Investigating the roles of R-loops and mutations in the pathogenesis of neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) – including intellectual disability, epilepsy, autism spectrum disorder and schizophrenia – affect >5% of the global population. However, the cause of most NDDs remains unknown, making it difficult to diagnose, mitigate or treat. Emerging evidence suggests that somatic mutations which occur during embryonic development represent one of the missing pieces in this puzzle, but how and where these mutations occur remain unclear. Dysfunction in UPF1 and UPF3B are associated with an inherited risk for developing NDDs.

Recently, I have discovered that these two genes suppress mutations at DNA double-strand breaks (DSBs) by stimulating the formation of R-loops, enigmatic three-stranded structures containing DNA-RNA hybrids. This finding suggests that reduced R-loop-dependent DSB repair (DSBR) may exacerbate the accumulation of somatic mutations in developing embryos, disrupting genes required for neurodevelopment, and presents us with an innovative way to identify these mutations.

I aim to investigate the mechanism of R-loop-dependent DSBR, and its role in suppressing mutations and neuronal dysfunction, by exploiting recent advances in single-molecule long-read sequencing, DSB mapping and stem cell technologies. This proposal will examine a novel mechanism for increased mental health risk to uncover new somatic mutations, risk factors or aetiology, contributing to improvement in diagnosis or mitigation of NDDs.