Joe Marsh Research Group

Research in a Nutshell 

Most known Mendelian genetic disorders are caused by changes in protein-coding regions of DNA, yet clinically relevant variants account for only a tiny fraction of those seen in humans. We are interested in understanding the molecular mechanisms by which protein variants can cause disease. While past work has often focused on how sequence changes can cause a loss of protein function, we are especially interested in protein mutations that cause disease via gain-of-function or dominant-negative effects. We believe that through better understanding of the molecular mechanisms, we can improve our ability to predict which variants of uncertain significance are most likely to be pathogenic. Moreover, understanding molecular mechanisms can open the door to future treatment possibilities.

To address this, we use three complementary strategies. Structural bioinformatics can provide great insight into the molecular mechanisms underlying disease mutations, but has historically been less useful for identifying deleterious mutations.  In contrast, computational variant effect predictors are very good at identifying pathogenic mutations in certain genes, but tell us nothing about why they are damaging. Finally, deep mutational scanning (DMS) experiments, performed in collaboration with the Kudla lab, enable direct high-throughput measurement of variant effects, and are proving tremendously valuable for identifying disease mutations and explaining molecular mechanisms.

We also have a strong interest in protein complexes. The emergence of new experimental and computational techniques, along with the increasing availability of diverse structural, proteomic and genomic datasets, have created huge potential for investigating protein complex structure and assembly on a large scale. Consideration of protein quaternary structure is often tremendously useful for understanding the molecular mechanisms underlying disease mutations. We are also interested in the biology of protein complex assembly, seeking to understand how assembly occurs within cells, how it is regulated, how it contributes to normal biological function, and how it has evolved.

1. Badonyi M & Marsh JA (2022) Large protein complex interfaces have evolved to promote cotranslational assembly. eLife 10.7554/eLife.79602
2. Gerasimavicius L, Livesey BJ & Marsh JA (2022) Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure. Nature Communications 13:3895
3. Backwell L & Marsh JA (2022) Diverse molecular mechanisms underlying pathogenic protein mutations: beyond the loss-of-function paradigm. Annual Review of Genomics & Human Genetics 10.1146/annurev-genom-111221-103208
4. Livesey BJ & Marsh JA (2020) Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations. Molecular Systems Biology 16:e9380
5. Williamson KA, Hall HN, Owen LJ, Livesey BJ, ...(24 more)..., van Heyningen V, Marsh JA* & FitzPatrick DR* (2020) Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction. Genetics in Medicine 22:598-609

Full publication list can be found on Research Explorer: Joseph Marsh — University of Edinburgh Research Explorer

• Medical Research Council
• European Research Council
• Lister Institute of Preventative Medicine