The high mutation load within and phenotypic differences between modern human populations remain poorly understood. Understanding these phenomena would lead to a better understanding of the origins of complex phenotypes, including genetically-influenced diseases, and their geographic distributions.

The aim of this thesis is to uncover the genetic origins of complex human phenotypes, from the Last Glacial Maximum until the Bronze Age in western Eurasia. Specifically, it aims to assess the contributions of differentiated genetic ancestries which existed in this period, and link this to modern-day differences in disease susceptibility.

To achieve this, methods were developed to infer local ancestry in a large modern panel, the UK Biobank, using new ancient reference genomes. Modern samples were selected based on a ‘typical ancestral profile’ for each country represented in the UK Biobank. This dataset was then used to infer the genome-wide ancestry components of modern populations, and the contribution of each ancestry to a polygenic phenotype using a new statistic analogous to a polygenic risk score based on local ancestry probabilities. An in-depth investigation into the origins of Multiple Sclerosis (MS) was performed.

This project was the first to use ancient DNA to infer local ancestry in a very large modern panel to assess ancestral contributions to polygenic phenotypes. Simulations showed that the accuracy of ancestry assignment was good. Differences in average ancestry components were calculated per-country within Eurasia and north Africa, and per-county within Britain, reflecting past episodes of migration and admixture. Aggregate ancestral contributions to phenotypes known to be over-dispersed in ancient populations were then calculated, including height, BMI and some psychiatric traits. Finally, the origins of the genetic risk for MS were traced to the Bronze Age Steppe populations; positive selection drove these variants to higher frequency, likely in response to novel pathogen exposure resulting from lifestyles changes and leading to a heterogeneous risk profile across Europe today.

These results demonstrate the power of combining large ancient and modern DNA panels, using local ancestry assignment methods, to investigate the histories of genetic variants and associate them with selection due to differing ancient lifestyles, or drift. This can explain geographic differences in genetic risk, and highlights the importance of the Bronze Age as a determinant of modern immune response. This may have clinical implications for the treatment of auto-immune diseases, for example concerning childhood pathogen exposure.