Exploring natural selection due to the Black Death and continuous human population genetic structure

The study of ancient human DNA has been revolutionary in identifying large-scale admixtures and genetic variants subject to natural selection. Yet, key knowledge gaps persist. First, ongoing genetic mixing within spatially continuous populations is poorly understood. Second, the underlying selective pressures, particularly of infectious diseases, remain debated. To bridge both gaps, I propose sequencing 500 victims of the Black Death, one of the deadliest pandemics in human history, from a site in Central Europe and using this data synergistically with novel computational tools to make two breakthroughs. My first objective is to pioneer linking a large number of ancient and modern genomes through shared long haplotypes (known as IBD segments). IBD-sharing with modern genomes across Europe will reveal, for the first time, how genetic ancestry spread across space, starting from a large sample of a singular position and time. New inference tools using IBD-sharing will offer unprecedented insights into the European population structure of recent centuries, including mobility and effective population densities, and address a critical lack of population genetic models for spatially continuous populations. The second objective is to pinpoint genetic variants relevant to Black Death mortality. Observing the removal of alleles, for the first time in molecularly confirmed plague mass graves, will directly link an infectious disease and the resulting natural selection. The findings will decisively resolve long-standing debates regarding the human selective impact of the Black Death. Both IBD-sharing with modern Europeans and selection screens will greatly benefit from the large sample size of Medieval genomes. The synergy between the new analysis and tools I propose will break new ground for two key topics in population genetics relevant beyond humans, inferring the structure of continuous populations and the impact of natural selection.