Understanding the evolution of structural variation of the drug metabolising gene CYP2D6

About the project

About the Project The way our bodies process medicines is not uniform across individuals, and a significant part of that variation is written into our DNA. The gene CYP2D6 encodes a cytochrome P450 enzyme responsible for metabolising approximately 25% of all clinically prescribed drugs, including opioid pain relief, antidepressants, and antipsychotics. Individuals who carry extra copies of CYP2D6 metabolise these compounds unusually rapidly, sometimes rendering standard doses ineffective or, in the case of opioids such as codeine, converting the prodrug to its active form so quickly that dangerously high concentrations accumulate in the bloodstream. Conversely, those with fewer functional copies metabolise drugs slowly, risking toxicity at normal doses. CYP2D6 therefore sits at the intersection of pharmacogenomics and personalised medicine, which are two fields with enormous public health implications. What makes this gene even more remarkable is that copy number of the gene varies extensively between humans in ways that suggest it has been shaped not just by genetic drift but by natural selection across human evolutionary history. Understanding why carries both medical and evolutionary significance. Our preliminary work has identified a striking pattern: individuals of East Asian ancestry show unusually high CYP2D6 copy numbers compared to other global populations. The statistical signature of this elevation is consistent with recent positive selection, meaning that at some point in the evolutionary past of East Asian populations, carrying more copies of CYP2D6 conferred a survival or reproductive advantage. A large-scale phenome-wide association study (PheWAS) of multiallelic copy number variants in the UK Biobank has further demonstrated that increased CYP2D6 copy number is associated with adverse reactions to opiates, confirming that the copy number difference has real pharmacological consequences today. But why would extra copies of a drug-metabolising enzyme be advantageous before the era of pharmaceutical drugs? The leading hypothesis is that elevated CYP2D6 activity was selected to detoxify naturally occurring plant alkaloids and other dietary toxins encountered by human populations adopting particular subsistence strategies — a compelling example of gene-culture coevolution. The identity of these dietary drivers, and the precise timing and geography of selection, remain open questions. This PhD project will resolve that evolutionary history by applying population genetic analysis to existing large datasets of ancient human genomes spanning the last 50,000 years, alongside whole-genome sequences from archaic hominins including Neanderthals and Denisovans where CYP2D6 data are recoverable. By tracking allele frequency trajectories through time, the project will reconstruct when copy number expansions arose, and in which populations, and whether the selected haplotypes carry signatures of gene-culture co-evolution with dietary change. The findings will directly inform clinical pharmacogenomics by placing modern population differences in copy number in their evolutionary context, and will contribute to the broader understanding of how structural variation at metabolic loci responds to selective pressure across human prehistory. Training Opportunities This PhD provides interdisciplinary training in evolutionary and population genomics, combining bioinformatics, coalescent modelling, and the analysis of ancient and modern DNA. The student will gain hands-on experience with large biobank datasets, structural variation analysis, and computational simulations of selection. Supervision spans expertise from human genomic variation (Dr Hollox), population genetics modelling (Dr Freund), and ancient genomics (Dr Tucci, Yale). The student will also develop transferable skills in data science, public engagement, and scientific communication, supported by the College of Life Sciences’ outreach and training programmes. Outputs Expected outputs include high-impact publications on the global evolutionary history of the CYP2D6 gene, alongside open-access datasets of CYP2D6 copy number variation across modern and ancient populations. Results will be presented at international conferences in human genetics and evolutionary biology. The project will also generate public-facing articles, such as contributions to The Conversation , to engage audiences with the evolutionary and medical significance of the Rhesus blood group system. Collectively, the outputs will advance both academic understanding and public awareness of how our genes record the history of disease and adaptation. Apply at: https://le.ac.uk/study/research-degrees/research-subjects/genetics PhD entry requirements: https://le.ac.uk/study/research-degrees/entry-reqs Supervisor contact details: Prof Ed Hollox - ejh33@le.ac.uk Dr Fabian Freund - Ff95@le.ac.uk

Research areas