased adaptation rates. Specific cell states, such as foetal Pre-Pro B cells and adult T resident memory CD8+ cells show highly elevated rates of adaptation. We further analysed activated cell states, specifically, iPSC-derived macrophages responding to various challenges, including pro- and anti-inflammatory cytokines or bacterial and viral infections, the latter simulating the evolutionary arms race between humans and pathogens. Here, we found positive selection to be concentrated in early immune responses, suggesting benefits for the host to adapt to early stages of infection to control pathogen numbers and spread. Together, our study reveals spatio-temporal and functional biases in human immune populations with evidence of rapid adaptive evolution and provides a retrospect of forces that shaped the complexity, architecture, and function of the human body. ### Competing Interest Statement HH is co-founder and shareholder of Omniscope, member of the Scientific Advisory Board of Nanostring and MiRXES and consultant to Moderna and Singularity. JCN is a consultant to Omniscope.