Stoichiometric imbalance and haploinsufficiency in human protein complexes

Why are some human genes dosage-sensitive while others tolerate loss of one copy? Haploinsufficiency is a major mechanism underlying dominant genetic disorders, but its molecular basis remains poorly understood. This project will investigate whether stoichiometric imbalance in protein complexes helps explain gene dosage sensitivity — a long-standing but under-explored hypothesis.

Our hypothesis is that subunits produced in limiting amounts are more likely to be critical for complex assembly, and therefore more likely to cause phenotypic consequences when expression is halved. In contrast, subunits produced in excess may be buffered through degradation. We hypothesise that this balance underlies many cases of haploinsufficiency, particularly in genes encoding members of multiprotein complexes.

The student will combine computational and experimental approaches to investigate this question. In Edinburgh, they will integrate protein complex data with proteomics, structural models, and gene constraint metrics to systematically identify limiting subunits and explore their relationship to gene dosage sensitivity. They will also analyse tissue-specific expression datasets to investigate whether stoichiometric imbalances — and hence haploinsufficiency — vary across human tissues, helping to explain tissue-specific disease phenotypes.

During a ~3-month visit to the Selbach lab at the MDC Berlin, the student will receive training in pulse-chase proteomics and contribute to pilot experiments using AHA/SILAC labelling in human cell lines. These will support validation of predicted stoichiometric imbalances and provide a foundation for further collaborative work.

This project offers a unique opportunity to address a fundamental problem in human genetics by integrating data-driven and experimental approaches. The student will receive cross-disciplinary training in structural bioinformatics, quantitative proteomics, and variant interpretation in a highly collaborative environment. 

For informal enquiries about this project, please contact Joe Marsh (Joseph.Marsh@ed.ac.uk).