Graduate Research Prize Winners Spring 2014
I studied Medicine at Cambridge and Oxford, and then pursued a conventional route of junior doctor posts across South East England. Returning to Oxford as a nephrology specialist registrar I belatedly realised that to find out what was making my kidney patients ill I needed to get involved in basic science. I want to understand the genetics of renal and autoimmune disease. Oxford has the resources to explore this, with outstanding genomics and bioinformatics at the Wellcome Trust Centre for Human Genetics and a renal-friendly immunology group in the Centre for Cellular and Molecular Physiology next door under Professor Richard Cornall.
My DPhil was funded by a Wellcome Trust Clinical Student Fellowship and explores forward genetic methods to understand renal disease. This work placed me at the interface between bioinformatics and ‘wet lab’ molecular biology to identify and characterise genetic variation. In collaboration with Gerton Lunter and Andy Rimmer in the WTCHG we developed a method to use low coverage whole genome sequencing to isolate causative ENU mutations without the need for out-crossing to another strain. This had not previously been demonstrated and our efficient method reduces breeding, avoids unseen phenotypic modifiers and accelerates gene discovery. I went on to identify and describe a hypomorphic ENU mutation in Lamb2 which causes heavy protein leak from the kidneys (the nephrotic syndrome) and models the milder spectrum of human Pierson syndrome, a rare cause of kidney failure.
I have also been involved in a project performing whole genome sequencing of patients with steroid resistant nephrotic syndrome and a cohort with early onset systemic lupus erythematosis. The aim of this work is to identify rare variants of large effect that may inform our understanding of more complex disease. Validating and testing candidate variants from these patients will form part of ongoing research, which I hope to continue as a clinical lecturer in Oxford from 2014.
I have benefited throughout my DPhil from excellent mentoring and stimulating collaborations, as well as a supportive supervisor and group. These have enabled me to move from clinical trainee to budding clinician scientist.
Bull KR, Rimmer AJ, Siggs OM, Miosge LA, Roots CM, Enders A, et al. Unlocking the Bottleneck in Forward Genetics Using Whole-Genome Sequencing and Identity by Descent to Isolate Causative Mutations. PLoS Genet. Public Library of Science; 2013 Jan 31;9(1):e1003219.
Bull KR, Mason T, Rimmer AJ, Crockford TL, Silver KL, Bouriez-Jones T, et al. Next-generation sequencing to dissect hereditary nephrotic syndrome in mice identifies a hypomorphic mutation in Lamb2 and models Pierson's syndrome. J Pathol. John Wiley & Sons, Ltd; 2014;233(1):18–26.
Bergmann H, Yabas M, Short A, Miosge L, Barthel N, Teh CE, et al. B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A. J Exp Med. 2013 Jan 14;210(1):31–40.