Leveraging large-scale genetic and epigenetic data to infer genomic responses to environmental pressures in humans (360G-Wellcome-224575_Z_21_Z)

This project has two main components, each exploring how the genome mediates our phenotypic responses to environmental pressures. The first component will develop new statistical methodology to pinpoint genetic sequence variants that have facilitated humans' ability to adapt over long-term time-scales to their environments, and hence are vital for influencing health. Specifically, this work will leverage large-scale cohorts (e.g. UK Biobank) containing people of mixed ancestry, whom typically are ignored in such analyses, to provide a substantial increase in the power to infer and characterise adaptation signatures. For the second project component, we will leverage available epigenetic data from hundreds of studies to identify loci that show high methylation variability across multiple tissues, ethnicities and ages, and for which methylation marks likely are established in the early embryo and stable throughout the life course. Cross-referencing such loci with published epigenome-wide association studies (EWAS) can indicate causal pathways whereby specific exposures modify methylation, which in turn influences health outcomes (e.g. disease susceptibility) throughout the life course. By combining both project components, we will test the hypothesis that these regions of variable methylation are conserved in human populations as a means to enable efficient adaptation to rapidly changing environments.