Understanding the evolution of structural variation of the Rhesus blood group genes

About the Project

The Rhesus (Rh) blood group system, one of the most medically important human genetic systems, has long puzzled scientists due to the high global frequency of the Rh-negative phenotype. This phenotype arises from a homozygous deletion of the RHD gene, which should be strongly selected against because D-negative mothers risk haemolytic disease of the newborn when carrying D-positive fetuses—a major cause of infant mortality before modern prophylaxis. Yet, the RHD deletion persists at intermediate frequencies, especially in Europe. Classic evolutionary models, beginning with J.B.S. Haldane, proposed that frequency-dependent selection could maintain this balance (1,2). However, how the RHD deletion allele initially rose to such levels remains unresolved.

Recent technological and data advances now allow this question to be revisited. Large-scale biobank data, ancient DNA, and powerful coalescent-based modelling of structural variants can be combined to reconstruct the evolutionary history of the RHD locus. Our group’s recent work using the UK Biobank shows that the RhD- allele correlates with smaller red blood cell volume (p=2.8×10⁻²⁵) and higher haemoglobin concentration (p=4.3×10⁻⁵), but with no other phenotypic effects. These red blood cell traits are consistent with known protective effects against malaria (3–5), suggesting that the RhD- allele may have conferred resistance to malaria—perhaps particularly non-falciparum species—in now malaria-free regions such as Europe.

This PhD project will investigate that hypothesis by integrating global datasets of modern and ancient genomes to trace RHD allele frequencies across time and geography. The student will apply advanced population genetic analyses, including coalescent simulations that explicitly model copy number variation, to test for historical signals of selection. By combining evolutionary modelling with biomedical insight, this project aims to reveal how infection, immunity, and human migration have jointly shaped one of our most clinically significant genetic systems. The findings will deepen understanding of human adaptation and may illuminate new aspects of malaria susceptibility and red blood cell physiology, with potential biomedical relevance for transfusion medicine and maternal–fetal health.

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 RHD gene and its potential role in malaria resistance, alongside open-access datasets of RHD 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.