Project SummaryThe current SARS-COV2 pandemic has brought to light that more efforts are needed to evaluate the pandemicpotential of viruses that can spill over in human populations. To assess the pandemic potential of specificviruses over the next five years my lab will ask if similar viruses caused epidemics not only during the recentdocumented past but during the much longer time scale of human evolution. Viruses that caused epidemics inthe past are indeed the most likely to cause epidemics again in the future and hundreds of viral epidemicslikely plagued human populations during their evolution. This work will fill gaps in knowledge on epidemics inancestral human populations and by doing so will enable a better assessment of the viruses that represent afuture pandemic threat. To study ancient epidemics my lab will exploit host genomic adaptation driven by ancient viruses.Arms races with viruses have shaped the host immune system by driving a large number of adaptations. Irecently showed that viruses left abundant signals of adaptation not only in immune genes but across theentire human genome. The lab will examine signals of adaptation left by specific viruses in human genomes todetect date and functionally characterize ancient epidemics. To this aim we will develop new statistical toolsbased on recent advances in machine learning and in the reconstruction of Ancestral Recombination Graphs(ARGs). These new approaches with increased power to detect and date genomic adaptation will allow us to askthe following questions:1) Which viruses drove ancient epidemics in human evolution?My lab will create deep learning tests with high power to detect complex genomic adaptation within the past~200000 years of human evolution.2) When did specific viruses drive ancient epidemics?We will use ARGs and Approximate Bayesian Computation to date ancient epidemics by dating the hostadaptive events driven by specific viruses.3) Which functional host genetic changes were selected during ancient epidemics in whichgenes and how do they influence genetic susceptibility to present viruses?We will investigate regulatory adaptation to viruses and the overall impact of virus-driven host adaptation onthe genetic susceptibility of different human populations to specific present viruses thereby providingvirologists with strong candidate host genes for further inquiry. My lab is uniquely suited to decipher ancient epidemics by linking host-pathogen interactions togetherwith the latest developments in the population genomics of adaptation.