Characterizing the genetic and evolutionary determinants of population variation in transcriptional responses to pathogens

Project Summary Pathogens are one of the strongest selective pressures on the human genome. As modern humans migrated out of Africa, they encountered markedly different pathogenic environments, likely resulting in population-specific selection of immune phenotypes. Consistent with this hypothesis, some of the most compelling evidence for local positive selection in the human genome has been detected among genes involved in immunity and host defense. Yet, our understanding of the role that local adaptation plays in shaping phenotypic variation in immune responses across populations is still in its infancy. To better understand the complex relationship between pathogens and host adaptation we propose to explore the effects of natural selection and genetic ancestry on gene expression, epigenetic traits, and immune responses to infection across a large array of human populations. Our research program is grounded on three outstanding questions in the fields of genomics, population variation in host response to pathogens, and evolutionary biology: (i) the degree to which immune responses to pathogens are differentiated across ancestry groups; (ii) the genetic variants that account for such differences; and (iii) the evolutionary mechanisms (neutral genetic drift vs positive selection) that led to the establishment of these variants in modern human populations. Addressing these questions is not only important for understanding the recent evolution of the human immune system but may also help reveal the molecular basis to interindividual differences in susceptibility to infectious diseases, chronic inflammatory disorders, and autoimmune disorders.