Evolutionary basis of human diseases in western Eurasia: Insights from ancient genomics (360G-Wellcome-214300_Z_18_Z)

Although large differences in disease susceptibility among present-day human populations have been widely reported, their evolutionary underpinnings remain poorly understood. This project aims to examine how, and to what extent, pathogens shaped disease susceptibility among present-day western Eurasians. We will use whole-genome sequence data from ancient humans and their pathogens to identify novel human genetic variants targeted by past selection, and catalogue novel pathogen variability, including that of now-extinct lineages. Next we will reconstruct the evolutionary history of these newly identified variants and lineages, along with those already known to be associated with disease susceptibility in present-day populations. Finally, we will uncover new associations between human genetic variants and infectious diseases. The focus will be on the last 10,000 years of human history, which encompass some of the greatest changes in our lifestyle, including the agricultural revolution, first known epidemics, and early urbanisation. The proposed study will provide fundamental insights into the evolutionary basis of disease susceptibility in present-day human populations, as well as the evolution of human pathogens. These findings will inform future experimental and clinical research, impact upon current and future healthcare strategies, including the design of diagnostic tests and drug development, and improve global pathogen outbreak monitoring.